Cortico-striatal tracking of mood fluctuations at rest and
its disturbance in depression
Admon R. & Diego A. Pizzagalli
McLean Hospital & Harvard Medical School
Mood is an emotional state that tends to fluctuate over time in
an implicit manner. Nevertheless, majority of neuroimaging
studies investigating mood have focused on the acute
emotional response to a stimuli, overlooking temporal
fluctuations in affect that may follow stimuli offset. Such
shortcoming may especially limit our understanding of Major
Depressive Disorder (MDD), which is, by definition, a mood
disorder. Indeed, whether decreased positive mood in
depression is due to failure in the acute response to positive
stimuli, or in the ability to sustain positivity following stimuli
offset is not entirely clear. In order to address this issue 25
MDD individuals and 25 matched healthy controls underwent
functional MRI (fMRI) scan while engaged in a novel
procedure to implicitly induce positive mood. Neural basis of
mood fluctuations that occur in the absence of external stimuli
were captured via three resting state scans, acquired prior to
mood induction, immediately following it, and half an hour
later. Interestingly, while both groups experienced equivalent
elevation in positive mood immediately following the
manipulation, only controls were able to sustain positive affect
over time. fMRI data reveled that sustainment of positive mood
in controls was associated with a change towards a more
reciprocal cortico-striatal connectivity pattern following
compared to prior to mood induction. In MDD, despite acute
response to the manipulation, cortico-striatal connectivity did
not change which may have contributed to their inability to
sustain positive mood.
Targeting the endocannabinoid system: A novel approach
to the treatment of stress-related disorders
Akirav I.1,
1
Department of Psychology, University of Haifa;
We have recently provided preclinical evidence that targeting
the endocannabinoid system facilitates extinction, prevents
stress-related symptoms, and could prevent stress-induced
alterations in behavior and physiology in rat models of PTSD.
Here we examined whether chronic cannabinoid treatment can
compensate for early adverse events that may predispose
individuals to develop PTSD in adulthood. Our results show
that early neglect significantly enhanced anxiety and impaired
performance in adulthood in social, novel object and spatial
recognition tasks. Chronic administration of cannabinoids
during the late-adolescent period, but not during adolescence,
resulted in intact performance and normalized anxiety levels
during adulthood. These preventing effects of cannabinoids
were found to be mediated by alterations in the expression of
cannabinoid CB1 receptors and glucocorticoid receptors (GRs)
in the brain's fear circuit. These findings suggest that there may
be an optimal developmental period for treatment with
cannabinoids during the late-adolescent period that can reverse
the detrimental effects of early neglect stress on emotional
behavior and working memory in male and female rats.
Allostatic regulation of inhibition in the ventral
hippocampus after combined Juvenile/Adult stress
Albrecht A.1,2, Maggio N.3, Çalışkan G.4, Richter-Levin G.1,2,5,
Segal M.6, Stork O.4,7,
1
Sagol Department of Neurobiology, University of Haifa,
Haifa, Israel; 2The Institute for the Study of Affective
Neuroscience (ISAN), Haifa, Israel; 3Department of Neurology,
The Chaim Sheba Medical Center, Tel HaShomer, Israel;
4
Institute of Biology, Otto-von-Guericke-University
Magdeburg, Magdeburg, Germany; 5Psychology Department,
University of Haifa, Haifa, Israel; 6Department of
Neurobiology, The Weizmann Institute, Rehovot, Israel;
7
Center for Behavioral Brain Sciences, Magdeburg, Germany;
Childhood adversity is an important risk factor for developing
anxiety disorders and depression later in life. In rodents, it is
modeled by stress exposure in their postweaning/ prepubertal
life phase. Such juvenile stress (JS) alters the adaptation to
subsequent stress exposure in adulthood (AS), resulting in
lastingly increased anxiety, altered emotional memory
formation and reduced coping in aversively motivated learning
paradigms. On the network level, combined JS/AS leads to a
long-lasting enhancement of long-term potentiation in the
ventral compared to the dorsal hippocampus. In the current
study, we investigated lasting alterations in expression of
molecular factors determining GABAergic and glutamatergic
neurotransmission in sublayers of the ventral and dorsal CA1
after combined JS/AS, using laser microdissection and
quantitative real-time PCR. Combined JS/AS resulted in
reduced mRNA expression levels of the GABA A receptor
alpha 1 subunit in the Stratum radiatum of the ventral CA1,
accompanied by a differential expression regulation of GAD65
after exposure to single JS or AS in the same layer. Led by
such differential and lasting (14 d after AS) expression
regulation of GABAergic factors, we also assessed the impact
of JS/AS on excitatory-inhibitory balance using paired pulse
facilitation protocols in acute hippocampal slices. Here, JS/AS
increased paired pulse facilitation in the ventral, but not in the
dorsal CA1. Together, the specific molecular and physiological
alterations in the ventral CA1 after combined JS/AS suggest a
reduced inhibitory tone in the ventral but not dorsal CA1 that
may relate to facilitated network activity of the ventral
hippocampus, a region highly relevant for anxiety, emotional
memory formation and modulation of the stress response. This
CRF involvement in the consolidation of a traumatic event
in the fear circuit of rats
Aisenberg N.1, Louise - Sabban E.2, Olsson E.2, Akirav I.1,
1
Department of Psychology, University of Haifa, Haifa Israel;
2
Department of Biochemistry and Molecular Biology, New
York Medical College, ;
Background: Exposure to excessive or uncontrolled stress is a
major factor associated with various diseases including posttraumatic stress disorder (PTSD). Among other, stressful
events may results in increase of the HPA-axis activity which
is under the control of the corticotropin-releasing factor (CRF).
The CRF’s ligand and receptors family are important for the
central stress system regulation and for behavioral response for
stressful events. Here we examined the involvement of CRF
receptors in the fear circuit in the consolidation of a traumatic
event. Rats were exposed to an intense shock followed by
exposure to five contextual 1 min reminders of the shock over
a 25-day period. Acoustic startle response (ASR) was tested
before the shock (day 0) and after the last reminder (day 26).
Vehicle or the CRF1 antagonist CP-154526 were microinjected
into the CA1 five minutes after the shock. We measured fear
retrieval, extinction and anxiety levels. In another group, rats
were decapitated 60 min after the shock and fear-related brain
areas were examined for mRNA CRF expression using RT
PCR. Results: Rats microinjected with the CRF1 antagonist
demonstrated reduced freezing levels when exposed to a
situational reminder of the trauma and reduced ASR levels
measured one month after the trauma. However, CRF rats did
not demonstrate reduced fear retrieval and their fear extinction
kinetics was delayed. When looking at the expression of CRH
mRNA levels after the shock, there was a significant elevation
of CRH mRNA in the basolateral amygdala, but not in the
central area. Conclusions: This study provides evidence that
blocking of CRF-R1 in the CA1 at the time of footshocks
attenuates anxiety but does not affect fear learning. An increase
in CRF activity in the BLA may contribute to fear.
1
work was supported by the German Israeli Project Cooperation
(DIP; RI 1922/1-1 HE 1128/16-1).
response to TMS stimulation. Single pulses produced an
elevated early (15-30 ms) local response over the stimulation
area which was significantly lower in the ADHD compared to
the healthy participants group. In addition, activity components
in both paradigms were correlated with ADHD symptoms as
reported by participants. Both response to TMS stimulation and
P300 amplitude in the Stop Signal task uniquely predicted
Conners’ Adult ADHD Rating Scale (CAARS) t scores and
together explained 40% of its variance. Taken together, the
results are in accordance with prior studies and suggest hypo activity of the right pre-frontal hemisphere in ADHD. Both
measurements - TMS-EEG response and Stop Signal ERP may
serve as bio markers to quantify effectiveness in future clinical
trials for treatment of ADHD.
Seeking Rare Inherited Variants Associated with
Schizophrenia
Alkela A.1, Olender T.2, Mernick B.1, Lancet D.2, Lerer B.1,
1
Biological Psychiatry Laboratory, Dept. of Psychiatry,
Hadassah - Hebrew University Medical Center; 2Dept. of
Molecular Genetics, Weizmann Institute of Science, Rehovot,
Israel;
Despite an intensive search for schizophrenia genes for more
than three decades, no single gene mutations of large effect
have been identified. High heritability of schizophrenia
suggests that most cases are the result of inherited genetic
variation. There is a strong basis for considering the possible
contribution of extremely rare inherited variants with a major
pathogenic effect. We have accumulated a unique cohort of
large families multiply affected with schizophrenia. Wholeexome sequencing was applied to some of these families in the
Weizmann Institute of Science and additional families were
subjected to whole-genome sequencing in the laboratory of
Prof. David Goldstein from Columbia University. Here we
report the analysis of one of these families of Jewish Yemenite
origin with 5 affected with schizophrenia members and
dominant mode of inheritance. Whole-exome sequencing was
applied to 2 individuals from this family (the proband and his
uncle), and candidate rare (allele frequency<0.01) mutations
were identified using a novel phenotype-based variation
prioritizer, VarElect, based on GeneCards database. The
variant with the best prioritization score, is located in the exon
of the VAMP2 (vesicle-associated membrane protein 2
(synaptobrevin 2)) gene, that is thought to participate in
neurotransmitter release. The variant has a zero frequency in all
control samples and is predicted to be damaging by three
prediction sources. Additional interesting candidate variants
were found in genes which are harboring previously reported in
schizophrenia patients de-novo variants like NID1, SPAST,
PTPRF and WRN. These preliminary results support
hypotheses regarding a possible role for rare variants in
schizophrenia and strengthen the importance of sequencing
efforts in large affected family samples.
The search for safer alternatives to lithium: The antiimpulsive effects of ebselen in a rat behavioral model
Amit B.1,2,3, Barkus C.3, Sharp T.3,
1
Research Unit, Geha Mental Health Center, Petah Tiqva,
Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel
Aviv, Israel; 3Pharmacology Department, Oxford University,
Oxford, UK;
BACKGROUND: While lithium is an efficacious treatment for
a variety of psychiatric indications, including bipolar disorder
and disorders associated with increased impulsivity, it carries a
substantial burden of side effects. In the search for safer
alternatives, ample research has been conducted to elucidate
the mechanism of action of lithium, demonstrating inhibition of
inositol monophosphatase (IMPase) to be a potential target.
Recently, ebselen, an anti-inflammatory and antioxidant
seleno-organic compound with an established safety in
humans, was demonstrated to both inhibit IMPase and decrease
impulsivity in mice, suggesting it as a prospective alternative to
lithium. OBJECTIVE: To assess whether ebselen possesses
anti-impulsive effects in a rat behavioral model. METHODS:
Sixteen adult Lister hooded rats were randomized using a Latin
square design to receive intraperitoneal ebselen (0.5, 1 or 5
mg/kg) or vehicle, one hour prior to assessment of performance
in the T-maze delayed reinforcement model for impulsivity.
The rate of impulsive (low reward) vs. non-impulsive (high
reward) choices, as well as the latency to choice, were
compared between the groups using Repeated Measures
ANOVA. RESULTS: No significant effect was observed for
either dose of ebselen compared to vehicle on the rate of
impulsive choices (F = 0.218, df = 3, 39, p=0.884; With G-G
correction for sphericity: p=0.869). The latency to choice was
also not demonstrated to be significantly affected by
administration of ebselen (F = 2.151, df = 3, 42, p=0.108; With
G-G correction for sphericity: p=0.134). CONCLUSIONS: The
results of this study do not support an anti-impulsive effect for
ebselen in this dose range. Further studies, using other animal
models of psychiatric disorders, as well as clinical studies in
humans, could establish whether ebselen possesses useful
psychotropic effects, in the hope of improving the therapeutic
arsenal for the treatment of bipolar and impulse-related
disorders.
A novel TMS-EEG tool indicates right PFC hypoactivity in
adults with ADHD and contributes to objective diagnosis
Alyagon U.1, Lazarovits A.1, Cohen D.1, Barnea-Ygael N.1,
Shahar H.1, Shalev H.2, Zangen A.1,
1
Department of Life Sciences, Ben-Gurion University of the
Negev, Beer-Sheva, Israel; 2Department of Psychiatry, Soroka
medical center, Beer sheva, Israel.;
Attention-deficit hyperactivity disorder (ADHD) is a clinically
heterogeneous disorder with multifaceted pathophysiology
which makes precise diagnosis allusive. Current diagnosis is
primarily based on symptomatic clinical criteria and its
subjective nature calls for more objective and robust
procedures. The right prefrontal cortex (right PFC) is a key
area in executive regulation of cognitive functioning, and
modified activity in this area is associated with ADHD. The
current study investigated such differences between adults with
ADHD and healthy controls using a combined TMS-EEG
protocol targeting the right PFC, as well as cognitive task
which measures inhibitory control – a function that is known to
recruit this specific area. Participants were stimulated with
single TMS pulses targeted to the right PFC and underwent a
Stop Signal task that asses their ability to withhold a planned
response. ADHD patients demonstrated longer stop signal
reaction times (SSRTs) and higher rates of errors. Furthermore,
N200 and P300 ERP components in response to the Stop
Signal had lower amplitudes in the ADHD group. Marked
differences between the groups were also demonstrated in
Long-term alterations in GABAergic and glucocorticoid
receptors’ gene expression in a rat model of Posttraumatic
stress disorder
Ariel L.1,3, Edut S.2,3, Inbar S.1,3, Richter-Levin G.1,2,3,
1
Psychology Department, University of Haifa, Israel;
2
Neurobiology and Etiology Department, University of Haifa,
Israel; 3The Institute for the Study of Affective Neuroscience
(ISAN), Israel;
To gain insights into underlying neurobiological processes of
posttraumatic stress disorder (PTSD), we used a rat model in
which a brief submerging under water serves as the traumatic
event (underwater trauma, UWT) and is combined with pre-
2
pubertal stress (juvenile stress, JVS) as an important risk factor
for PTSD. Previously, we found in our lab increased anxiety
and altered plasticity and local circuit activity in the dentate
gyrus (DG) 24h after the trauma, as well as increased anxiety
and altered gene expression in the DG granule cell layer 4
weeks after the UWT in rats with a history of JVS. In the
current study we further studied gene expression alterations of
GABAergic receptors (GABRA1 & GABRA2) and markers
(GAD65 & GAD67) and corticosteroid receptors (GR & MR)
in ventral and dorsal regions of the hippocampus and the
basolateral amygdala (BLA) 4 weeks following UWT, with or
without exposure to JVS. We found that GABRA1 and GR
levels were decreased in the vCA1 region of the hippocampus
in rats exposed to UWT only without a previous exposure to
JVS, although these rats' behavioral results were actually
similar to the controls. Additionally, behavioral profiles were
compiled to classify rats based on anxiety measures in the
EPM. In ‘affected’ rats, regardless of the previous stress
experience, the expression of GABRA2 was increased in the
vCA1, while the expression of GR was decreased in the BLA.
Corticosteroids serve as a master switch in the control of
neuronal and network responses that underlie behavioral
adaptation (de Kloet, 2005). Alterations in GR and GABRA1
expression in the vCA1 without increased anxiety-like
behavior, following a stressful event, might indicate an
adaptive response to stress. In contrast, the alterations we
found in the 'affected' rats might indicate a non-adaptive
response.
density of SERT compared to mice treated with crude C.
Pinnatifida, saline or home cage group.
Prenatal fluoxetine exposure and the response to an
immune challenge
Avitsur-Hamiel R.1,
1
School of Behavioral Sciences, The Academic College of Tel
Aviv-Yaffo;
Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is
commonly prescribed in pregnant women suffering from mood
disorders. Fluoxetine readily crosses the placenta, consequently
altering serotonergic neurotransmission in the fetus. In utero
exposure to SSRIs was associated with increased likelihood for
a variety of physiological and behavioral disturbances in the
newborn. Studies have shown that serotonin plays a role in
modulating immune signaling. Thus, the goal of this study was
to assess the effects of prenatal exposure to fluoxetine on the
response to an immune challenge in offspring mice. Results
indicated that prenatal fluoxetine modulated aspects of the
response to an endotoxin challenge in a gender- dependent and
age-specific manner. Prenatal fluoxetine altered the kinetics of
proinflammatory cytokine secretion following an endotoxin
challenge. In addition, endotoxin-induced sickness behavior
and depressive-like symptoms were modulated by in utero
exposure to fluoxetine. Our findings further indicate that
changes in maternal behavior were not involved in mediating
these effects. Together, these results provide an indication that
prenatal modulations of the serotonergic system had lasting
implications for host response to an immune challenge. These
findings may contribute to the understanding of the effects of
prenatal environment on the development of physiological
systems that are important to coping with infectious challenges,
and assist in understanding the limitations and precautions that
should be taken in the use of SSRIs during pregnancy.
A novel herbal treatment for anxiety: Pharmacological
effects of C. Pinnatifida ethanol extracts
Armoza Eilat S.1, Doron R.3,4, Rehavi M.1,2,
1
Department of Physiology and Pharmacology, Sackler Faculty
of Medicine, Tel Aviv University; 2The Dr. Miriam and Sheldon
G. Adelson Chair and Center for the Biology of Addictive
Diseases; 3Dept. of Behavioral Science, The Academic Col. of
Tel-Aviv Yaffo; 4Dept. of Education and Psychology, The Open
University;
Altered activity of brain serotonergic system has been
implicated in a wide range of behavioral disorders, including
anxiety. Serotonin transporter (SERT) inhibition by selective
serotonin reuptake inhibitors (SSRIs) serves as the first line
treatment for anxiety disorders, however cause many side
effects which led us to develop a novel herbal treatment. The
mixture consists of 4 Chinese herbs: Crataegus pinnatifida,
Triticum aestivum, Lilium brownii and Fructus zizyphi jujube.
Previous experiments in our laboratory found that C.
Pinnatifida showed SSRI like effect. Therefore, we explored
the pharmacological effects of his ethanol extracts on SERT in
mice brain. The aim of the present study was to evaluate the
effect of C. Pinnatifida ethanol extracts on SERT in vitro as
well as after chronic administration to mice. SERT was
characterized using high affinity [3H]citalopram binding to
brain membranes as well as [3H]5HT uptake to brain
synaptosomes. At the age of 30 days mice have underwent an
Unpredictable Chronic Mild Stress (UCMS) paradigm for 4
weeks. Following the UCMS the mice were randomly divided
into 7 groups: (a) mixture (30mg/kg) (b) C. Pinnatifida 50%
ethanol extract (30mg/kg) (c) C. Pinnatifida 50% ethanol
extract (3mg/kg) (d) crude C. Pinnatifida (30mg/kg) (e)
escitalopram (15mg/kg) (f) home cage (g) saline. The mice
were sacrificed after 21 days of i.p injections and the
hypothalamus and pre frontal cortex (PFC) was dissected for
biochemical analysis. All C. Pinnatifida ethanol extracts except
the 50% extract had no effect on [3H]citalopram binding
whereas the 50% extract had a significant enhancement effect.
Additionally, the 50% and 70% ethanol extracts were active
inhibitors of [3H]5HT uptake. Mice treated with 50% C.
Pinnatifida ethanol extract (30mg/kg) demonstrated higher
The therapeutic impact of Liraglutide on cognitive and
behavioral impairments in mice following mTBI
Bader M.Rubovitch V.Tweedie D.Li Y.Greig N.Pick C.
1
Dept. of Anatomy and Anthropology, Sackler Faculty of
Medicine, Tel-Aviv University, Israel; 2Drug Design and
Development Section, IRP/NIA/NIH, Baltimore, Maryland,
USA;
Traumatic Brain Injury (TBI) affects 2.5 million people
annually in USA alone, causing substantial suffering, currently,
with no effective treatment. Mild TBI (mTBI) is a common
neurological event, which exists in almost 80% of TBI patients.
Previous experiments in our lab have shown that mTBI may
lead to short and long-term cognitive and behavioral deficits as
well as apoptotic changes in the brains of mice. Apoptosis may
be caused by oxidative stress and glutamate excitotoxicity.
Liraglutide, a human modified glucagon-like peptide-1
receptor (GLP-1R) agonist, is used in type 2 diabetes treatment
and has anti-apoptotic and proliferative effects on pancreatic βcells. Previous studies have shown that GLP-1 protects
hippocampal neurons from apoptosis, and enhances associative
and spatial learning. In the present experiments we examined
the neuroprotective properties of Liraglutide in neuronal cell
culture and in our non-invasive weight drop closed-head mTBI
mice model. The effect of Liraglutide was characterized in
neuronal cell cultures exposed to H2O2 and glutamate. High
doses of Liraglutide significantly ameliorated H2O2-induced
toxicity and glutamate excitotoxicity via preserving cell
viability. In the animals study, control and mTBI mice were
administered a 7 days regime of Liraglutide s.c injections
starting 1 hr post sham or actual head trauma. Behavioral tests
were conducted at two time points, 7 and 30 days post trauma
using the “Novel object recognition” and the “Y maze”.
Liraglutide proved to be well tolerated and ameliorated mTBI
deficits in novel object recognition measured at both 7 and 30
3
days post trauma. In the Y maze paradigm, the Liraglutide
amelioration of the spatial memory deficit did not reach
significance, but a trend was detected. These findings may
offer a new potential therapeutic agent to treat damages caused
by mTBI. Further studies will continue to investigate the
neuroprotective effects and the mechanism of action of
Liraglutide.
Relapse to drug use following a period of self-imposed
abstinence is a major hallmark of drug (and especially cocaine) addiction. In both humans and animal models such relapse
can be reliably triggered by exposure to drug-associated cues, a
phenomenon termed cue-induced relapse (CIR). It has been
suggested that CIR is, at least in part, the resultant of druginduced changes in neuronal activity within the medial
prefrontal cortex (mPFC). To further explore this notion we
used a chronically-implanted bilateral linear microelectrode
array (LMA) within the mPFC of rats trained to self-administer
(SA) cocaine in the conflict model. The LMA were used to
record local field potentials (LFPs) throughout the experiment
and to induce intracranial electrical stimulations (ICES) as a
possible relapse prevention treatment. Our preliminary results
indicates that repeated cocaine SA is associated with increased
cue-induced N1 and P1 amplitude and with increased alpha and
beta mPFC activity. The results also indicates that indeed ICES
is capable of reducing relapse rate, as only 33% of the treated
rats (n=6), compare to 80% of the untreated rats (n=5),
'relapsed' to cocaine seeking. Moreover, we found that the
reduced relapse rate in the ICES treated group was
accompanied by normalization of the P1 amplitude and the
beta activity. Taken together, it seems that repeated cocaine SA
is associated with increased saliency of the drug-associated
cues, a tendency that can be normalize by mPFC stimulation.
Results of this study may provide insights into the mechanisms
underlying CIR and offer novel therapeutics alternatives for
relapse to drug use in human addicts.
Animal models of Tourette syndrome
Bar-Gad I.1,
1
Gonda Brain Research Center, Bar Ilan University;
Motor tics are brief, repetitive, involuntary muscle contractions
that interfere with ongoing behavior and are a symptom of
several neural disorders, most notably Tourette syndrome.
While the pathophysiology of tics is still largely unknown,
multiple lines of evidence suggest the involvement of the
cortico-basal ganglia loop, and specifically the striatum, in tic
formation. The striatum is a major input structure of the basal
ganglia, which contains a complex internal inhibitory
(GABAergic) network comprised of interneurons and
projection neuron collaterals. We transiently induced motor tics
in freely behaving rats and primates by local microinjections of
the GABAA antagonist bicuculline into the dorsolateral
striatum. Acute multi-electrode (primate) and chronic multiwire (rat) recordings were used to assess tic related neuronal
activity following the injections. We characterized these tic
related changes in neuronal activity and their modulation by
multiple pharmacological agents. Our results indicate an
intricate dopaminergic and glutamatergic modulation of the
striatal GABAergic disinhibition leading to profound
behavioral and neurophysiological changes. The results of this
study shed light on the basic mechanisms underlying the
generation and expression of motor tics and their association
with the cortico-basal ganglia system.
Aberrant A-I Rna Editing Profile In The Brains Of
Schizophrenia Patients: A Multi-Level Analysis In Two
Different Cohorts
Barzilay R.1, 2, Khermesh K.3, Shalev L.3, Ben-Zur T.1,
Weizman A.2, Eisenberg E.4, Offen D.1, Levanon E.3,
1
Neuroscience lab, Felsenstein Medical Research Center,
Sackler Faculty of Medicine, Tel Aviv Univer ; 2Research Unit,
Geha Mental Health Center, Sackler Faculty of Medicine, Tel
Aviv University; 3Mina and Everard Goodman Faculty of Life
Sciences, Bar-Ilan University; 4Raymond and Beverly Sackler
School of Physics and Astronomy, Tel Aviv University, Israel;
Background: RNA editing is a wide spread modification that
can ‘re-code’ the genome and regulate gene expression, thus
contribute to brain development and proper function. In this
study, we conducted global and targeted analysis on two
different schizophrenia brain cohorts in an attempt to identify
novel target genes subjected deregulated RNA editing and to
obtain a global RNA editing pattern of schizophrenia.
Methods: In the 1st cohort, cortical brain tissue (BA10) of
schizophrenia (n=20) and controls (n=20) was used. We
quantified the editing levels for 118 predominant RNA editing
sites using targeted PCR and deep sequencing. In the 2nd
cohort, we analyzed RNA-seq data to decipher the prevalence
of RNA-editing in the transcriptome of hippocampus and
prefrontal cortex of schizophrenia (n=15) and controls (n=15).
Results: Analysis of BA10 brain samples revealed both total
and site-specific decrease in the levels of A-to-I RNA editing
in schizophrenia samples compared to controls. Significantly
decreased editing (P<0.05) was found in 25 editing sites
located in neurotransmitter receptors and ion channels, already
linked to schizophrenia pathophysiology. Analysis of RNA-seq
data also revealed a decrease in cumulative and in site-average
RNA editing in hyper-edited cluster regions across the
transcriptome in both prefrontal and hippocampus tissue of
schizophrenia samples compared to controls. Conclusions: We
show global and site-specific decrease in RNA editing in
schizophrenia brains using different complementing
methodologies in two separate cohorts. These results suggest
that aberrant A-I RNA editing may play a role in the etiology
of schizophrenia and might be used as a biomarker for disease.
“State” and “trait” binge eating predict cocaine craving in
rats
Barnea R.1,2, Bekker L.3,2, Zifman N.1,2, Marco A.1,2,
Yadid G.1,2, Weller A.3,2,
1
Faculty of Life Sciences, Bar Ilan University, Ramat Gan
52900, Israel; 2Gonda (Goldschmied) Brain Research Center,
Bar Ilan University, Ramat Gan 52900, Israel; 3Psychology
Department, Bar Ilan University, Ramat Gan 52900, Israel;
Binge eating (BE) and drug addiction are two brain disorders
that are co-morbid and are both linked to the reward system.
These disorders are characterized by loss of control over
consumption and by compulsive seeking of the craved
substance. Previous studies demonstrated the complex
interaction between "state" BE, produced by intermittent access
to a palatable diet, and "trait" BE, a characteristic recently
described in humans. We hypothesized that providing limited
access to a palatable diet in a rat strain prone to BE could serve
as a model for examining the potential continuity between trait
binge eating and drug seeking behavior. Using three different
approaches, we found that the degree of binge eating predicted
the pattern of craving for self-administered cocaine after it
ceased to be available. Lower levels of dopamine D2 receptors
in the prefrontal cortex were correlated with increased drug
craving. Our findings support the communality of food- and
drug-craving, and the joint role of "state" and "trait" BE as risk
factors for drug addiction.
Prefrontal correlates of addiction and the effect of
subconvulsive electrical stimulation on cue-induced relapse
in the rat conflict model
Barnea-Ygael N.1, Waghmare R.1, Waghmare I.1, Gal R.1,
Zangen A.1,
1
Department of Life Sciences, Ben-Gurion University of the
Negev, Beer-Sheva, Israel;
4
Normobaric Hyperoxia Treatment of Schizophrenia
Belmaker RH, Yuly Bersudsky
Ben Gurion University of the Negev
Beersheva Mental Health Center, Beersheva, Israel
Several studies of normobaric hyperoxia in neurological
conditions have found positive results. The impaired energy
metabolism due to mitochondrial dysfunction and frontal lobe
hypofunction in schizophrenia might be improved by
increasing O2 supply to the brain. Normobaric hyperoxia may
be a potential treatment for schizophrenia. Participants in this
study, outpatients suffering from chronic schizophrenia and
inhabitants of community-based psychiatric institutions
(hostels), underwent baseline psychiatric/cognitive assessment
and were randomly assigned to either a treatment intervention
of oxygen enriched air inhalation (normobaric hyperoxia of
40% FiO2), or to regular air inhalation (21% FiO2), through a
nasal tube, for four weeks. Patients were given the air/oxygen
inhalations during the night (mainly while sleeping), for at least
7 hours a night. After completing four weeks of treatment,
patients were switched (crossed-over) to the other treatment
intervention. Fifteen patients completed the entire study. Five
additional patients completed Phase A only. There was
significant improvement in total PANSS score of patients that
received oxygen compared with control group. There were
positive effects of oxygen on memory and attention in
neuropsychological performance tests. The effect size is small
despite the statistical significance but the patient group was
extremely chronic and severely impaired. These results are a
proof of concept and normobaric hyperoxia should be studied
in patients with milder forms of the illness and earlier in the
course of illness.
Impairments in the synthesis of complex I of the
respiratory chain as a possible cause for mitochondrial
dysfunction in schizophrenia
Bergman O.1, Karry R.1, Ben-Shachar D.1,
1
Laboratory of Psychobiology, the Ruth and Bruce Rappaport
Faculty of Medicine, Technion.;
Background: Mitochondrial respiratory chain impairments
have been observed in several mental disorders including
schizophrenia. Given that abnormal complex I (CoI) assembly
has been reported in patients with CoI deficiencies, often
associated with psychotic symptoms, we hypothesize that
defects in CoI synthesis can play a crucial role in mitochondrial
dysfunction in schizophrenia. Methods: In the present study we
investigated mitochondrial respiration, protein level, in-gel
enzymatic activity, and synthesis rate of CoI as well as
mitochondrial import of 35S-methionine labeled NDUFV2, in
Epstein-Barr virus transformed lymphocytes from healthy
subjects and schizophrenia patients. Results: Cellular oxygen
consumption was significantly reduced (23±0.46%, P<0.001),
and was more susceptible to dopamine inhibition by two-folds
in schizophrenia-derived cell lines (P<0.001). Protein level and
In-gel activity of CoI and complex IV holoenzyme, their sub
and super-complexes studied by Blue-Native PAGE showed no
differences in molecular weight and protein levels. However
CoI activity, but not that of Co-IV showed a significant
decrease in schizophrenia derived mitochondria (69.6±11.8 vs.
113.6±10.9 OD/mg protein/h, P=0.008). Synthesis rates of CoI
were significantly lower in patients (1.02±0.15 vs. 1.96±1.8,
P=0.01). Finally, import of patient-derived NDUFV2 into
healthy mitochondria was three-folds lower than that of control
NDUFV2. Overall import into schizophrenia-derived
mitochondria was lower than into healthy mitochondria, yet
import of control NDUFV2 was several folds higher than that
of patients. Thus, both the protein and mitochondrial import are
impaired in patients. Conclusion: The results of the present
study suggests that impaired NDUFV2 import into the
mitochondria could contribute to the lower CoI synthesis rate,
thereby leading to reduced activity CoI-driven respiration in
schizophrenia. These results suggest CoI as a novel target in
schizophrenia.
Aggressive Symptoms in Children with Tic disorders
Benaroya-Milshtein N.1,2, Shmuel-Baruch S.1,3, Apter A.1,2,
Friling M.1, Steinberg T.1,2,
1
The Matta and Harry Freund Neuropsychiatric Tourette
Clinic, SCMCI; 2Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv; 3Department of Psychology, Bar Ilan
University, Ramat Gan; Israel;
Introduction: Sudden and explosive episodes of anger or
aggression are a postulated to be a significant source of
psychosocial morbidity in children and adolescents with tic
disorders but this is controversial Objectives: To study the
relationship between tic disorders, their associated
comorbidities, and aggressive behavior Methods: Fifty six
children and adolescents (ages 7-17) suffering from Tourette
syndrome or other chronic tic disorder were assessed. Thirty
two healthy children served as control group. The participants
were assessed by the following questionnaires: Yale Global Tic
Severity Scale; Yale Brown Obsessive Compulsive Scale;
ADHD Rating Scale IV; Screen for Child Anxiety Related
Emotional Disorders; Child Depression Inventory; Overt
Aggression Scale. Results: No significance difference in
aggression score was found between tics group and control
group. However, boys with tic disorders reported significantly
more aggressive behaviors than girls with tic disorders. Verbal
aggression was found in 69.6% of the subjects with tic
disorders, which was also the most prevalent type of
aggression. The level of aggression was not correlated to tic
severity. ADHD and OCD enhanced the probability of
explosive outbursts in the group with tic disorder. Aggression
score was significantly associated with compulsions.
Regression analysis showed that the only significant predictor
of aggression was ADHD severity score. Conclusions: Our
study suggests that there is no difference in aggressive
behavior between children with uncomplicated tics and a
control group. Thus, aggressive behavior in children with tic
disorders is not related to having tics, but rather to the
associated co morbidities; ADHD and compulsions.
Autonomic Responsivity After Sleep Restriction – Effects of
Trait Anxiety and Neuroticism
Bergman O.1, Cohen-Zion M.1, Hairston I.1,
1
Tel Aviv Yaffo Academic College;
Introduction: Chronic sleep problems are commonly associated
with mood difficulties, and neurophysiological hyperarousal,
thereby conferring risk for neuropsychiatric as well as
metabolic risk. However, identifying mechanisms that underlie
the effects of impaired sleep in experimental settings has
proven challenging. Here we assessed the role of anxiety and
neuroticism in the effects of repeated sleep restriction on the
autonomic responses associated with emotion. We tested the
hypothesis that individuals high on these traits would be more
sensitive to the effects of sleep restriction. Methods: Fifteen
healthy participants (28% men, ages 25±2.2) were assessed for
trait anxiety (State-Trait Anxiety Inventory) and neuroticism
(Big Five Inventory), and for state anxiety during subsequent
visits. Data collection of autonomic function and emotion
occurred twice, following three nights of partial sleep
deprivation (5hrs/night) and 3 well-rested nights (WR;
8hrs/night), in counterbalanced order. On each visit, after a 2min baseline, participants viewed validated neutral and sad
film clips. Electrocardiography data was used to derive heart
rate (HR; beats/min) and heart rate variability (HRV),
measured as the ratio of the low (0.04-0.15Hz) to high (0.150.4Hz) frequency (LH/HF) components of the HR spectrum,
wherein HF reflects vagal tone, and the ratio indicates the
balance between the sympathetic and parasympathetic arms of
5
the autonomic system. Results: Neuroticism and trait anxiety
(TA) were highly correlated (p<.001). Individuals with high
TA experienced reduced state anxiety after PSD compared to
WR, and visa versa (p=.013); but changes in state anxiety were
not related to neuroticism. Irrespective of sleep condition,
subjects reported feeling sadder during the "sad" compared
with the "neutral" clips (p<.001). Baseline HR, HF and LF/HF
did not vary with sleep condition. HR decelerated while
viewing the film clips only under PSD, with significant
decelerat
25 controls, cognitive performance improved, but state anxiety
did not abate after a recess. In two additional studies, 5 controls
were evaluated at baseline and after receiving methylphenidate,
and showed improvement in cognitive assessment but not in
state anxiety. Five ADHD adults were assessed at baseline and
after a recess, and showed no improvement. Study 2:
Preliminary results: The initial resting state Magneto
encephalography (MEG)data of 10 ADHD subjects, each with
two recording sessions (with either placebo or
Methylphenidate), has been pre-processed, rigorously cleaned
for artifacts, and undergone a spectral analysis. We report here
on statistically significant regression coefficients of the thetabeta ratio (p<0.05) and gamma band activity (p<0.025) with
state anxiety. In addition, and of high significance, is the fact
that no correlations were found for the theta-beta ratio values
with success in the attentional task. Conclusion: The theta-beta
ratio, a suggested biomarker for ADHD diagnosis, correlates
with self-reports of state anxiety but not with success in an
attentional task. This supports the importance of the non
cognitive dimension in the pathphysiology of ADHD.
Hemispheric Processing of Idioms in Schizophrenia and
Autism Spectrum Disorder
Bezalel R.1, Hermesh H.2,3, Dolfin D.2, Hess S.2, Vishne T.4,
Mashal N.1,5,
1
School of Education, Bar-Ilan University, Ramat-Gan; 2Geha
Mental Health Center, Petah-Tikva; 3Sackler Faculty of
Medicine, Tel-Aviv University; 4Maayanei- Hayeshua Medical
Center; 5Gonda Multidisciplinary Brain Research Center, BarIlan University;
Background: Studies involving individuals diagnosed with
either Schizophrenia (SCZ) or Autism Spectrum Disorder
(ASD) point to difficulties in comprehension of figurative
language and a tendency to interpret it in a literal manner.
Methods: 10 adults diagnosed with SCZ, 14 adults diagnosed
with ASD and 24 typically developing (TD) adults participated
in the study. The SCZ and the ASD groups were matched
according to gender and verbal abilities. We tested hemispheric
differences in accessing either the literal or the idiomatic
meaning of idioms for targets presented to either the left or the
right visual field using the divided visual field paradigm.
Results: Whereas the TD group showed a right hemispheric
advantage in the processing of the literal interpretation of
idioms, both the SCZ and the ASD groups showed a different
pattern of hemispheric involvement. Although both SCZ and
ASD groups performed poorer than the TD group, they did not
show a major impairment in understanding figurative language.
Furthermore, while the SCZ group processed the idiomatic and
the literal interpretation of the idioms bilaterally, the ASD
group showed faster response times in the right hemisphere to
idiomatic meanings. Conclusions: Our findings suggest that
brain lateralization is atypical in adults with SCZ or ASD. The
atypical hemispheric processing in addition to relatively
unimpaired understanding of figurative language can point to a
compensation mechanism in SCZ and ASD, although it seems
to differ between the two groups.
Normobaric Oxygen Treatment of Depression
Bloch Yehudit RN
A number of studies have shown that consumption of oxygen
enriched air can increase oxygen pressure in brain tissue and
lead to therapeutic effects and improve brain function.
Normobaric oxygen treatment through a nasal-tube is a simple
medical intervention that is given successfully and without
serious complications to millions of patients suffering from
respiratory diseases worldwide. It is thus surprising that such a
simple, safe and useful intervention has not been investigated
as a treatment for depression. We are conducting a randomized,
double-blind study to examine the efficacy of normobaric
hyperoxia treatment among patients with depression.
In order to be included in the study participants must have a
Hamilton Rating Scale for Depression (HRSD) ≥ 8 and a
psychiatrist approval of the diagnosis and participation. Fifty
percent of the participants receive oxygen-enriched air (40%
O2 through a nasal tube) for a month; this constitutes the
intervention group. The other 50% of participants receive
regular air (21% O2 through a nasal tube) for a month; this
constitutes the control group. Supplementation of oxygenenriched air (40% O2) and regular air (21% O2) to study
participants are performed randomly in an identical manner.
Assessment of the efficacy of normobaric hyperoxia treatment
is done using the following tools: HRSD; Clinical Global
Impression (CGI) questionnaire, Sense of Coherence (SOC)
13-item questionnaire; WHO-5 Well Being Index questionnaire
for the estimation of quality of life (QOL); and, the Sheehan
Disability Scale (SDS).
Statistical analysis and difference between the groups will be
determined by comparing the mean and standard deviation of
the groups (in terms of HRSD, CGI, SOC, WHO-5 QOL and
SDS values) before, at 2 and 4 weeks after initiation of the
study interventions. Twenty seven patient have participated in
the trial so far and preliminary results will be opened and
presented at the conference.
What typifies ADHD? being inattentive or being anxious
about being inattentive. Preliminary Magneto
encephalographic findings of the significance of state
anxiety in ADHD
Bloch Y.1-3, Hirsh E.1, 3, Dor-Zaiderman Y.4, Avni C.1,3,
Goldstein A.4,
1
The Emotion-Cognition Research Center, Shalvata Mental
Health Care Center, Hod-Hasharon, Israel; 22Child and
Adolescent Outpatient Clinic, Shalvata Mental Health Care
Center, Hod-Hasharon, Israel; 33Sackler Faculty of Medicine,
Tel-Aviv University, Tel-Aviv, Israel; 4Gonda Brain Research
Center Bar-Ilan University, Israel;
Background: One way to improve our understanding of ADHD
would be to study mechanisms extending beyond the cognitive
contribution. We hypothesize that the pathophysiology of
ADHD is better typified by combining the evaluation of
anxiety and distress to the cognitive performance measures.
Study 1:: Method: State anxiety and cognitive performance on
a continuous performance test were assessed in ADHD patients
and controls with and without taking methylphenidate. Results:
State anxiety and cognitive performance improved from
baseline in 36 ADHD adults after taking methylphenidate. In
Clinical, demographic and laboratory predictors for
response to clozapine treatment in schizophrenia patients:
a retrospective analysis
Brauner R.1, Fishcel T.1,2, Weizman A.1,2,3, Taler M.1,3,
Krivoy A.1,2,3,
1
Sackler Faculty of Medicine, Tel-Aviv University; 2Geha
Mental Health Center; 3Biological Psychiatry Lab, Felsenstein
Medical Research Center;
Response to clozapine might be predicted a-priory to treatment
by patient-related parameters. Such data would be of
immeasurably importance to clinicians, primarily in avoiding
6
unnecessary side effects, but also impeding clozapine treatment
where it is indicated. Our aim was to explore whether data of
medical history combined with laboratory data before and
during clozapine treatment could differentiate between
responders and non-responders. . We retrieved data on all
schizophrenia patients who had been exposed to clozapine
treatment during 2003- 2011 in Geha. Patients were divided
into groups of non-responders (patients who sustained a high
level of schizophrenia symptoms while being treated with
clozapine, as measured by PANSS>80), or responders (a
combination of clozapine and another neuroleptic drug for at
list four weeks, following by a monotherapy trial with
clozapine). The clozapine responders group, included 75
patients (43%). The remaining 100 patients were included in
the clozapine non-responders group (57%). A multivariate
model revealed that the predictive variables for clozapine
response among all the demographic, clinical and laboratory
data examined are co-diagnosis of OCD (OR 4.9), less
treatment trials before clozapine (OR 5.46) for 2 trials in
respect to more than 4 trials), less hospitalizations before
clozapine, early age of clozapine initiation (OR 2.19) for older
than 30 years old) and lack of drug abuse (OR 5.35 for nonabuse). Our data suggest that the profile of clozapine responder
is of a young schizophrenia (less than 30) patient, following
two unsuccessful treatment trials, who has comorbid OCD and
has no substance abuse. From a practical clinical point of view,
we cannot use this model, yet, to exclude treatment trial with
clozapine in an unfit patient. Nevertheless, this profile may
assist in risk stratification and informed decision before
commencing clozapine.
directly, standard TMS treatment protocols for OCD showed
diversified results. The use of special deep TMS (dTMS) coils
allows direct stimulation of deeper neuronal pathways relative
to those affected by standard TMS coils. Here we evaluated
whether dTMS targeting the medial prefrontal and the anterior
cingulate cortices may influence symptom severity. Methods:
40 OCD patients were treated with either dTMS or a sham coil
for five weeks in a double-blind controlled study. The patients
were divided into groups receiving either high (20Hz) or low
(1Hz) stimulation frequencies, and were simultaneously
administrated with symptom provocation. EEG measurements
were taken at baseline and at the end of treatment. Results: The
active 20Hz dTMS group improved significantly in YBOCS
score compared to the 1Hz and placebo groups (28% vs. 6%
reduction), {t (93) = -2.29 (p=0.0243)}. Moreover, follow-up
assessments revealed 3 months stability in improvements as
measured by the YBOCS scores. EEG evoked responses
measured over the anterior cingulate cortex correlated with
clinical response. Conclusions: High frequency dTMS
treatment, targeting the medial prefrontal and the anterior
cingulate cortices is a promising therapeutic intervention in OCD.
The Effects Of Oxytocin On Preferred Interpersonal
Space: A Pharmacological Neuroimaging Study
Cohen D.1, Perry A.1,4, Gilam G.2,3, Mayseless N.1,
Hendler T.2,3, Shamay-Tsoory S.1,
1
University of Haifa; 2School of Psychological Science, Faculty
of Medicine, Sagol School Neuroscience, Tel Aviv University;
3
Functional Brain Center, Wohl Institute for Advanced
Imaging, Tel Aviv Sourasky Medical Center; 4UC Berkeley;
Background: Interpersonal distance, a space two people share,
creates and defines the dynamics of social interactions.
Considering that oxytocin (OT) plays a key role in social
behavior, it has been recently suggested that it mainly increases
the salience of social agent. Based on this hypothesis, the
current study examined if the administration of OT would have
a differential effect on the preferred space between friends and
strangers. We hypothesized that two systems mediate
interpersonal distance preference, the social cognition system
(prefrontal cortex) and the threat system (amygdala) and that
these networks would be modulated by OT administration.
Methods: In a double blind, within-subject crossover design, 19
subjects were scanned, while performing an interpersonal
distance task following the administration of either placebo or
OT. The task involved watching different protagonists (a friend
or a stranger) approaching the participant, and stopping them
when feeling uncomfortable (CID task). Results: Behavioral
results demonstrated that the friend was stopped at the closest
distance, and stranger at the furthest distance. The fMRI results
show an interaction between the effects of OT upon the
different protagonists. The right amygdala, parahippocampal
gyrs, anterior and posterior cingulate, and the left medial
prefrontal cortex (BA9), were found to be more active
following the administration of OT. Conclusions: The findings
suggest that OT affects the activity of brain networks related to
social cognition and threat. It is concluded that OT, which
enhances the salience of social agents, modulates interpersonal
distance between individuals depending on the relationship
with the protagonist.
Extinction of fear is facilitated by social interaction and
prefrontal oxytocin
Brill-Maoz N.1, Sarussi-Eliyahu A.1, Maroun M.1,
1
Sagol Department of Neurobiology, Faculty for Natural
Sciences, University of Haifa, Haifa;
Based on the idea that information can be socially transmitted
in rodents and that social interaction can be beneficial on
behavior, we have recently established a behavioral paradigm
in which we trained animals to extinguish memory in pairs.
Taking advantage of the role of oxytocin in the medial
prefrontal cortex (mPFC) in the mediation of memory
extinction and social interaction, we also sought to study its
role in social interaction-induced effects on extinction. Our
results clearly show that social interaction facilitates extinction
of fear and that this facilitation is mediated through mPFC
oxytocin. Our results suggest that social interaction could be a
positive regulator of fear inhibition, and this may suggest that
social interaction mediated by physical contact could be an
easy, accessible therapeutic tool for the treatment of fearassociated disorders.
Deep Transcranial Magnetic Stimulation in Obsessive
Compulsive Disorder (OCD) patients
Carmi L.1, Al-Yagon U.2, Zohar J.3, Dar R.1, Zangen A.2,
1
University of Tel-Aviv, Department of Psychology, Tel-Aviv,
Israel. ; 2Ben-Gurion University, Department of Life Sciences,
Beer-S; 3University of Tel-Aviv, Sackler faculty of medicine,
Tel-Aviv, Israel. ;
Background: Characterized by compulsive rituals and
Obsessive thoughts, OCD is a chronic and disabling disorder.
Despite converging evidence pointing towards the involvement
of dysfunctional cortico-striato-thalamo-cortical (CSTC) circuit
in OCD, the neurophysiological pathology of OCD is still not
well characterized. Indeed, 40%-60% of patients do not
respond adequately to standard treatments. Transcranial
magnetic stimulation (TMS) is a noninvasive therapeutic
technique, recently applied to treat and investigate OCD.
However, lacking the ability to target the CSTC circuit
Circadian variations in BDNF and spine density at the PVN
underlie resilience\vulnerability to traumatic stress
Cohen S.1, Vainer E.2, Zohar J.3, Cohen H.1,2,
1
Department of Psychology, Ben-Gurion University, BeerSheva, Israel; 2Stress anf anxiety research unit, Mental Health
Center, Beer-Sheva, Israel; 3The Chaim Sheba Medical Center,
Tel-Aviv, Israel;
Recent studies indicate a role for BDNF in adaptive brain
responses including, neuronal plasticity, memory functions and
7
stress resilience. Previous study in our lab found higher
vulnerability of rats to traumatic exposure at the inactive phase,
and conversely, higher resilience at the active phase. the
diurnal rhythms in the responsiveness to stress are modulated
by the neural network that regulates NPY levels at the
paraventricular nucleus (PVN) of the hypothalamus. Higher
basal NPY at the onset of the active phase facilitated higher
resilience to posttraumatic behavioral disruptions. Since NPY
is known to induce BDNF, the current study aimed to find
circadian variations in basal expressions of BDNF at the PVN.
Our hypothesis was that the high expression of BDNF at the
beginning of the active phase will facilitate neuronal plasticity.
PVN immunoreactivity for BDNF, GR, and MR was evaluated
in several different time points at the rat's active and inactive
phases. Golgi staining was applied to evaluate dendritic spine
density at the PVN. Results show higher expression of BDNF
and MR, and higher GR translocation in PVN neurons at the
beginning of the rat's active phase, when compared to the
inactive phase. Spine density on PVN dendrites displays
variance across diurnal phases as well, with higher density at
the beginning of the active phase when compared to inactive
phase. Elevation of resilience factors such as BDNF, as well as
spine density at the beginning of the active phase is in line with
our previous study that found higher resilience to traumatic
stress, when encountered at the active phase. Higher basal
levels of these various resilience factors at the PVN may
facilitate better preparedness of the organism to encounter
stress at the active phase and therefore more efficient stress
response and subsequent resilience to long term stress related
pathology.
The effects of SIRT6 overexpression on memory and
behavior in young and aged mice
Dikshtein Y.1, Marton D.1, Franko M.2, Huly A.2, Cohen R.2,
Kermesh K.1, Levanon E.1, Doron R.2,
1
The Mina & Everard Goodman Faculty of Life Sciences, BarIlan University, Ramat-Gan 52900, Israel; 2School of
Behavioral Sciences, Academic College of Tel Aviv-Yaffo, TelAviv, Israel;
SIRT6 has been shown to increase life span. It is yet unknown
whether this increased life span is associated with preservation
of cognitive abilities at old age such as reversal of the agerelated decline in memory. SIRT1 has been demonstrated to
have a role in learning and memory. Therefore, we examined
the effect of SIRT6 on memory in young and old mice. Young
and old, male and female mice underwent a series of
behavioral tests including open field, elevated plus maze,
object recognition and Morris water maze. In all groups tested,
SIRT6 overexpressing (OE) mice demonstrated increased
performance in the Morris water maze test, and this increase
was strongest in old mice. BNDF, but not CREB, RNA levels
are decreased in the hippocampus of old mice, yet this decrease
appears to be independent of SIRT6 expression. SIRT1
hippocampal protein, but not mRNA levels are also decreased
in old mice. Microarray analysis of hippocampal tissue of old
mice revealed increased expression of ADAR3, but not
ADAR1 and ADAR2. We next examined more than 5000 RNA
editing sites in the hippocampus of young and old, WT and
SIRT6 OE mice and found changes in editing levels of
hundreds of sites, some of which are in the coding sequence of
genes known to regulate learning and memory processes.
Interestingly the editing levels of several of these genes, among
them GRIA2, KCNA1 and GABARA3, were changed with
aging and were normalized in old mice that over-express
SIRT6. There specific changes were correlated with increased
learning and memory in those mice. Altogether our results
point to increased memory performance in old mice
overexpressing SIRT6, possibly via influence on RNA editing
levels in memory related genes in the hippocampus.
Searching for anxiety and depression patterns in ERPs of
adult Post Traumatic Stress Disorder (PTSD):
Danon S.1,2, Amit A.1,3,5, Caspi Y.4, Klein E.4,
Richter-Levin G.1,2,3,
1
The Institute for the Study of Affective Neuroscience (ISAN),
University of Haifa, Israel; 2Psychology Department,
University of Haifa, Israel; 3Sagol Department of
Neurobiology, University of Haifa, Israel; 4Department of
Psychiatry, Rambam Medical Health Center, Haifa, Israel;;
5
Elminda LTD, Herzliya, Israel;
Post Traumatic Stress Disorder (PTSD) is considered one of
the most prevalent and disabling psychiatric disorders in
civilian and military populations. Recent pre-clinical research
suggests that it is possible to distinguish between two
subpopulations within the PTSD group – Post-traumatic
anxious and Post-traumatic depressive types. The purpose of
the present study was to identify these two subpopulations by
combining neuropsychological evaluation scores with EEG/
ERP measurements. The evaluation scores are based on two
methods of analysis: a classic set and a newly developed virtual
one. Data has been collected from 20 healthy controls, 19
subjects who were exposed to traumatic event without PTSD,
and 15 PTSD patients. ERPs data was recorded with 32
electrodes cap and analyzed using the Brain Vision Analyzer
software. Preliminary results suggest that we were able to
replicate Lewin et al. (2002) results, and confirm the presence
of two subgroups, of augmenters and reducers, within the
PTSD population. Furthermore, we found a main effect and
interaction of group membership and sound level between
these two subgroups. Unfortunately, these dissociations did not
distinguish between depressive and anxious subgroups. The
existence of two subgroups, of augmenters and reducers, within
the PTSD population suggests that PTSD may be a post
traumatic spectrum disorder.
Behavioral consequences (for risk taking) of unilateral
tDCS-induced activation depend on baseline activation
level
Dorman S.1, Tomer R.1,
1
Dept. of Psychology, University of Haifa;
Asymmetric activation of the dorsolateral prefrontal cortex
(DLPFC) results in a bias towards appetitive approach-related
behavior or towards avoiding aversive consequences,
depending on the more active hemisphere. When the
opportunity to obtain reward co-exists with a potential for
harm, a conflict arises, and its solution towards greater or less
risk taking may depend on the balance of activation between
the left and right DLPFC. Anodal transcranial direct current
stimulation (tDCS) increases cortical excitability locally. Thus,
applying anodal tDCS to the left DLPFC may change the
balance of activation between the two hemispheres towards
more active left DLPFC, and vice versa. The current study
employed tDCS, to examine whether the effect of this
manipulation may augment or reduce the individual’s tendency
towards risk taking, depending on the relative strength and
direction of the individual’s trait asymmetry. Seventeen
healthy, right handed young adults completed a baseline EEG
resting state recording. Then, subjects performed the Balloon
Analogue Risk Task [BART], a well-known computerized
measure of risk taking, under three tDCS conditions (in a
counterbalanced order): anodal tDCS to the right DLPFC,
anodal tDCS to the left DLPFC, and sham stimulation.
Immediately after stimulation conditions, resting state EEG
was recorded again. We predicted that increasing left DLPFC
excitability will be associated with increased risk taking,
8
especially among subjects with higher baseline asymmetry
toward the left. Surprisingly, we found that when left anodal
stimulation was applied, subjects with increased baseline
asymmetry toward the left displayed lower levels of risk
taking. These results suggest that there is an optimal range of
baseline frontal asymmetry for approach behavior, that
determines the effects of tDCS stimulation on the decision to
approach or avoid risk.
appropriate therapeutic approaches from being adopted.
Various studies focusing on mood disorders have indicated that
stress dramatically affects different forms of synaptic plasticity
and memory processes in the hippocampus. For example,
experience of continued stress can impair high-frequency
stimulation to induced long-term potentiation, whereas the
induction of long-term depression by prolonged low-frequency
stimulation is facilitated. Stress-induced modifications in
synaptic plasticity could therefore represent a useful model to
examine whether physical chronic pain state affects subsequent
responsiveness to psychogenic stressors. We have recently
described a relatively unique role for the dentate gyrus (DG) of
the hippocampus. Under stressful conditions, the DG response
is variable and complex, much like the behavioral outcomes of
such circumstances. In this study, we investigated the impact of
chronic pain on activity and plasticity in the DG. We have
employed the Sciatic nerve ligation model of neuropathic pain,
a most common form of chronic pain and have examined
synaptic transmission/plasticity in the DG of anesthetized rat.
Results indicate that alterations in activity and plasticity in the
DG reflect chronic pain experience. Thus, the results seem to
indicate that the DG is involved in the processing of the
translation of pain sensing to distress experiencing.
Herbal Treatment for depression and Anxiety Disorders
Doron R.1,2,
1
3School of Behavioral Sciences, Academic College of Tel
Aviv-Yaffo, Tel- Aviv, Israel; 2Department of Education and
Psychology, The Open University of Israel, Raanana, Israel ;
Anxiety and Depression disorders are prevalent and severe
diseases with deleterious impact on both patients and society.
Selective serotonin reuptake inhibitors (SSRIs) were shown to
be effective in treating a wide spectrum of anxiety and
depression disorders. Despite their therapeutic actions, SSRIs
are associated with a wide variety of side effects such as
weight changes, insomnia, gastrointestinal disturbances and
sexual dysfunction. Furthermore, recent studies show that their
success rates are not high, reaching 50% at most. Therefore,
there is a clear need to explore alternative treatments for
anxiety and depression disorders. We have recently produced a
novel herbal mixture for the treatment of anxiety disorder. The
novel treatment displayed anxiolytic and antidepressant-like
effects in treated mice previously exposed to stress. The aim of
the present study was to examine whether the novel treatment
induce two common side effects normally induced by the
conventional treatment with the SSRI escitalopram, namely,
sexual dysfunction and weight gain. Mice were treated with
either: (a) herbal treatment; (b) one of the four herbal
components; (c) escitalopram; or (d) control group. Following
treatment, sexual behavior and weight gain were evaluated in
the different groups, as well as changes in prefrontal cortex
serotonin transporter levels. We have found that the novel
treatment has not altered sexual behavior and did not cause a
weight gain, while escitalopram did lead to these two side
effects. Interestingly, serotonin transporter levels in the
prefrontal cortex of the escitalopram treated group were
significantly lower compared to the other treatment groups.
These results suggest that the novel treatment may have the
same behavioral anxiolytic and antidepressant efficacy as
SSRIs, while causing fewer side effects, possibly due to
different biological mechanisms. Further studies are now
conducted in order to explore the underlying biological
mechanisms through w
Oxytocin and the Brain Basis of PTSD; Testing
Mechanisms and Implications for Intervention
Eidelman-Rothman M., Goldstein A., Weisman O.,
Schneiderman I., Zagoory-Sharon O., and Feldman R.
Gonda Brain Sciences Center, Bar-Ilan University
Post-traumatic stress disorder (PTSD) is a debilitating disorder,
associated with hyper-vigilance, numbness, and social
dysfunction. Oxytocin (OT), a neuropeptide implicated in
social processing, has been suggested as a pharmacotherapeutic
agent for disorders involving severe social dysfunction.
However, the effects of OT on brain patterns in PTSD have not
been tested.
We investigated brain oscillatory patterns
associated with social processing in trauma-exposed veterans
and whether they can be impacted by OT administration.
Participants were 43 young veterans, including 28 exposed to
combat-related trauma and 15 controls. Utilizing a doubleblind within-subject design, participants underwent a wholehead magnetoencephalography (MEG) scan twice, a week
apart, following OT/Placebo administration and brain activity
was measured during "rest" (task free) and a pain perception
paradigm considered to index empathy to others' pain. During
"rest", exposed veterans showed higher alpha activity in the left
dlPFC, indicating reduced activity in areas implicated in
working memory and cognitive control that are disrupted in
PTSD. Importantly, OT attenuated the aberrant alpha activity
and under OT group differences were no longer found. In
tapping social processing, we found that, unlike controls who
showed greater activity (alpha suppression) to pain versus nopain stimuli, trauma-exposed veterans exhibited high and
undifferentiated response in areas implicated in social
processing, including structures implicated in action
observation (SMA), social salience (STG), and mentalizing
(PCC). Such undifferentiated response was observed at both
an early (0-200ms) and later (760-900ms) post-stimulus timewindows, indicating disruptions in both automatic social
perception and higher-level socio-cognitive "mentalizing"
processes, and possibly suggesting social-regulatory deficits.
OT had no effect on brain activity in the trauma-exposed
group, possibly due to intense unmodulated response to others'
pain. Findings may contribute to further understanding brain
mechanisms involved in the social dysfunction in PTSD, and
underscore the need to further investigate dosage and
frequencies of OT administration in this disorder.
The Dentate gyrus in chronic pain – between sensing and
experiencing
Edut S.1, Ritter A.3, Kigel-Tsur K.4, Meilin .4,
Richter-Levin G.1,2,3,
1
The Sagol Department of Neurobiology, Faculty of Natural
Sciences, University of Haifa; 2The Institute for the Study of
Affective Neuroscience (ISAN), University of Haifa,;
3
Department of Psychology, Faculty of Social Sciences,
University of Haifa, 199 Aba Khoushy; 4Neurology Service,
MD Biosciences Ltd, Nes-Ziona, Israel;
Chronic pain, is an emotional condition as well as a physical
sensation. It is a complex experience that affects thought,
mood, and behavior. Clinical reports estimate that over half of
chronic pain patients also possess a robust stress-like
component, reflecting a significant affective cognitive aspect.
Although many clinical aspects were studied, little emphasis
has been placed by pain neurobiologists on studying the
mechanisms contributing to the emotional component of pain.
The physiologic basis for the comorbidity of chronic pain and
depressive illnesses is not well understood, impeding
9
Behavioral outcomes of chronic and intermittent
administration of ketamine in mice – possible relationship
with autophagy
Einat H., Nirit Kara, Grant Anderson and Galila Agam
Recent data, from human and animal model studies
demonstrate that the acute administration of the NMDA
receptor antagonist ketamine has a fast and long lasting
antidepressant effect. This effect is related to the antagonistic
action of ketamine in glutamatergic receptors and the
downstream consequences of this inhibition. One of these
downstream effects is the activation of mTOR and this
mechanism was suggested to be involved in the therapeutic
effects of the drug. However, activation of mTOR may also
result in the inhibition of autophagy, especially when chronic
treatment is involved. Different sets of recent data implicate
enhancement of autophagy as a potential antidepressant target
due to the effects of autophagy to increase cellular resilience,
therefore suggesting that inhibition of autophagy can induce
depression in susceptible individuals.
To examine this
possibility, we tested the effects of chronic ketamine
administration on affective-like behavior in a number of doses
and a number of strains of mice. The results of our studies
show only minimal effects of chronic ketamine on affectivelike behaviors. Preliminary results also show some changes in
autophagy but not a clear effect. The results suggest that
whereas the effects of acute ketamine on depression are clear,
the outcome of chronic ketamine at the behavioral and
biochemical levels needs further examination.
that the cannabinoid system could represent a therapeutic target
for the treatment of stress- and anxiety-related disorders such
as post-traumatic stress disorder (PTSD). The enhancement of
the endocannabinoid anandamide by blocking the enzyme
FAAH has been shown to decrease anxiety in several rodent
models. Here, rats were exposed to a traumatic event followed
by situational reminders of the trauma. After developing
PTSD-like symptoms, rats were chronically treated with the
FAAH inhibitor URB597 (0.2 mg/kg) for 3 weeks. Results: We
found that activating the cannabinoid system using URB597
prevented PTSD-like symptoms measured 1 month after the
traumatic event. Compared to URB597-treated rats, vehicle
treated rats demonstrated enhanced avoidance behavior,
impaired extinction and enhanced startle response. In addition
we found that the effects of URB597 on the trauma-induced
behavioral changes were partly blocked by IP coadministration of the CB1 receptor antagonist AM251 (0.3
mg/kg), suggesting that some of the preventive effects induced
by URB597 are mediated by CB1 receptors. Conclusions: Our
findings suggest that enhancing the endocannabinoid system
could serve as a promising strategy to treat anxiety, while
avoiding widespread and unspecific activation of cannabinoid
receptors.
The effect of antidepressant herbal treatment on brain
Monoamineoxidase activity in mice
Franko M.1, Versano Z.1,3, Rehavi M.3,4, Doron R.1,2,
1
School Of Behavioral Science the Academic College Tel Aviv
Yaffo; 2Dep. Of Education and Psychology, the Open
University; 3Department of Physiology and Pharmacology,
Sackler Faculty of Medicine, Tel Aviv University; 4The Dr.
Miriam and Sheldon G. Adelson;
Major depressive disorder is a chronic repetitive phenomenon
which can be life-threatening. Previous studies have shown that
exposure to stress can be related to genetic risk factor which
raises the prospect of major depressive disorder. Recently we
have developed in our laboratory an herbal mixture consisting
of 4 Chinese herbs: Crataegus pinnatifida, Triticum aestivum,
Lilium brownii and Fructus zizyphi. Plants were carefully
selected from a host of Chinese herbs based on studies that
have shown that they have anxiolytic and anti- depressive
effects and those they have the ability to regulate the HPA axis
as well as the ability to raise monoamines levels in brain. The
purpose of the study was to examine the effect of the herbal
mixture chronic treatment on monoamine oxidase A and B
(MAO-A, MAO-B) activity and the level of BDNF in mice
brain. In the first stage we treated naive ICR mice with the
herbal mixture (30 mg/kg) and compared between the MAOactivity
in
the
different
treatment
groups
(Escitalopram15mg/kg and Saline). In the second stage we
induced symptoms like depression in ICR mice by exposing
them to Unpredictable Chronic Mild Stress (UCMS)
manipulation. In the end of the manipulation mice were
randomly assigned to one of 3 treatment groups for 21 days: (a)
A control group receiving only the vehicle (saline) (b)
Conventional treatment, escitalopram 15 mg/kg (c) A novel
herbal treatment 30mg/kg Brain hippocampus BDNF levels
were examined using ELISA .MAO-A and MAO-B activity
were assessed in several brain regions: the striatum,
hypothalamus and prefrontal cortex by using a radioactive
assay. There was a significant difference in MAO –A activities
between the saline group and the herbal treatment group only
in the Hypothalamus of ucms mice. No significant difference
could be found in MAO-A activities between the other groups.
Clinical Application of Pharmacogenetic Testing for the
Guidance of Psychiatric Treatments
Espadaler Jordi 1,*, Miquel Tuson 1, Jose Miguel Lopez Ibor 2,
Franciso Lopez Ibor 3, Maria Ines Lopez Ibor 4,5
1
AB-Biotics SA (Barcelona, Spain) 2 Center Dr. Lopez-Ibor
SA (Madrid, Spain) 3. Quibor SL (Madrid, Spain) 4 College of
Medicine, University Complutense of Madrid (Madrid, Spain)
5
Institute of Neurological Investigations Lopez-Ibor (Madrid,
Spain)
Clinical response to psychotropic drugs varies considerably
among patients treated with the same pharmacological agent
and dose. While some patients experience clinical
improvement, others exhibit efficacy problems (partial
response or non-response) or even develop adverse drug
reactions. Pharmacogenetics is the discipline that analyzes how
inherited genetic variation affects individual response to drugs.
We have developed a pharmacogenetic test and service for
psychiatry that analyses genetic polymorphisms associated to
drug response, metabolism and tolerability of a wide selection
of antidepressants, antipsychotics and mood stabilizers and
evaluated its application in a naturalistic clinical setting with a
cohort of 191 patients of different mental conditions. Patients
were evaluated at baseline and at 3-month follow-up for
clinical severity using the Clinical Global Impression –
Severity (CGI-S) scale. At follow-up, clinical improvement
increased in the group treated following the test
recommendations (multivariate logistic regression OR (95%CI)
= 3.05 (1.14 to 8.15)). Moreover, a prospective single-blind
randomized controlled trial (with blinded evaluation of the
main outcome) is currently in progress in 18 major hospitals in
Spain to analyze the clinical use of pharmacogenetics in the
treatment of patients with major depressive disorder.
Chronic cannabinoid treatment after a traumatic event can
reverse the stress-induced behavioral response
Fidelman S.1, Akirav I.1,
1
Department of Psychology, University of Haifa;
Background: The cannabinoid system is part of the complex
circuitry that regulates anxiety and stress and is a crucial
mediator of emotional learning. Recently, it has been suggested
11
Unilateral STN DBS effects on risk-taking, affect and
motor symptoms in patients with Parkinson’s Disease
Gelbard H.1, Hassin-Baer S.2,3,4,5, Cohen O.2,3,4,5,
Israeli-Korn S.2,3,4, Elincx-Benizri S.2,3,4, Yahalom G.2,3,4,5,
Spiegelmann R.3,5, Tomer R.1,
1
Department of Psychology, University of Haifa; 2The
Movement Disorders Institute; 3The Department of
Neurosurgery; 4The Sagol Neuroscience Center and
Department of Neurology; Chaim Sheba Medical Center, Tel
Hashomer; 5Sackler Faculty of Medicine, Tel-Aviv University,
Tel-Aviv;
Parkinson’s disease (PD) is characterized by asymmetric
dopamine (DA) loss, which was found to predict approach and
avoidance motivations, such that greater left deficit was
associated with higher avoidance behaviors, while greater right
deficit was associated with higher approach behaviors. Deep
brain stimulation (DBS) of the subthalamic nucleus (STN)
serves to ameliorate the motor symptoms in PD. As the
electrodes can be activated unilaterally, it allows for
examination the effects of left- vs. right stimulation. In the
present study we assessed the effects of unilateral STN
stimulation on risk-taking behaviors (an index of increased
approach bias) and self-reported affect. Ten PD patients
performed the Balloon Analogue Risk Task [BART] and
completed the PANAS, a self-report of positive and negative
affect ratings, while off dopaminergic medications and
undergoing unilateral left and right STN stimulation, as well as
no stimulation at all. Findings revealed that as expected,
unilateral left – but not right - stimulation decreased negative
affect compared to no stimulation and resulted in an increased
risk taking. These findings suggest that left STN stimulation
induces motivational bias towards approach behavior. A
similar pattern of motivational bias has been shown to reflect
asymmetric activation in the frontal cortex as well as
asymmetric striatal and frontal DA signaling. Thus, the current
findings support the hypothesis that unilateral STN DBS results
in asymmetric increase in subcortical and frontal DA signaling.
Attentional bias in patients with anorexia nervosa
Gilon T.1, Hamdan S.1, Bar Haim Y.2, Stein D.3,4,
1
Tel Aviv Academic College, Tel Aviv, Israel; 2Department of
Psychology, Tel Aviv University, Tel Aviv, Israel; 3Pediatric
Psychosomatic Department, Sheba Medical Center, Tel
Hashomer, Israel; 4Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel;
Anorexia Nervosa (AN) is a life-threatening condition, often
associated with a chronic course and unfavorable prognosis.
Systematic reviews and meta-analyses highlight problems in
several domains in patients with AN, including attachment,
social communication, perception and understanding of others,
and social comparison. These problems may be associated with
a tendency in these patients to perceive social stimuli in a
negative way (i.e. cognitive bias). Thus, experimental studies
show that people with AN have a negative interpretation bias
of ambiguous social scenarios. These patients show,
accordingly, increased attentional bias towards faces
expressing anger, rejection, and social-rank related poses (i.e.
dominance, submissiveness), while at the same time rejecting
neutral and compassionate facial expressions. These findings
are of considerable prognostic importance, as the anxiety and
social difficulties of these patients, potentially resulting from
their negative attentional bias, worsen with the effects of
starvation on the brain and the body, interfere with treatment
success, and disrupt the relationships with family and treatment
providers. To change this process, a few recent studies have
attempted to assess the influence of short computer trainings on
the severity of the attentional bias in patients with AN,
showing post-treatment reductions. This may have an
important potential in the attempt to reduce the chronic anxiety
that controls the life of many patients with ongoing AN, and
hopefully to improve also their eating and body-related
concerns. This presentation will explain the concept of
attentioal bias in AN, and elucidate on recent development of
relevant treatments, including our project of computerized
cognitive training.
Acceptance of premonitory urges and Tics
Gev E.1,2, Pilowsky Peleg T.4,5, Fennig S.2,3,
Benaroya -Milshtein N.1,3, Apter A.1,2,3, Steinberg T.1,
1
Matta and Harry Freund Neuropsychiatry Tourette Syndrome
and Tic Disorders Clinic; 2Sackler school of medicine , Tel
Aviv university; 3Department of Child and Adolescent
Psychiatry, Schneider Children Medical Center; 4The
Neuropsychological Unit, Schneider Children’s Medical
Center ; 5Tel Aviv-Yaffo Academic College ;
Premonitory urges (PU) often precede motor and vocal tic
expression, and are relieved by completion of the tic. PU are
often reported as even more bothersome than tics. However,
most treatments for tic disorders focus more on tics than on
PU. The objective was to examine the effect of an acceptance
based procedure on PU. Forty five participants, aged 8 -17,
diagnosed with Tourette syndrome (TS) completed the trial.
The procedure included three conditions (neutral, tic
suppression, and urge acceptance). For each condition,
participants monitored PU frequency and intensity and then
reported on their discomfort level. Results indicated that there
was a significant decrease in frequency and intensity of urges
as well as decreased discomfort during acceptance compared to
the other conditions. Examining the relationship between
acceptance and PU may lead to new insights regarding therapy.
It appears that nuances of PU interpretation can reduce the
frequency, intensity and discomfort caused by the PU and that
optimal treatment requires a balance between acceptance and
suppression.
Disruption of the ErbB signaling in adolescent mice affect
alcohol preference but not avoidance learning
Golani I.1, Tadmor H.2,3, Dvir E.3, Kremer I.2,4, Shamir A.2,4,
1
Department of Biotechnology, ORT Braude College, Karmiel,
Israel; 2Psychobiology Research Laboratory, Mazra Mental
Health Center, Akko, Israel; 3Faculty of Medicine in the
Galilee, Bar-Ilan University, Zefat, Israel; 4The Ruth and
Bruce Rappaport Faculty of Medicine, Technion - Israel
Institute of Technology, Haifa;
The ErbB signaling pathway has been functionally implicated
in developing and regulating complex behaviors. Numerous
findings support the dysregulation of the ErbB signaling in
complex behaviors as learning and memory, social interaction,
reward seeking and fear. However, the critical period for the
involvement of the pathway in the development and regulation
of complex behaviors is unknown. We recently reported that
alteration of the ErbB signaling during adolescence led to
elevated striatal dopamine levels, reduced preference for
sweetness without affecting locomotor activity and exploratory
behavior. In the current study, we extend our findings and
explore whether inhibition of the pathway during adolescent
also affect alcohol preference and avoidance learning in
adolescence and adult mice. We demonstrated that chronic
administration of the pan-ErbB kinase inhibitor JNJ28871063
(JNJ) to adolescent mice reduced alcohol preference as
compared with the saline injected group. However, inhibition
of the pathway during this critical period did not affect
avoidance learning as measured by increasing concentrations
of quinine in the bitter avoidance test. Adolescent JNJ treated
mice continue to demonstrate low alcohol preference in
adulthood as compared with their saline injected controls.
11
(University of Haifa, Israel); 3Department of Statistics
(University of Haifa, Haifa, Israel);
These data support our initial findings that interruption of the
ErbB pathway during adolescence emerges in reducing hedonic
capacity that persists into adulthood. Here, we propose that the
ErbB pathway might be involved in the regulation and
development of reward behavior but not in avoidance behavior.
Social touch has been shown to affect our emotional
well-being and diminish distress or pain in various
settings. Although previous studies provide first evidence
for the pain alleviating effects of touch the underlying
mechanisms that explain this effect is largely unknown.
The goal of the current study was (1) to examine the
analgesic effects of social touch in the context of
romantic intimacy and to test the moderating role of
toucher’s empathy in this process (3) to characterize the
effects of intimacy and affective touch during pain on the
synchronization of two brains using an EEG
hyperscanning technique in a real time social setting. In
the first experiment participants facing each other, while
painful stimuli are intermittently administered to female
participant while the other (partner) is watching/touching
her free hand (‘partner touch’ and ’partner non-touch’) or
absent at all ’pain-alone’ . The same procedure as in the
partner touch condition was designed for the ‘stranger
touch’ condition, but this time instead of a partner, a
trained male experimenter participated in this condition.
The statistical analysis revealed less pain in “partner
touch” relatively to ’partner non-touch’, ’stranger touch’
and ’pain-alone’ conditions. Furthermore, taking into
account dyadic dynamic, we found a significant
relationship between the toucher’s empathy and the pain
experience of his partner, which occurred only during the
touch condition. In the second experiment with similar
settings EEG and ECG were recorded simultaneously in
pairs of participants. Preliminary dual EEG findings will
be presented and discussed. Combining behavioral
observations
with
electrophysiology
(novel
hyperscanning EEG) in the experiments with natural
(ecological) settings offer a unique opportunity to
characterize the mechanisms of social synchrony during
pain and contributes for better understanding the neural
architecture of analgesia affected by social interactions.
A biological computerized modeler for a biologic barrier
Golani I.1, Golani M.2,
1
Department of Biotechnology Engineering, ORT Braude
College, P.O. Box 78, Karmiel 21982, Israel; 2Department of
Software Engineering, ORT Braude College, P.O. Box 78,
Karmiel 21982, Israel;
The overall central nervous system therapeutic drug market is
evaluated at an estimated $80 billion in 2015; however, 96% of
developed drugs do not sufficiently penetrate the Blood Brain
Barrier (BBB). Potential drug candidates with good BBB
penetration, should be of small molecular size, moderately
lipophilic, has a low level of plasma protein binding, has a
volume of distribution of around 1 liter/kg, and is not a strong
ligand of an efflux pump at the BBB. In order to improve the
drug development process, an effective assessment model is
required. This work addresses the challenge by means of an
artificial neural net (ANN) based assessment tool. The input set
is composed of drug physicochemical and pharmacokinetic
properties such as: Lipophilicity, Molecular Size, Plasma
Protein Binding, Polar Surface Area, Volume of Distribution,
and Plasma Half Life. The taken output is the prediction of the
drug’s barrier penetration as Brain to plasma ratio. Given a
relatively small learning data-set, leave one out (LOO), which
is a special case of k-fold cross validation, is conducted. In
such cases ANNs yield much better model fitting and
prediction results than the logistic regression. Most
combinations provided similar and satisfactory results of 89%
success rate.
Fast processing of facial social cues in normal and clinical
populations using MEG
Goldstein A.1, Morgenstern L.1, Riwkes S.1, Arviv O.1,
Gilboa-Schechtman E.1,
1
Bar-Ilan University;
Humans are able to pick up subtle social cues from facial
information such as facial expressions and social rank
information manifested in posture. We took advantage of the
temporal and spatial resolution of magnetoencephalography
(MEG) to investigate the mechanisms and temporal dynamics
of the processing of such cues in normal and clinical
populations. We have found that both emotional expressions
and social rank cues influence face perception already at the
first stages of processing, but they do so via distinct neural
networks. Furthermore, the activity in those networks is
differentially influenced by target and observer characteristics
(such as gender) as well as the relevance of the social cues to
the task at hand. In addition, we studied whether social cues are
processed differently in people suffering from social anxiety
disorder. In socially anxious individuals, facial social cues
elicited less brain activity in early stages reflecting structural
encoding of faces but more activity in later stages related to
emotional modulation. Our findings on the dynamic pattern of
brain activity highlight the importance of adopting a temporal
perspective in understanding individual differences in social
cognition.
Neurobiological mechanisms of interpersonal emotional
transmissions and their relevance to the Borderline
Personality Disorder
Golland Y.1,2, Levit-Binnun N.1,2,
1
Sagol Center for Applied Neuroscience, Interdisciplinary
Center Herzliya; 2Baruch Ivcher School of Psychology,
Interdisciplinary Center Herzliya;
Ample research demonstrates that we tend to catch the
emotions of other people. Indeed, recent models conceptualize
emotional experiences as emerging interactive processes which
unfold in time and across people. This view has been largely
supported by research in social interactions, which suggests
that in social contexts individuals mutually and continuously
adapt to the emotional signals coming from others. Taking this
dynamic interactive approach, a series of studies conducted in
our lab investigated the neural mechanisms of non-verbal
emotion propagation during “mere co-presence” – that is in copresent, but not directly communicating individuals. We found
that even in such minimal social situation, the emotions spread
across people, leading to convergent emotional experiences.
These interpersonal emotional processes were associated with
temporal synchronization of the autonomic signals across copresent participants. At the brain level, synchronization with
the emotional input from another individual was evident in the
limbic, insular and medial prefrontal regions. Taken together,
these studies suggest that the emotions of other people shape
ones’ own emotional experiences by eliciting moment-tomoment coupling of physiological responses with the social
emotional input. The contagious spread of emotional signals
across individuals has been suggested to serve fundamental
Getting in touch: empathy predicts an experimental pain
reduction during touch
Goldstein P.1,3, Shamay-Tsoory S.1, Yellinek S.1,
Weissman-Fogel I.2,
1
Department of Psychology (University of Haifa, Haifa,
Israel); 2Faculty of Social Welfare and Health Sciences
12
social processes such as empathy and interpersonal attunement.
Accordingly, in-depth characterization of its underlying neural
mechanisms can have a significant impact on understanding of
psychiatric conditions, associated with social dysfunctions.
Thus, recent clinical models suggest that the devastating
interpersonal difficulties in BPD incorporate overactive and
dysregulated emotional resonance with others. The results
presented above suggest that studying interpersonal neural
synchronization in individuals with BPD might shed light on
the mechanisms underlying social adversity in BPD.
NRXN1, 15q11.2 and 22q11.2 and microduplications at
16p11.2 and the Angelman/Prader–Willi Syndrome (AS/PWS)
region. Finally, we will describe the known and putative
mechanisms for the strong association between 22q11.2
deletion syndrome (velocardiofacial/DiGeorge syndrome) and
schizophrenia.
Ladostigil: a Novel Treatment for Mild Cognitive
Impairment; Preliminary interim results of phase 2 clinical
trial
Geffen Y
Avraham Pharmaceuticals ,Yavneh, Israel
Ladostigil is a small molecule which has already demonstrated
neuro-protective activity by mechanism of action that includes
decrease of oxidative stress, reduction of microglial activation
and inhibition of pro-inflammatory cytokines. Thus, it
constitutes a drug candidate that may have the potential to slow
progression to Alzheimer's disease in patients diagnosed with
mild cognitive impairment (MCI).
The molecule was designed by Professor Marta WeinstockRosin of the Hebrew University of Jerusalem, and Professor
Moussa B.H. Youdim of the Technion Israel Institute of
Technology and synthesized by Professor Michael Chorev of
the Harvard University.
Based on a rich body of preclinical data which has amply
demonstrated the molecule's potential in animal models,
especially in studies of ageing rats which had encouraging
cognitive results, Ladostigil is currently being clinically
evaluated in a large safety and efficacy Phase 2b clinical trial.
This on-going study is a 3-year, multi-national, multi-center,
randomized, double-blind, placebo-controlled trial which has
already completed enrollment of 210 patients in 16 centers in
Germany, Austria and Israel.
Positive interim results from the study were first obtained In
July 2014. Besides a clear green light to continue the trial from
an independent safety monitoring board, Interim efficacy data
suggest a positive trend, evident by reduction in loss of brain
volume as determined by MRI, improved biomarker-based
immune system data and trends in improvement of cognitive
parameters. The next interim analysis is expected in Q3 2015,
and final results in Q3 2016.
Memory replacement by post-retrieval
counterconditioning: a new approach of relapse prevention.
Goltseker K.1, Levy L.1, Barak S.1,2,
1
School of Psychological Sciences, Tel Aviv University; 2The
Sagol School of Neuroscience, Tel Aviv University;
Relapse to drug abuse is a critical clinical issue, often caused
by exposure to drug-associated cues. Thus, relapse could be
prevented through disruption of cue-drug memory. Upon their
retrieval, memories become labile for a temporary
"reconsolidation window", during which they restabilize. Thus,
relapse can be prevented by disruption of drug memory
reconsolidation, typically by protein synthesis inhibitors.
However, the latter evoke serious side-effects. Therefore,
behavioral procedures capable of disrupting memory
reconsolidation are crucial. Aversion therapies have been used
to prevent cue-induced craving with limited success. In this
approach, drug-paired cues are re-associated (via
counterconditioning, CC) with aversive outcomes. However,
the previous drug-cue memory may recover, triggering relapse
to drug seeking. The present study tested whether aversive CC
applied within the “reconsolidation window” could interfere
with the cue-drug memory, and abolish relapse to cocaine
seeking. Mice were trained in a conditioned place preference
(CPP) procedure. One side of a CPP box was associated with
cocaine, and was later counterconditioned with the emetic
effect of LiCl. We found that when CC was applied without a
prior memory retrieval, mice relapsed to cocaine seeking, but
conducting CC shortly after memory retrieval (within the
reconsolidation window) prevented relapse. Moreover, mice
relapsed when counterconditioned outside the reconsolidation
window (before or long after memory retrieval). Finally, when
mice were first conditioned to place aversion, and then
counterconditioned with cocaine during reconsolidation,
relapse of place aversion was also prevented. Our findings
suggest that post-retrieval CC leads to replacement of the
existing cue-drug memory with a cue-aversion memory, and
thereby prevents relapse, as the cue ceases to evoke craving.
Thus, this novel behavioral paradigm can possibly serve as a
safe method to prevent relapse to maladaptive behaviors.
Acceptance of premonitory urges and Tics
Gev, A. 12, Pilowsky Peleg, T. 45, Fennig S. 23 , BenaroyaMilshtein N.13, Woods D.W.6 , Piacentini J.7 Apter, A. 123 &
Steinberg, T. 1
Matta and Harry Freund Neuropsychiatry Tourette Syndrome
and Tic Disorders Clinic1, Sackler school of medicine , Tel Aviv
university2, Department of Child and Adolescent Psychiatry,
Schneider Children Medical Center 3 ,The Neuropsychological
Unit, Schneider Children’s Medical Center 4, Tel Aviv-Yaffo
Academic College5 , Department of Psychology, Texas A&M
University6, University of California at Los Angeles7 .
Premonitory urges (PU) often precede motor and vocal tic
expression, and are relieved by completion of the tic. PU are
often reported as even more bothersome than tics. However,
most treatments for tic disorders focus more on tics than on
PU. The objective was to examine the effect of an acceptance
based procedure on PU. Forty five participants, aged 8 -17,
diagnosed with Tourette syndrome (TS) completed the trial.
The procedure included three conditions (neutral, tic
suppression, and urge acceptance). For each condition,
participants monitored PU frequency and intensity and then
reported on their discomfort level. Results indicated that there
was a significant decrease in frequency and intensity of urges
as well as decreased discomfort during acceptance compared to
the other conditions. Examining the relationship between
acceptance and PU may lead to new insights regarding therapy.
It appears that nuances of PU interpretation can reduce the
The emerging evidence for the role of copy number
variations (CNVs) in the genetic etiology of schizophrenia
Gothelf D.
The Child Psychiatry Department, Sheba Medical Center, Tel
Hashomer; Sackler Faculty of Medicine, Tel Aviv University
The traditional hypothesis of 'common disease-common
variant' that prevailed in the field of psychiatric genetics during
the last two decades has been recently challenged following the
emergence of the microarray based comparative hybridization
(array-CGH) technique also known as chromosomal
microarrays. The chromosomal microarrays enable us to screen
the entire genome and to detect microscopic microdeletions
and microduplications collectively named copy number
variations (CNVs). It has been shown that CNVs are more
common in individuals with several psychiatric disorders
including schizophrenia and autism. We will review the
evidence for the most established CNVs associated with
schizophrenia. These CNVs include microdeletions at 1q21.1,
13
frequency, intensity and discomfort caused by the PU and that
optimal treatment requires a balance between acceptance and
suppression.
primed burst stimulation-induced long-term potentiation (LTP)
in the hippocampus was enhanced significantly relative to
control. Changes in synaptic plasticity were accompanied by
markedly reduced hippocampal mRNA expression of Insulinlike Growth Factor (IGF-1) and Brain-Derived Neurotrophic
Factor (BDNF). Finally, the protein level of the AMPA
receptor subunit GluA1 was markedly elevated in the
hippocampi of Sub mice, which was exacerbated with age. In
summary, our study clearly demonstrated linkage between
depressive-like behavior and propensity to develop age-related
cognitive impairment. Furthermore, insufficient expression of
essential factors regulating synaptic plasticity linked to a
depressive-like phenotype may affect AMPAR-based
glutamate neurotransmission, leading to the development of
cognitive impairment with age.
A system regulation view of motivational basic elements
and their clinical implication in psychiatry
Gonen T. 1,2, Admon R. 1, Eldar E. 4, Soreq E. 1, Sharon H. 1
Raz G. 1, Hendler T. 1-3
1
Functional Brain Center, Wohl Institute for Advanced
Imaging, Tel Aviv Medical Center, Israel; 2Sch. of
Psychological Sciences, Tel Aviv University, Israel; 3Sagol
Sch. of Neuroscience and Dep. of Physiology and
Pharmacology, Tel Aviv University, Israel; 4Princeton
Neuroscience Institute, Princeton University, USA.
Motivation is a key mechanism underlying adaptive responses
to environmental incentives and threats. It is assumed that our
motivational behavior (approach/avoidance) is not only driven
by the expected outcome of reward or punishment, but also by
the reinforcement's incentive and hedonic accounts.
Accordingly, certain psychopathological symptoms (e.g.
anhedonia, poor initiation, mood imbalances) can be viewed as
abnormal neural integration of these elements.
Using fMRI and two naturalistic game-paradigms we have
deconstructed the neural motivational mechanism into three
state-dependent systems (reward, punishment, goal conflict)
and their concomitant accounts (incentive, hedonic) in healthy
humans. Our findings suggested a motivational regulation
system involving the hippocampus and ventro-medial PFC
(vmPFC) which were both involved in goal-conflict resolution
and in the interactive processing of the incentive and hedonic
accounts. In addition, we related personality traits of high
reward-sensitivity and low punishment-aversion to increased
individual tendency to approach (vs. to avoid), to greater
activity in the ventral tegmental area (VTA) and ventral
striatum (VS); and importantly, to stronger hippocampusvmPFC connectivity as well.
To conclude, we highlight the contribution of core regions
underlying motivational processing under both reward (VTA,
VS) and goal conflict (hippocampus, vmPFC) to motivational
behavioral regulation; as well as to behavioral and personality
individual differences, which in their extremes may resemble
the psychological abnormalities observed in affective
disorders. Depicting the relevant circuit underlying each subprocess will eventually allow for patient- and symptomspecific treatments rather than the broad ranged
pharmacological treatments offered today.
Alterations in GAD65 within limbic regions in response to
‘Controllable vs. Uncontrollable stress’ in adult rats.
Hadad-Ophir O.1,3, Brande-Eilat N.2, Richter-Levin G.1,2,3,
1
Neurobiology and Etiology Department, University of Haifa;
2
Department of psychology, University of Haifa; 3The Institute
for the Study of Affective Neuroscience (ISAN);
Brief periods of mild stress can potentiate memory formation,
whereas more severe or prolonged stress can have deleterious
effects upon broad aspects of cognition (McEwen and
Sapolsky, 1995). The impact of a stressful event is strongly
determined by its actual or apparent controllability, i.e. the
perceived ability to alter the onset, duration, intensity or pattern
of an aversive experience (Maier and Seligman, 1976). These
mechanisms are critical for the effect of stress on emotional
states and the performance in cognitive tasks. For example,
uncontrollable electric foot shocks in rodents interfere with
subsequent learning of operant tasks (Overmier and Seligman,
1967; Seligman and Maier, 1967). A previous study
demonstrated alterations in GABAergic interneurons' related
genes in hippocampal sub-regions and in the BLA following
learning the water maze task (Hadad-Ophir et al., 2014). We
now investigate potential alterations of expression of these
genes following exposure to two-way shuttle (TWS) avoidance
task. We used the TWS avoidance task in order to achieve
different levels of controllability. Rats were exposed to 6 days,
50 trials each day, of controllable and uncontrollable stress.
Whereas rats in the 'Controllable' group underwent active
avoidance training in the TWS, animals in the 'Uncontrollable'
group were exposed to comparable amounts of footshocks but
could not avoid by shuttling to another compartment. 14 days
later, rats were tested in the TWS and examined for anxiety
levels (elevated plus maze). After the behavioral tests rats were
decapitated and blood and brain areas of interest were collected
for analysis of alterations in GABA-related gene expression.
Results suggest differences in expression which reflect the
level of controllability in the TWS task, indicating a role for
GABA related genes in defining the outcome of stress
controllability.
Enhanced hippocampal GluA1 expression and altered
synaptic plasticity accompany early-onset cognitive
impairment in Submissive mice
Gross M.1, Shenin A.2,3, Nesher E.1, Tikhonov T.1, Baranes D.1,
Michaelevski I.2,3, Pinhasov A.1,
1
Department of Molecular Biology, Ariel University;
2
Department of Biochemistry and Molecular Biology, Tel-Aviv
University; 3Sagol School of Neuroscience, Tel-Aviv
University;
Memory deficit is a common manifestation of age-related
cognitive impairment, of which depression is a frequently
occurring comorbidity. In turn, depression has been identified
as a risk factor for cognitive impairment and the development
of dementia with age. The present study made use of the
previously validated Submissive (Sub) mouse model of
depressive-like behavior to identify functional correlates of
aging-related cognitive impairment. Using learning paradigms
testing hippocampus-dependent spatial and non-spatial
memory, we demonstrate here that Sub mice developed
cognitive impairments at earlier age (3 months), compared to
wild type (wt). Furthermore, acute hippocampal slices from
Sub animals failed to display paired-pulse facilitation, while
Cognitive and Neurobiological Changes Associated with
Extensive Use of Smartphones
Hadar A.1,2, Eliraz D.1, Avi L.1, Uri A.1, Abraham Z.1,
1
Ben Gurion University, Be'er Sheva, Israel; 2City University
London, UK;
The use of ‘Smartphone’ devices is gradually becoming an
integral part of human behaviour. Current studies of the
behavioural and cognitive changes associated with smartphone
usage provide little behavioural data and no reference to
changes in brain activity. The primary objective of the present
study was to establish whether smartphone usage is, associated
with, and, may cause, measurable changes in cognitive
capacities, behavioral tendencies and relevant prefrontal neural
activity. The first experiment compared participants lacking
14
any previous experience with Smartphone (n=35) to a matched
group of heavy Smartphone users (n=15) on timed arithmetic,
response inhibition, monetary delay discounting tasks and
behavioral questionnaires. In addition the degree of long
intracortical inhibition (LICI) from the right dorsolateral
prefrontal
cortex
(DLPFC)
as
measured
by
Electroencephalography with transcranial magnetic stimulation
(EEG-TMS) was compared between the two groups. In the
second experimental stage a longitudinal intervention was
implemented in which half of the nonuser group was randomly
selected to receive Smartphone while the remaining half served
as controls. The above measurements were repeated 3 months
following this intervention. Results of the first experiment
showed higher tendency to ADHD like behavior in heavy
smartphone users particularly on subscales of impulsivity and
hyperactivity (p<0.01). Furthermore, heavy users also showed
poor performance arithmetic task. These patterns were then
corroborated by the second experiment in which nonusers who
received smartphones showed a significant decrease in the
arithmetic task performance and an increased tendency to
impulsivity in the delay discounting task. Neural data revealed
that heavy usage is associated with lower prefrontal LICI. We
conclude that smartphone usage is causally linked with
increased impulsivity and decreased information processing
capacity
and escitalopram attenuates anxiety in stressed mice but
apparently via distinct mechanisms.
Domain general regulatory role of the Dorso-Medial
Prefrontal Cortex: implication to mood disorders
Harel E.1,5, Moran Artzi1, Alon Erdman1,2, Amir Geva3, Ziv
Perman2, Dafna Ben Bashat1,2, Gabi Pell4, Talma Hendler1,2
1
. Functional Brain Center Tel Aviv Sourasky Medical Center
2
. Tel Aviv University; 3. Ben Gurion University; 4. Hebrew
University of Jerusalem; 5. Beer Yaaqov Mental Health Center
Introduction: Mood disorders are characterized by a wide
range of behavioral deficits including reward system related
hedonic dysfunction, emotional dysregulation, impairments in
cognitive control and a tendency for ruminative thought
pattern. In this study we implemented a domain approach
testing the link between ruminative thought pattern in healthy
participants and a battery of tasks targeted on domains
involved in mood disorders.
Methods: Event related fMRI/EEG signals were obtained from
35 healthy individuals while performing cognitive tasks stand
for implicit control in three domains; executive (GO vs
NOGO), Emotional (congruent vs incongruent) and Motivation
(reward/punishment outcome). Ruminative Response Style
(RRS) questionnaire was used to measure tendency for
rumination thoughts among individuals.
Results: fMRI analysis of whole brain correlation using FSFAST; FreeSurfer, revealed a significant correlation across
tasks between domain contrast activity and the RRS scores in
the DorsoMedial Prefrontal Cortex (DMPFC) (FDR corrected).
In specific, the more individuals tend to ruminate the greater
activity was found for the NoGo verses Go, punishment versus
reward and adaptation for incongruent relative to congruent.
Further analysis will examine network functional connectivity
of DMPFC during different conditions.
Discussion: The DMPFC has strong projections to limbic
structures and is proposed as a regulatory prefrontal hub. We
therefore suggest that a tendency to ruminate might imply
diminished implicit regulatory processes and affective
dysregulation. These findings point to the DMPFC as a
therapeutic target for specific cognitive element in mood
disorder.
Acknowledgment: This work was supported by grant from the
MAGNET program of the Israeli OCS at the ministry of
economy
The anxiolytic effects of clonazepam or NHT in relations to
GABAA receptor density in the mice brain
Handelsman A.2, Toledano R.1, Franko M.1,2, Savar A.3,
Doron R.1,2, Rehavi M.3,4,
1
School Of Behavioral Science the Academic College, Tel Aviv
Yaffo; 2Dep. Of Education and Psychology, the Open
University.; 3Department of Physiology and Pharmacology,
Sackler Faculty of Medicine, Tel Aviv University; 4The Dr.
Miriam and Sheldon G. Adelson Chair and Center for the
Biology of Addictive Diseases;
Anxiety disorder is characterized as a disruption of the wellbeing, and represents one of the most common and
proliferating
health
problems
world-wide.
Current
pharmacological treatment for anxiety has focused on selective
serotonin reuptake inhibitors (SSRIs) and benzodiazepines
(BDZ). Nonetheless, SSRIs and BDZ are far from optimal and
have some disadvantages. This has led to the search for
alternative treatment for anxiety such as the use of herbal
treatments. One such potent candidate investigated in our
laboratory is a novel herbal treatment (NHT) which is
composed of four different herbs chosen based on studies
demonstrating their anxiolytic effects. Studies in our laboratory
have shown NHT to be a potent anxiolytic effector that differs
in its mechanism than escitalopram. The aim of this study is to
examine via what mechanisms NHT induces its anxiolytic
effect. Since, treatment for anxiety with BDZ that target the
GABAA receptor is of high prevalence, and our NHT seems to
aim for the same construct, here we aim to asses chronic
treatment with NHT to chronic treatment with clonazepam of
the BDZ family, in relations to behavior and GABAA receptor
modifications. Adult mice underwent 4 weeks of Unpredictable
Chronic Mild Stress (UCMS) in order to induce anxiety-like
symptoms, followed by 3 weeks of treatment with NHT,
clonazepam or saline, tailed by behavioral assessment for
anxiety and biological assessment (GABAA receptor density)
in the Pre Frontal Cortex (PFC) and Hypothalamus (HYP).
Chronic treatment with NHT or clonazepam had significantly
attenuated anxiety-like behavior in stressed mice without
inducing anxiety in naïve mice. Opposed to clonazepam,
chronic treatment with NHT was found to reduce GABAA
receptor density in the HYP of stressed mice. Together, these
findings imply that NHT, in a similar manner to clonazepam
MRI study of SR141716A-induced hyperactivity in mice
Harpaz T.1,2, Hajbi M.1, Sasson E.3, Blumenfeld-Katzir T.3,
Greig I.4, Fride E.1, Anavi-Goffer S.1,
1
Department of Behavioral Sciences, Ariel University, Ariel,
Israel; 2The Mina and Everard Goodman Faculty of life
Sciences, Bar-Ilan University, Ramat-Gan, Israel; 3BioImage
Company, Haifa; 4School of Medical Sciences, Institute of
Medical Sciences, University of Aberdeen, Aberdeen, UK;
Background: Attention Deficit Hyperactive Disorder (ADHD)
is a common disorder, which affect 6-7% of children. ADHD is
characterised with attention deficit, hyperactivity and
impulsivity. We have recently shown that hyperactivity can be
induced by the cannabinoid SR141716A, a selective antagonist
of the cannabinoid receptor CB1. As alterations in the brain
structure of children and adolescents with ADHD have been
documented, we performed an MRI study in order to examine
whether the effect of SR141716A induced long term changes
to the structural anatomy of the brain of hyperactive mice. In
addition, we have tested the effect of Ritalin®
(methylphenidate), one of the most common drugs for
treatment of hyperactivity and ADHD, on SR141716A-induced
hyperactivity. Results: At age 1 month, SR141716A induced a
significant increase of locomotor activity in female but not in
male mice. A quantitative MRI measurement (T2 analysis) at
15
age 1 month revealed that compared with the brain structure of
vehicle-treated mice, the tissue density of several brain areas
was significantly higher in the SR141716A-treated mice. The
areas that were affected are related to movement (caudate
putamen and thalamus), the reward system and addiction
(nucleus accumbens and septal nuclei), memory (hippocampus)
and impulsivity (nucleus accumbens and amygdala). In
addition, at age 4 months, the female mice were still
hyperactive, and the locomotor activity of the SR141716A
group that had been treated with Ritalin® remained higher than
that of the control group. Conclusions: Our results suggest that
postnatal inhibition of the CB1 receptor induces irreversible
changes to the brain structure. The lack of response to
methylphenidate suggests that dopamine transporter is not
involved in the mechanism of SR141716A-induced
hyperactivity. These results further support the view that the
endocannabinoid system is involved in hyperactive behaviour.
disorders was recently extended by the DSM-5, to be applied to
manic/hypomanic episode. However, data regarding the
significance of manic episode seasonality for the course of
bipolar disorder are lacking. In the present study we attempted
to identify clinical and demographic features that discriminate
between BD-I patients with and without SP of manic
admissions. Methods: BD-I patients (n=148) admitted to a
mental health center, with at least two admissions of the same
mood polarity, were retrospectively followed between 2005
and 2013. Demographic and clinical characteristics were
compared between BD-I patients with or without SP of manic
admissions. Results: SP of manic episode admissions was
found in 31 (26%) of the 117 BD-I patients who were admitted
at least twice with manic episode during the study period.
Higher rates of male gender, presence of psychotic features and
comorbid substance use were associated with BD-I patients
with SP of manic episode admissions compared to BD-I
patients without SP [26 (83.9%) vs. 50 (58.1%), χ2 = 6.6,
p<0.01; 30 (96.8%) vs. 66 (76.7%), χ2 = 6.2, p<0.01 and 21
(67.7%) vs. 39 (47.0%), χ2 = 0.6, p<0.05, respectively]. In a
multivariate analysis, presence of psychotic features during the
manic episodes was associated with SP of manic episode
admissions (OR 2.48, 95% CI: 1.02-5.99, p<0.05), but
comorbidity of substance use disorder was not (OR 1.68, 95%
CI: 0.67-4.24, p=0.26). Conclusions: Male gender and presence
of psychotic features are associated with SP of manic episode
admissions among BD-I patients. These results suggest the SP
of manic admissions might be associated with more severe
form of the disorder and most likely with a poorer outcome.
Diet-dependent opposite effects of nitric oxide on feeding
after satiation
Hazut N.1,2, Susswein A.1,2, Shbiro L.1, Weller A.1,3,
1
Gonda Brain Research Center; 2Goodman Faculty of Life
Sciences; 3Department of Psychology, Bar Ilan University,
Ramat-Gan, 52900, Israel;
We tested whether the unconventional neurotransmitter nitric
oxide (NO) is an inhibitor of feeding when animals have a
relatively low drive to eat, and therefore snack, rather than
eating large meals. The experiments were prompted by data
from the marine slug Aplysia that both the amino acid Larginine (the precursor of NO), as well as NO inhibit feeding
when animals are weakly motivated to eat. To establish
conditions of low drive to eat, adult male Wistar rats were
given 60% of the chow that they regularly consume during the
night, and then in the morning they were presented with
abundant chow for 0.5 hr. After they had become satiated, they
received an intra-peritoneal injection of either a competitive
inhibitor of L-arginine (N (G)-nitro-L- arginine methyl ester
(L-NAME) - 50 mg/kg) for access to NO synthase (NOS), or
an NO donor (S-Nitroso-N-acetyl-penicillamine (SNAP) -10
mg/kg), or L-arginine (400 mg/kg) or saline. They were then
offered chow for 1 hr and feeding during this second period of
food access (i.e., snacking) was measured. The NO inhibitor
significantly increased measures related to feeding behavior. In
contrast the NO donor and L-arginine significantly reduced
measures related to feeding behavior. In addition we examined
the effect of the NO blocker on ‘hedonic snacking”. We used
the same method but for the post-satiety feeding we replaced
regular chow with a highly attractive high fat food.
Interestingly, NO blocker induced an opposite effect,
significantly reducing food intake compared to saline-treated
control rats. This result is consistent with findings of others
that NO mediates orexic effects in animals that are highly
motivated to feed animals. The findings support the hypothesis
that NO is a weak inhibitor of feeding in mammals, and its
inhibitory effects are prominent in conditions of low feeding
motivation, but it is a facilitator of feeding when eating
motivation is increased by highly palatable food.
Cardiac steroids and the Na+, K+ -ATPase in the manic
phase of bipolar disorder
Hodes A.1, Rosen H.2, Ovadia H.3, Lifschytz T.4, Deutsch J.5,
Lichtstein D.1,
1
1. Department of Medical Neurobiology, The Hebrew
University of Jerusalem, Israel; 22. Department of
Microbiology and Molecular Genetics, The Hebrew University
of Jerusalem, Israel; 33. Deprtment of Neurology, The Hebrew
University of Jerusalem, Israel; 44. Department of Psychiatry,
The Hebrew University of Jerusalem, Israel; 55. Institute for
Drug Research, School of Pharmacy, The Hebrew University
of Jerusalem, Israel;
Bipolar disorder (BD) is a devastating mental illness
characterized by extreme mood changes: cycling episodes of
mania and depression. The etiology of BD and other mood
disorders is not completely clear. Cardiac steroids (CS) and
their only established receptor, Na+, K+-ATPase, have been
hypothesized to be involved in mood disorders. We have
shown that reduction of CS in the brain has an anti-depressive
effect in a behavioral depression model in rats. In the present
study we tested the effects of reduction or inhibition of brain
CS in mice in an amphetamine-induced hyperlocomotion
model. Here we show that introduction of anti-ouabain
antibodies directly into the lateral ventricle (i.c.v.), by reducing
CS levels in the brain abolishes the increase in mobility caused
by amphetamine. This effect was reversed by pre-incubating
the antibodies with ouabain, indicating that the effect of the
antibodies is indeed due to the reduction in endogenous
ouabain. The behavioral changes were accompanied by
molecular changes in the brain: whereas amphetamine
treatment alone induced an increase in CS immunoreactivity,
the levels were significantly lower in animals treated with antiouabain antibodies. Furthermore, amphetamine treatment
induced an increase in the levels of phospho-Erk and phosphoAkt in the frontal cortex, which were reduced in the animals
receiving anti-ouabain antibodies. We also examined the effect
of a synthetic 3αOH 19-nor androsterone derivative on animal
behavior. This compound, termed “Compound 16”, resembles
CS in structure, but does not inhibit Na+, K+-ATPase ion
Seasonal pattern of manic episode admissions among
Bipolar I disorder patients is associated with male gender
and higher rates of psychotic features
Hochman E.1,2, Weizman A.1,2,3, Krivoy A.1,2,3,
1
Geha Mental Health Center, Petach-Tikva, Israel; 2Sackler
Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;
3
Felsenstein Medical Research Center, Petach-Tikva, Israel;
Objectives: Bipolar I disorder (BD-I) patients demonstrate
abnormal chronobiology expressed as greater seasonal
fluctuations in mood than unipolar depression patients or
healthy controls. The seasonal pattern (SP) specifier of mood
16
transport activity, thus acting as a functional antagonist of CS.
This
steroid
attenuated
the
amphetamine-induced
hyperlocomotion in mice. Taken together, our results
strengthen the hypothesis that the CS- Na+, K+-ATPase system
is involved in BD, particularly in the less-studies manic phase,
and suggest that this system should be regarded as a novel
target for future studies and drug development.
exhibit similar gene expression pattern as primary human
astrocytes as well as functional properties including: I)
Secretion of neurotrophic factors that protect motor neurons'
survival (BDNF, GDNF and VEGF). II) Capacity of glutamate
uptake thus reducing glutamate toxicity and III) Protection of
neurons from free radicals and oxidative stress in vitro. These
hPSC derived astrocytes can be kept frozen and used upon
need. In preliminary proof of concept study we assessed the
therapeutic properties of these human astrocytes in-vivo, for
that aim the cells were transplanted intrathecaly into tg hSOD1
mice (high copy number of SOD1 G93A, a commonly-used
mouse model for ALS disease). Human astrocytes
transplantation resulted in significant improvement (P<0.05) in
motor performance in all functional tests. In addition, positive
effect on survival and disease duration was observed in
transplanted mice.
The Association between Creatine Phoshpo Kinase (CPK),
Mood and Psychosis
Hollander S.1, Hochman E.1,2, Tromer S.1, Hermesh H.1,2,
Weizman A.1,2,3, Krivoy A.1,2,3,
1
Sackler Faculty of Medicine, Tel-Aviv University; 2Geha
Mental Health Center; 3Biological Psychiatry Lab, Felsenstein
Medical Research Center;
Increased serum CPK activity was found in hospitalized
patients with acute schizophrenia and patients with affective
psychoses. Previous research demonstrates variable but
consistent high levels of CPKemia in the majority of patients
undergoing acute psychoses. We explored this question further
by examining levels of CPK in acute psychosis, using a very
large sample size and adjusting for variables known to affect
levels of CPK. Methods: Hospitalized patients between 2008
and 2013 were selected. Baseline serum CPK values were
obtained from each newly admitted patient at the time of
admission. PANSS was taken within the first 3 days of
admission in all patients.1054 patients hospitalized at Geha at
least once during this period, and had PANSS and CPK
measurements upon admission. Of them, 743 have been
diagnosed with schizophrenia (Sz), 170 with schizoaffective
disorder (SzA), and 158 with bipolar disorder. Additionally,
LnCPK differed significantly between groups (p<.005). Posthoc analysis revealed that the increase in LnCPK in patients
with bipolar disorder was statistically significant (p<0.05) from
patients with Schizophrenia, but not significantly different
(p=.658) to patients with schizoaffective disorder. A multivariate analysis using linear regression model in which LnCPK
was predicted by several predictors such as PANSS, total, and
positive subscore, PANSS-excited, IM injection upon
admission, BMI, gender, and age among patients at each of the
diagnoses revealed that PANSS-Depression was inversely
associated with CPK level. Only in bipolar and SZA and not in
Sz there was a positive association between PANSS-Positive
and CPK, adjusting for other covariates.The interplay between
psychoses, mood and sCPK level is complex. Serum CPK level
is more associated with affective component rather than
psychosis, after controlling for excitability and gender. Our
finding suggest that sCPK may serve as a biomarker for
affective exacerbation rather than psychosis.
Drug screening assays using oligodendrocytes progenitors
cells derived from human pluripotent stem cells
Izrael M.Granit A.Krush L.Skorvsky M.Yair T.
Slutsky G.Hasson A.Revel M.
1
Neurodegenerative diseases team Kadimastem, Weizmann
Science Park, Nes-Ziona, Israe;
Clinical studies using imaging techniques have reported white
matter changes in schizophrenia, depression, Autism and
Alzheimer disease. Furthermore, behavioral animal studies
showed that manipulating glial activity modulated behavioral
response to psychostimulant abuse. These data strengthen the
need to find drugs affecting glial targets for treating psychiatric
disorders. Mechanistic studies of human oligodendrocyte
differentiation and functional myelination have been hindered
by the lack of human specific culture system assays in-vitro.
We derive an enriched population of human oligodendrocytes
progenitor cells from pluripotent stem cells (PSC). Here, we
describe a versatile high throughput content screening cellbased assays that allows quantitated processing of microscopy
images, and molecular analysis of distinct stages of human
oligodendrocyte differentiation and myelination. We show that
it is feasible to use the unique and typical morphologies
acquired during oligodendrocyte development in vitro, alone
(differentiation process) or co-cultured with DRGs neurons
(myelination process), for screening for drugs that affect
oligodendrocyte differentiation, functionality and myelination.
This system allows to study effect of potential psychiatric
agents on cell biology and functionality of oligodendrocytes.
Abnormal development of monoaminergic neurons is
implicated in mood fluctuations and bipolar disorder
Jukic M.1, Carrillo-Roa T.2,3, Bar M.1, Becker G.1,
Jovanovic V.1, Zega K.1, Binder E.2, Brodski C.1,
1
Zlotowski Center for Neuroscience, Faculty of Health
Sciences, Ben-Gurion University ; 2Department of
Translational Research in Psychiatry, Max-Planck Institute of
Psych', Munich Germany; 3Faculty of Biology, LudwigMaximilian University of Munich, Munich, Germany;
Subtle mood fluctuations are normal emotional experiences,
whereas drastic mood swings can be a manifestation of bipolar
disorder. Despite their importance for normal and pathological
behavior, the mechanisms underlying endogenous mood
instability are largely unknown. During embryogenesis, the
transcription factor Otx2 orchestrates the genetic networks
directing the specification of dopaminergic and serotonergic
neurons. Here, we behaviorally phenotyped mouse mutants
overexpressing Otx2 in the hindbrain, resulting in an increased
number of dopaminergic neurons and a decreased number of
serotonergic neurons in both developing and mature animals.
Over the course of one month, control animals exhibited stable
locomotor activity in their home cages, whereas mutants
showed extended periods of elevated or decreased activity
Cellular therapy of Amyotrophic Lateral Sclerosis by
transplantation of human pluripotent stem cells derived
human astrocytes
Izrael M.Slutsky G.Granit A.Krush L.Skorovsky M.
Tal Y.Chebath J.Revel M.
1
Neurodegenerative diseases team Kadimastem, Weizmann
Science Park, Nes-Ziona, Israel;
Amyotrophic lateral sclerosis (ALS) is characterized by death
of motor neurons in the CNS. Yet, cellular abnormalities are
not limited only to motor neurons (MNs); multiple
observations suggest that malfunctioning astrocytes in ALS
patients as well as in rodent transgenic (tg) ALS models
(hSOD1 G93A mutation) also contribute to the progression of
the disease. Kadimastem has developed a unique and robust
protocol for generating a highly homogenous population of
astrocytes (>90% GFAP, S100b) from human pluripotent stem
cells (hPSC). Our differentiation protocol, together with our
scalable culturing technology, allow us to produce large
quantities of astrocytes in vitro. These hPSC-derived astrocytes
17
Aviv University, Tel-Aviv; 5College of Pharmacy, University of
Minnesota, Minneapolis, Minnesota, USA;
Asenapine is indicated for the treatment of schizophrenia and
manic episodes in bipolar disorder (BPD). There is a paucity of
information on the effects of asenapine in animal models of
BPD, but such work is essential to discover its scope of effects
and its mechanisms of therapeutic action. This study evaluated
the effects of asenapine in a validated test battery for maniclike behaviors in Black Swiss mice. Male Black Swiss mice
received asenapine at 0.03, 0.1, and 0.3 mg/kg twice daily for 7
days and were tested for spontaneous activity, sweet solution
preference, forced swim test, social interaction, and
amphetamine-induced hyperactivity. Asenapine treatment
resulted in dose dependent, clinically relevant plasma levels.
Asenapine, at the 0.1 and 0.3 mg/kg doses, reduced activity,
with the 0.3 mg/kg dose also resulting in increased time in the
center of an open field, increased immobility in the forced
swim test, and reduced amphetamine-induced hyperactivity.
Asenapine exerted no effects in the social interaction or sweet
solution preference tests. The results suggest that asenapine
exerts antimanic-like effects in some of the behavioral tests
performed in Black Swiss mice. These data support the
utilization of asenapine in the treatment of BPD.
relative to their individual average. Additional behavioral
paradigms, testing for manic- and depressive-like behavior,
demonstrated that mutants showed an increase in intraindividual fluctuations in locomotor activity, habituation, risktaking behavioral parameters, social interaction, and hedoniclike behavior. Olanzapine, lithium, and carbamazepine
ameliorated the behavioral alterations of the mutants, as did the
mixed serotonin receptor agonist quipazine and the specific
5HT2C receptor agonist CP-809101. Testing the relevance of
the genetic networks specifying monoaminergic neurons for
bipolar disorder in humans, we applied an interval-based
enrichment analysis tool for genome-wide association studies.
We observed that the genes specifying dopaminergic and
serotonergic neurons exhibit a significant level of aggregated
association with bipolar disorder but not with schizophrenia or
major depressive disorder. The results of our translational
study suggest that aberrant development of monoaminergic
neurons leads to mood fluctuations and may be associated with
bipolar disorder.
ADHD, Self-Efficacy and Gender Differnces as predictors
for weight loss after Bariatric Surgery
Kaizler-Martin S.1, Steinmann .2, Feldman .3, Avitsur-Hamiel .4,
1
Tel-Aviv Yaffo Academic College; 2Kaplan Medical Center;
3
Tel-Aviv Yaffo Academic College, Kaplan Medical Center;
4
Tel-Aviv Yaffo Academic College;
Background: Many studies have shown a link between ADHD,
obesity and non-adaptable eating patterns. In addition, studies
have found a link between self-efficacy beliefs and the ability
to control eating patterns. One of the treatments that have been
proven to be efficient in treating obesity resulting in weight
loss and maintaining weight is bariatric surgery. This study will
examine the relationship between ADHD, self-efficacy and
possible gender moderating effects to adaptive eating patterns
post bariatric surgery. Method: We performed the study on
patients who underwent bariatric surgery by administrating
self-report questionnaires. The study included 46 patients, 34
females and 12 males. Pearson correlations and multiple
regressions were used to test the hypothesis. Results : ADHD
was negatively correlated with cognitive restraint (r=.383,
p<.01), and positively correlated with disinhibition (r=.416,
p<.01) and hunger (r=.418, p<.01).Self efficacy was found to
be positively correlated with Cognitive Restraint (r=.284,
p<.05), but negatively correlated with disinhibition (r=-.305,
p<.01)and hunger (r=-.364, p<.05).In addition, hunger was
found to be negatively correlated with self-efficacy (β=-.282,
p<.05) but positively correlated with ADHD (β=.352,
p<.01).At last, an interaction between gender and self efficacy
was found. Amongst males, a positive association was found
between self efficacy and gender and cognitive restraint
(β=.694, p<.05) however, amongst females, no association was
found between these variables (β=.116, p=.515).Conclusions:
This study provides additional evidence of the importance of
ongoing multidisciplinary care after bariatric surgery. The
results from this study, although not causative, may provide
additional evidence that weight loss is associated with greater
scores of self-efficacy and with less symptoms of ADHD. The
results provide some guidance for the tailoring of an
individual’s long-term success in a weight management
program
Identifying the most effective component of a novel herbal
treatment for depression and anxiety disorders and its
influence on Serotonin transporter and BDNF levels in
mice brain
kazum S.1, Toledano R.1, Tal N.1, Armoza S.2, Rehavi M.2,3,
Doron R.1,4,
1
School Of Behavioral Science the Academic College. Tel Aviv
Yaffo; 2Department of Physiology and Pharmacology, Sackler
Faculty of Medicine, Tel Aviv; 3The Dr. Miriam and Sheldon
G. Adelson Chair and Center for the Biology of Addictive
Diseases; 4Dep. Of Education and Psychology, the Open
University;
Previous studies have established the association between
anxiety and depressive disorders and imbalance of the
serotonergic system as well as reduced levels of brain derived
neurotrohphic factor (BDNF). Since current pharmacological
treatment for these disorders is characterized by a low success
rate and associated with various side effects, it is highly
important to search for an alternative treatment. Therefore, we
have recently investigated in our laboratory a new herbal
treatment (NHT) consisting of four Chinese herbs: Crataegus
pinnatifida (Shan-za), Triticum aestivum (Fu-xiao-mai), Lilium
brownii (Baiha) and Fructus zizyphi (Da-zao). It was found
that the NHT has anxiolytic and anti-depressive effects while
causing less side-effects. The objective of the present study
was to identify the most effective component of NHT, by
comparing the neurochemical effects of each NHT component.
We exposed mice to 4 weeks of unpredictable chronic mild
stress (UCMS). Afterward, the mice were randomly assigned to
7 groups of treatment: NHT (30mg/kg), escitalopram
(15mg/kg), Shan-za (30mg/kg ), Da-zao (30mg/kg), Fu-xiaomai (30mg/kg), Baihe(30mg/kg) and vehicle. The mice were
sacrificed after 21 days of i.p injections and the hypothalamus
and PFC were dissected for biochemical analysis. We found
that mice treated with escitalopram demonstrated low levels of
serotonin transporter in the PFC, while neither Shan-za nor
NHT demonstrated such impact. In addition, we found that
Shan-za treatment induced a 30% increase in [3H]citalopram
binding level in the PFC, in comparison to different NHT
components. Moreover, treatment with Shan-za as well as NHT
and escitalopram resulted in an increase of BDNF levels in the
hippocampus. Taking together, these results show that Shan-za
works similarly as NHT and escitalopram, as it elevates BDNF
levels while having no negative effect on serotonin levles.
The effects of the atypical antipsychotic asenapine in a
strain-specific battery of tests for mania-like behaviors
Kara N.1,2,3, Ene H.3,4, Einat H.1,2,3,5,
1
Department of Clinical Biochemistry and Pharmacology, BenGurion University of the Negev, Beer-Sheva; 2Psychiatry
Research Unit, Ben-Gurion University of the Negev, BeerSheva, Israel; 3School of Behavioral Sciences, Tel-Aviv Yaffo
Academic College, Israel; 4Department of Psychology, Tel-
18
Future research efforts should be made to further examine its
theraputic action
presentation is to review the existing knowledge regarding the
potential gains and risks of early identification of and response
to risk in schizophrenia, and to present, using pilot data, a
novel approach to balance the two.
Structural network and graph theory application in PTSD
Keadan T.1, Reuveni I.2, Giesser R.2, Bonne O.2, Goelman G.1,
1
MRI Lab, Hadassah Hebrew University Medical Center
Jerusalem, Israel.; 2Department of Psychiatry Hadassah
Hebrew University Medical Center Jerusalem, Israel.;
Background: Functional and structural MRI studies in PTSD
showed significant correlations between PTSD symptoms and
the activity and volume of the medial prefrontal cortex
(mPFC). It has been shown that addressing brain regional
structural and functional features as part of a network is a
powerful tool for evaluating psychiatric conditions. We
hypothesized that volume alterations seen in PTSD affect the
topology of brain structural network. Methods: Our study
cohort consisted of 20 subjects meeting criteria for PTSD and
21 trauma exposed controls (TEC). We used subjects' T1 scans
to extract regional volume measures of 90 brain regions of
interest (ROI) using voxel based morphometry. For each group,
we built a structural network based on correlations between
ROI gray matter volumes. We compared the two networks
using graph analysis, then, ROIs that showed significant
regional between-group differences were tested for correlation
between their volumes and the behavioral scores. Results: The
left medial orbito-frontal (lmOrbF) cortex showed significant
between-group regional differences in all network measures.
lmOrbF cortex node-degree and betweenness were increased in
the PTSD network while the clustering of this ROI was
significantly decreased. Significant negative correlations
between lmOrbF cortex’s volume were observed in all the
behavioral scores. Conclusions: These results are consistent
with previous studies that highlighted the importance of mPFC
in PTSD. Higher node-degree of lmOrbF cortex means that its
volume is correlated with high number of volumes of other
structures compared to TEC. The behavioral results suggest
that reduced lmOrbF cortex volume indicate worse symptoms.
Graph analysis and behavioral results suggest that the reduction
in lmOrbF cortex volume apparently coexist with associate
reduction in high number of other ROIs. Our results suggest
that the lmOrbF cortex is a critical structure involved in PTSD.
We are not alone: a meeting with your gut microbiome
Omry Koren
Faculty of Medicine, Bar Ilan University, Safed, Israel.
A growing body of literature indicates that our “second
genome”- the genes in our resident microorganisms
(microbiome) - affects many aspects of our physiology. From
this perspective, we are “supraorganisms” coated and inhabited
by a number of microbial cells that are 10 times greater than
the sum of all our human somatic and germ cells, carrying150
fold more genetic information than our own human genome.
The intestine contains the largest collection of microbes among
all of our body “habitats” (sites for microbial colonization).
Together, gut microbes form a community, or microbiota, that
has a major impact on health through interactions with host
cells (including components of the innate and adaptive immune
systems), extraction of nutrients and energy from the diet, and
complex biotransformations of a variety of ingested
compounds, including potential carcinogens. Shifts in
microbiome composition occur at different stages in life, from
infancy, through puberty and gestation, to old age. Changes in
the composition of the gut microbiome (dysbiosis) have also
been associated with different disease states such as obesity,
inflammatory bowel disease (IBD), diabetes, and metabolic
syndrome.
It is also becoming widely known that our gut microbiome has
important effects on our moods and behavior. Studies have
linked gut bacterial composition with risk taking, anxiety,
stress, mating and sexual preferences in animals. However, the
precise components and signaling pathways have not yet been
identified and characterized.
Understanding the neural underpinning of the consoling
effects of human touch on physical pain- A hyperscanning
fMRI study
Korisky A.1, Weissman-Fogel .2, Eran A.3, Efraty B.1, Ron A.1,
Shamay-Tsoory S.1,
1
Department of Psychology, University of Haifa; 2Faculty of
Social Welfare and Health Studies, University of Haifa;
3
Departments of Radiology, Rambam Medical Center, Haifa;
Consolation is a pro-social behavior which involves contact
distress-alleviating behaviors of an observer towards the
suffering of a target. It has been shown that skin-to-skin touch
has analgesic effects and therefore diminishes levels of
experimental pain. Also, it has been shown that empathy to
distress, the ability to understand other person's emotions, is a
prerequisite for the occurrence of consolation. This study
aimed to establish a conceptual two-brain framework for
understanding consoling touch in both the observer (consoler)
and the target (consoled) using a pioneering hyperscanning
fMRI. It was hypothesized that consoling touch will activate in
the consoled brain regions related to pleasant touch and social
behavior. It was also predicted that in the consoler, empathy
related activations will be evident in the pain vs. no pain
condition. Romantic couples were scanned during a social
interaction task involving empathy to pain. The experiment
included two main conditions pain/no-pain and human
touch/ball squeeze. The consoled and the consoler were
scanned one after the other in two counterbalanced phases. As
hypothesized, during the pain condition the consoled's
pregenual anterior cingulate cortex (pgACC) was activated
during the skin-to skin condition, and was accompanied by
deactivation of the amygdala. On the other hand in the
consoler, during consolation the dorsal anterior cingulate
cortex (dACC) was activated while, at the ball condition, the
Early detection and intervention in risk for schizophrenia:
Encouraging data, unsettling concerns, and potential
answers.
Koren Danny
The “Bridge over Troubled Waters” Lab for the Study and
Advancement of Youth Mental Health, the Clinical Program,
Psychology Department, University of Haifa
Because schizophrenia is typically a progressively deteriorating
disease that negatively affects all aspects of life, the past two
decades have witnessed explosive interest in moving the time
of detection and treatment of the illness to the pre-onset or
“prodromal” period in the development of the
psychopathology. This interest has been motivated by the hope
that intervening at this point, when the disorder is not yet fully
developed or entrenched, may either eliminate or defer
psychosis onset or improve the long-term course of the illness
if it nonetheless occurs. Several recent comprehensive metaanalyses and reviews provide preliminary reasons for careful
optimism regarding this hope. At the same time, however, they
point to several important scientific, clinical and ethical
concerns that need to be addressed before early identification
and intervention in risk for schizophrenia can become a
standard of care. Of particular importance in this regard are the
lack of data about the reliability and validity of the ‘at-risk’
state in clinical settings, and about the potential harmful effects
that at-risk diagnoses may have on stigma and overprescription of anti-psychotic drugs. The purpose of this
19
medial prefrontal cortex (mPFC) was activated. Crucially, the
results suggest that consoling touch alleviates pain by
activation of areas that are related to pleasant touch, social
behavior and analgesia, while deactivating fear-related areas.
Also, the act of consolation activates empathy-related areas in
the consoler, and prevention of consoling touch activates
Theory of mind areas, possibly reflecting the consoler's effort
to imagine the pain felt by the consoled.
Derived Neurotrophic Factor (BDNF) and Vascular
Endothelial Growth Factor (VEGF) in a cross-sectional design.
For each patient clozapine clinical responsiveness was
determined using PANSS and other clinical measures. Our
sample consisted of 49 (57%) responders (67.3% males, mean
age 43.6±10.4 years) and 37 (43%) non-responders (73%
males, mean age 43.6±10.7 years). There was a significant
difference between groups on PANSS (53.7±13.7 vs.
85.2±13.3, P<0.0001, respectively). Responders had higher
mean BDNF level than non-responders ( (2066±814.4 pgr vs.
1668±820.7 pgr, p<0.05. respectively – see figure). There was
no significant difference between responders and nonresponders in mean VEGF (101.9±42.8 pgr vs. 109±50.6 pgr,
respectively). VEGF was, however, significantly correlated
with age (r=0.23, p<0.05). There was no significant correlation
between BDNF and gender, age or PANSS. Our findings
suggest association between serum BDNF and response to
clozapine among schizophrenia patients. Based on these
findings, we believe that there is an unmet need to expand the
search for other domains of clozapine activity as potential
biomarkers for response. Eventually we believe it will enable
us to construct a combined predictive model for clozapine
response.
Histone Deacetylase inhibitor sodium butyrate attenuates
social deficits in the BTBR mouse model and regulates the
transcriptic control of the excitatory/inhibitory balance in
the prefrontal cortex
Kratsman N.Getselter D.Elliott E.
1
Faculty of Medicine, Bar Ilan University;
Autistic Spectrum Disorder (ASD) is a neurodevelopmental
disorder defined by impairments in social, communicative, and
stereotypical behaviors. ASD is defined in terms of behavioral
phenotypes while the molecular mechanisms are not yet
understood. Preliminary studies have determined a central role
for chromatin remodeling in human brain development, and
autistic behavior. Histone modifications, particularly
acetylation, regulate gene activation and gene silencing, and
histone acetylation has been demonstrated to regulate behavior
and synaptic plasticity. Our aim is to identify the effects of
histone deacetylase (HDAC) inhibition on autistic-like
behavior and gene expression in the BTBR autism mouse
model. Molecular characterization is performed on the
prefrontal cortex (PFC), which is an area involved in social
behavior. We investigated the effects of an HDAC inhibitor,
Sodium Butyrate (SB), on social behaviors in BTBR mice. A
low concentration dose (100mg/kg) of SB induced elevated
social behaviors in BTBR mice in several tests, including the
social behavior, social novelty, and social odor behavioral
paradigms. In addition, both the low concentration and high
concentration (1.2g/kg) dosages induced a decrease in
repetitive behaviors in the marble burying test, although they
had no effects in the spontaneous alternation test. To better
understand the effect of SB on gene expression in the BTBR
mouse brain we performed RNA-seq high throughput
sequencing. This analysis revealed robust changes in the
expression of neuron activity-related genes in the prefrontal
cortex after low dose SB treatment. In particular, SB induces a
decrease in excitatory receptor related genes, voltage gated
channels, and neuron activation related genes, and the increase
of serotonin receptor genes. Overall, our data suggests that
sodium butyrate may improve social behaviors in an autism
mouse
model
through
the
regulation
of
the
excitatory/inhibitory balance in the prefrontal cortex.
Diffusion Tensor Imaging of Catatonic and Non-Catatonic
Schizophrenia Patients
Krivoy A.1,2, Shrot S.2,3, Avrahami M.1, Last D.3, Guez D.3,
Daniels D.3, Mardor Y.2,3, Fischel T.1,2,
1
Geha Mental Health Center; 2Sackler Faculty of Medicine,
Tel-Aviv University; 3Sheba Medical Center;
Catatonia is a psychomotor syndrome composed of mental
symptoms and aberrant motor manifestations. In a subset of
schizophrenia patients, exacerbations are manifested as
catatonia, while the remaining portion has only psychosis. It is
still unknown whether these two subsets of schizophrenia differ
or they represent a similar neuro-pathological process. Our aim
was to compare, for the first time, diffusion tensor imaging in
catatonic and non-catatonic schizophrenia patients, thus finding
a structural basis for the hypothesis that catatonia is a distinct
neural process in schizophrenia. Methods: Nine catatonic and
eight non-catatonic schizophrenia patients were evaluated
clinically using BFCRS and PANSS scales. Each patient was
evaluated with DTI at 3.0 T MR. Region of interest (ROI)based techniques were used to analyse fractional anisotropy
(FA) and mean diffusivity (MD) in the basal ganglia nucleoli,
corpus callosum, sub-cortical frontal and parietal white matter,
internal capsule and middle cerebellar peduncle (MCP).
Correlations between DTI changes and clinical parameters
were also queried. Results: Groups did not differ on mean age,
length of illness and PANSS. Significant differences were
found in the MD of the left MCP (p<0.05), in right to left ratio
of MD of posterior limb of the internal capsule (p<0.05), and in
the right to left ratio of FA of the putamen nucleus (p<0.05). In
most of examined brain areas, no significant DTI changes were
found. Patient’s age and chronicity of the disease had strong
influence on various areas’ DTI values, most prominent in the
genu of the corpus callosum, i.e. FA changes (r=-0.86,p<0.001
and r=-0.69, p=0.002, respectively). Conclusions: Patients with
catatonic schizophrenia might differ in brain connectivity
properties from patients with non-catatonic schizophrenia in
specific brain areas. This might imply that catatonic
schizophrenia is a distinct neuro-pathological process than noncatatonic schizophrenia.
Response to clozapine treatment and neurotrophic factors
level among schizophrenia patients
Krivoy A.1,2,3, Hochman E.1,2, Hollander S.2, Weizman A.1,2,3,
Taler M.2,3,
1
Geha Mental Health Center; 2Sackler Faculty of Medicine,
Tel-Aviv University; 3Biological Psychiatry Lab, Felsenstein
Medical Research Center;
Clozapine is the only effective therapy for about 30% of
schizophrenia patients otherwise refractory to anti-psychotics.
However, not only it is associated with numerous side effects,
some could be fatal, there is a substantial portion of this
population who will not respond to clozapine. Therefore, there
is an unmet need to find biomarkers for successful clozapine
therapy. Putative biomarkers of clozapine action are based on
the unique prominent serotonergic activity of the compound.
Neurotrophins, such as BDNF, which is regulated by
monoamines, including serotonin, are implicated in many
psychiatric disorders. Method:Blood samples of 86 clozapinetreated schizophrenia patients were analyzed for serum Brain
21
Pharmacogenetics: Principles and clinical utility
Kurnik D.
1
Director of Clinical Pharmacology, Rambam Health Care
Campus; 2Division of Clinical Pharmacology, Vanderbilt
University School of Medicine, Nashville, TN, USA.;
There is great interindividual variability in drug response, part
of which can be explained by variants in genes associated with
drug pathways. Conceptually, genetic variants in molecules
involved in a drug’s pharmacokinetic (PK) profile can affect
plasma and target organ concentration. For instance, genetic
variants in drug transporters can affect absorption, distribution
into target tissues, and renal or biliary excretion. Moreover,
genetic variants in drug-metabolizing enzymes can affect
bioavailability and clearance. On the other hand, variants
involved in the pharmacodynamic (PD) pathway of a drug can
affect drug potency and efficacy without affecting its plasma
concentrations. For instance, genetic variants in a target
receptor molecule can affect drug binding, coupling, and thus
signal transduction. Similarly to drug efficacy, drug toxicity
may also be predicted by genetic markers. Examples include
HLA genotypes with high positive and negative predictive
values for drug-induced hypersensitivity reactions. Variants in
genes known to mediate a drug’s pharmacokinetic or
pharmacodynamic pathways (candidate genes) were explored
first, but this approach requires detailed knowledge of a drug’s
biological pathways. To date, technical advances allowing
whole-genome sequencing allow an unbiased search across the
human genome for genetic markers linked to drug effectiveness
and toxicity. The clinical utility of pharmacogeneticallyinformed individualization of drug therapy will depend on: 1.
The magnitude of the contribution of genetic markers to
interindividual variability in drug response, 2. The
efficacy/toxicity ratio of the drug (therapeutic index), 3. The
presence of surrogate markers for drug effectiveness or
toxicity, 4. The feasibility of gradual dose titration in a specific
clinical setting. These principles are well illustrated by the
controversy about pharmacogenetically-based warfarin dosing.
differences between females were not found. In the SCPP task,
a main effect for CPF was found in males (F(3,28) =2.94,
p=.05.) No effect was found in the FCPP task. Conclusion:
Gestational exposure to CPF elicits gender specific alternations
in social but not in learning behaviors.
Differential roles of the infralimbic and paralimbic areas in
reconsolidation of traumatic memory
levin N.1, Akirav I.2, mouna M.3,
1
Department of Psychology, University of Haifa ; 2Department
of Psychology, University of Haifa ; 3Sagol Department of
neurobiology, University of Haifa;
Background: Memory reconsolidation is the process by which
a well consolidated memory returns to a labile state and
becomes susceptible to manipulation. The mammalian target of
rapamycin (mTOR) kinase is a critical regulator of mRNA
translation and is known to be involved in various long lasting
forms of synaptic and behavioral plasticity. The ventromedial
prefrontal cortex (vmPFC) is involved in the process of
extinction of fear conditioning and the retention of extinction.
The prelimbic (PrL) area is known to inhibit the HPA axis
following stress and is important in fear learning. The
infralimbic area (IL) is known in activate the HPA axis and is
important for extinction. Together, the PrL and IL compose the
vmPFC. Here we examined the role of the mTOR pathway in
the PrL and IL areas in the reconsolidation of a traumatic
memory. Rats are exposed to a single shock (1.5 mA, 10 sec)
in day 1 followed by an exposure to a reminder of the shock
(i.e., reactivation) a week later. Rapamycin or vehicle were
injected to the IL or PrL after reactivation and extinction
retention was assessed. Results: Rats were microinjected with
rapamycin, an inhibitor of mTOR, to PrL or IL after exposure
to a reminder of the traumatic event. PrL microinjection after
reactivating the memory resulted in facilitated extinction
whereas IL microinjection impaired extinction. These effects
were observed even after re acquisition of the fear memory,
suggesting that rapamycin affected the initial fear memory.
Conclusions: This study suggests differential involvement of
the IL and PrL in fear memory expression and extinction.
Understanding the mechanisms of reconsolidation is important
as this process may provide a novel means of disrupting
maladaptive memories in neuropsychiatric disorders such as
PTSD, persistently reducing symptoms of the disorder
following only a single (or few) treatment sessions combining
behavioral and pharmacological therapy.
Prenatal exposure to Chlorpyrifos elicits gender specific
behavioral alterations in adulthood in mice
Lan A.1, Kofman O.1, Dori A.2,
1
Department of Psychology and Zlotowski Center for
Neuroscience, Ben-Gurion University of the Negev; 2Talpiot
Medical Leadership Program, Department of Neurology and
Joseph Sagol Neuroscience Center;
Background: Chlorpyrifos (CPF) is a widely-used
organophosphate insecticide. Epidemiological studies have
reported that gestational exposure to CPF was linked to lower
birth weight, abnormal reflexes, increased risk for pervasive
developmental disorder and lower IQ in children. In rodents
gestational CPF exposure elicited decreased vocalizations in
pups and enhanced agonistic responses in adults. In this study,
we tested the effects of gestational CPF administration on
social and learning behaviors. Method: B6 pregnant mice were
treated with vehicle, 2.5/kg or 5mg/kg of CPF by gavage on
gestational days 12-15. Social and learning behaviors were
measured on PND 90: a) Social preference (SP) toward a
conspecific was measured by comparing the time spent in the
two side chambers of a three-chambered box, which contained
either an unfamiliar conspecific an inanimate object. b) Social
conditioned place preference (SCPP) task measured preference
toward an environmental cue that was previously conditioned
to a social home cage environment over another cue that had
been associated with isolated living conditions. c) Food
conditioned place preference (FCPP) task measured preference
toward an environmental cue that was previously conditioned
to a food reward. Results: Males that were exposed to 5mg/kg
of CPF showed reduced preference toward an unfamiliar
conspecific in the SP test (F(2,17)=3.57, p=.05), while
Review of novel pharmacological targets of future
therapeutic agents in schizophrenia.
Levkovitz H.
BeerYaakov Ness Ziona, Mental Health Hospital , School of
Medicine, Tel-Aviv University , Israel
Since the introduction of chlorpromazine and throughout the
development of the new-generation antipsychotic drugs
beginning with clozapine, the D(2) receptor has been the target
for the development of antipsychotic medications. A number of
novel non-D(2) mechanisms of action of antipsychotic
medications have been explored over the years but none has
definitively been proven effective. The relative success of
antipsychotics in treating positive symptoms is limited by the
fact that a substantial number of patients are refractory to
current medications and by their lack of efficacy for negative
and cognitive symptoms. There is an urgent need for more
effective and antipsychotic agents and to identify and develop
new molecular targets that can address the various symptom
dimensions of schizophrenia. A variety of new experimental
pharmacological approaches have emerged, including
compounds acting on targets other than the dopamine D(2)
receptor. Our talk will provide an update and critical review of
the pharmacology and molecular targets of current
21
antipsychotic medication and novel targets with potential to be
therapeutic agents in the future.
By combining results from new behavioral experiments with an
analysis of whole-brain functional networks, and then crossvalidating the data with robust neuroinformatic databases, our
research demonstrates that normal variation in gene expression
during neurodevelopment is eventually translated into a
continuum of global network metrics that serve as intermediate
phenotypes. Within this framework, we suggest that
organization of functional brain networks may result, in part,
from an adaptive trade-off between efficiency and resilience,
ultimately culminating in a phenotypic diversity that
encompasses dimensions such as emotional regulation and
cognitive function.
The role of oxytocin: from bonding and binding to social
dysfunction.
Levy T.1, Bloch Y.1, Apter A.2,
1
Department of Child and Adolescent Psychiatry, Shalvata
Mental Health Center, Hod Hasharon, Israel ; 2Feinberg Child
Study Center, Schneider Children's Medical Center of Israel,
Petach Tikva, Israel;
Oxytocin (OT) is a nine amino acid neuropeptide, produced
mainly in the hypothalamus. This endocrine hormone also
function as a central neurotransmitter. Accumulating data
suggests that OT plays a role in the expression of a broad
repertoire of social behaviors in humans and animals. In
humans, intranasal administration of OT improved subject's
ability to identify emotional states in others, presumably based
on improved capability to identify face expression, especially
fear. OT was also found to improve memory for facial
expressed emotion. Studies suggested OT to be related to
empathy. Polymorphism of the OT receptor was related to
empathy levels and stress reactivity. A correlation was found
between OT receptor density and levels of empathy,
generosity, and caring for others. OT administration improved
trust and shared risks taking, decreased trust loss and threat
reactivity, increased generosity towards others and reduced
stress response when combined with social support. Oxytocin
has
been suggested
as
a
promising anxiolytic
pharmacotherapeutic agent. In social anxiety disorder,
decreased baseline OT plasma levels have been observed, and
intranasal application of OT as an adjunct to exposure therapy
improved speech performance. Oxytocin attenuated excessive
amygdala activation in response to socially relevant or fearconditioned emotional stimuli, linked to social avoidance and
phobia. Polymorphisms, and epigenetic methylation of the
promoter region of the OT receptor gene are associated with
risk for autism. Children with autism demonstrate lower
plasma OT levels, and increased levels of OT precursor
peptides. Preliminary evidence suggests OT may have potential
as an intervention for autism. Studies associated SNPs in the
OT receptor gene with childhood-onset aggressive behaviors,
and with callous-unemotional traits in youth with disruptive
behavior disorder. The risk alleles of these SNPs were
associated with lower circulating OT levels.
Predator scent stress, ethanol consumption and the opioid
system in an animal model of PTSD
Manjoch H.1,2, Matar .2, Ifergan .3, Joseph .4, Kaplan .2, Cohen .1,2,
1
Ben-Gurion University of the Negev, Department of
Psychology, Beer Sheva, Israel; 2Beer-Sheva Mental Health
Center, Anxiety and Stress Research Unit, Ben-Gurion
University, Israel ; 3Headache Clinic, Department of
Neurology, Soroka Medical Centre, Ben-Gurion University,
Israel; 4The Chaim Sheba Medical Center, Sackler Medical
School, Tel-Aviv University, Tel Hashomer, Israel ;
Background: Posttraumatic stress disorder (PTSD) and alcohol
use disorder are highly comorbid. This co-morbidity is
associated with a more severe clinical presentation, including
increased co-occurrence of additional anxiety disorders and
depression and worse treatment outcomes. Converging
experimental data indicate that the endogenous opioid system
modulates alcohol consumption and stress regulation. The aim
of the present study was to examine the interplay between
stress exposure, behavioral stress responses, EtOH
consumption and the endogenous opioid system, in an animal
model of PTSD. Methods Rats were exposed to predator-scent
stress and then tested in a two-bottle free choice (TBC) assay
or in a conditioned place preference paradigm. In some
experiments,
the
endogenous
opioid
system was
pharmacologically manipulated prior to stress exposure. The
behavioral outcomes of stress exposure were assessed with the
elevated plus-maze paradigm, with the acoustic startle response
(ASR) paradigm, and by monitoring the freezing response to
trauma reminder. Immunoreactivity (ir) of phosphorylated
opioid receptors in hippocampal subregions was also measured.
Results Stress exposure significantly increased the
consumption of EtOH in the TBC assay. The severity of the
behavioral response to stress was associated with EtOH
consumption, cue-triggered freezing response to a trauma
reminder, and endogenous levels of phosphorylated opioid
receptors in the hippocampus. Pharmacologically manipulating
the endogenous opioid system prior to stress exposure
attenuated trauma cue-triggered freezing responses and blocked
PSS-induced potentiation of EtOH consumption. Conclusions
These data demonstrate a stress-induced potentiation of EtOH
self-administration and reveal a clear association between
individual patterns of the behavioral response to stress and
alcohol preference, while indicating a role for the endogenous
opioid system in the neurobiological response to stress.
Alterations in Expression of a Neurodevelopmental Gene
Exert Long-Lasting Effects on Cognitive-Emotional
Phenotypes and Functional Brain Networks: Translational
Evidence from the Ahi1 knockout mouse
Lotan A.1, Lifschytz T.1, Mernick B.1, Lory O.2, Goelman G.2,
Lerer B.1,
1
Biological Psychiatry Laboratory, Hadassah-Hebrew
University Medical Center, 2MRI Lab, Medical Biophysics,
Hadassah-Hebrew University Medical Center, Jerusalem;
Many psychiatric disorders are highly heritable and are likely
to represent the clinical outcome of aberrations in the
formation of neural networks in utero or during early postnatal
life. The placement of brain connectivity as an 'intermediate
phenotype' renders it an attractive target for exploring its
interaction with genomics and behavior. However, given the
complexity of genetic makeup and phenotypic heterogeneity in
humans, translational studies are indicated. Recently, we
demonstrated that a mouse model with constitutive knockout of
the key neurodevelopmental gene Ahi1 displays a consistent
stress-resilient phenotype in terms of behavior, physiology and
functional amygdalar connectivity. Extending these data, the
current research describes our multi-faceted effort to link early
variations in Ahi1 expression with long-term effects on
cognitive-emotional phenotypes and functional brain networks.
Generating original ideas: the neural underpinning of
originality
Mayseless N.1, Shamay-Tsoory S.1,
1
Department of Psychology, University of Haifa;
One of the key aspects of creativity is the ability to produce
original ideas. Originality is defined in terms of the novelty and
rarity of an idea and is measured by the infrequency of the idea
compared to other ideas. In the current study we focused on
divergent thinking (DT) – the ability to produce many alternate
ideas – and assessed the neural pathways associated with
originality. Considering that generation of original ideas
22
Medicine, Tel Aviv University; 3Child and Adolescent
Psychiatry Division, Geha Mental Health Center; 4Felsenstein
Medical Research Center;
Background: 22q11.2 deletion syndrome (22q11DS), also
known as velo-cardio-facial syndrome (VCFS) or DiGeorge
syndrome is the most common genetic syndrome associated
with schizophrenia. About one-third of individuals with
22q11DS develop schizophrenia by early adulthood. Therefore,
it is important to identify early signs of psychosis in this
population, a task which is complicated by the intellectual
disabilities that are common in 22q11DS. The purpose of our
study was to identify the prodromal symptoms that are
characteristic of 22q11DS in comparison to Williams
Syndrome (WS) and to typically developing (TD) controls.
Methods: Age and gender matched adolescents and young
adults with 22q11DS (n=51), WS (n=20) and TD controls
(n=23) underwent extensive psychiatric and cognitive
evaluations and the Structured Interview for Prodromal
Symptoms (SIPS). Results: Both 22q11DS and WS had
significantly higher rates of prodromal syndromes compared to
TD. The 22q11DS and WS groups had similar rates of
prodromal syndrome based on the positive symptoms. When
including the negative and disorganized symptoms, the
22q11DS had significantly higher rates of prodromal syndrome
compared to WS (42.5% vs. 15.0%, p=0.044). Reports of
probands and caregivers were higher in 22q11DS compared to
WS on several negative scales including avolition, decreased
expression of emotion, decreased experience of emotion and
self, and deterioration in role functioning. Conclusions: Our
results suggest that in terms of prodromal symptoms, negative
symptoms, and not positive symptoms, distinguish individuals
with 22q11DS from individuals with another developmental
disability. Those negative symptoms in 22q11.2DS youngsters
potentially predict the evolution of psychotic disorders.
involves both the ability to generate new associations and the
ability to overcome automatic common responses, we
hypothesized that originality would be associated with
activations in regions related to associative thinking, including
medial prefrontal areas, as well as with areas involved in
inhibition. Thirty participants were scanned while performing a
DT task that required the generation of original uses for
common objects. The results indicate that the ability to produce
original ideas is mediated by activity in the medial prefrontal
cortex (mPFC) and the posterior cingulate cortex (PCC).
Furthermore, individuals who are more original exhibited
enhanced activation in the ventral anterior cingulate cortex
(vACC), which was also positively coupled with activity in the
left occipital temporal area. These results are in line with the
dual model of creativity, according to which original ideas are
a product of the interaction between a system that generates
ideas and a control system that can act to inhibit unoriginal
ideas.
Difference in reading the mind in the eye of schizophrenia
and schizoaffective patients; a pilot study
Meiman M.1, Dadon T.1, Tadmor H.1,2, Levin M.2, Golani I.3,
Kremer I.1,4, Shamir A.1,4,
1
Psychobiology Research Laboratory, Mazra Mental Health
Center, Akko, Israel; 2Faculty of Medicine in the Galilee, BarIlan University, Zefat, Israel; 3Department of Biotechnology,
ORT Braude College, Karmiel, Israel; 4The Ruth and Bruce
Rappaport Faculty of Medicine, Technion - Israel Institute of
Technology, Haifa;
Deficit in the ability to attribute mental states of another person
such as thoughts, beliefs and intentions, also referred to as
‘Theory of mind’ (ToM) or “mentalization”, is a key
component in the functional impairment of social cognition in
schizophrenia. The difficulty of patients with schizophrenia to
interpret emotional expression, social contexts and mental state
of others can result in social withdrawal and social isolation,
and affect daily functioning. In the current study, we compared
the ability of first episode schizophrenic patients and
schizophrenic patients in remission to decode the mental state
of the other with healthy individuals and schizoaffective
patients. To evaluate the ability to mentalize emotion we
applied the ‘Reading the Mind in the Eyes’ (eyes) test , a
simple well defined and characterized task to infer the mental
state of others by looking at the eye region of different
complex emotions. Our preliminary results showing that
overall individuals with schizophrenia performed worse in the
eye test and scored on average significantly lower than healthy
individuals. Impairment in the performance was in inverse
correlation with PANSS-negative symptoms of schizophrenia,
but not with PANSS-positive or general symptoms. Within the
schizophrenia group, there was no significant difference in the
performance on this test between the first episode individuals
and schizophrenic patients in remission groups. However,
schizoaffective patients performed better on the eye test, and
score significantly higher than both first episode and
schizophrenic patients displaying symptomatic remission. Our
results provide further evidence for the impairment of decoding
the mental state of the other in schizophrenia, suggesting that
the deficit in mentalizing in patients with schizophrenia, but
not schizoaffective is trait dependent and may serve as a
marker of the disorder.
Predictors of short-term outcome variables in hospitalized
female adolescents with eating disorders
Mekori E.1, Halevy L.1, Ziv S.1, Moreno A.1, Enoch-Levy A.1,
Weizman A.2,3, Stein D.1,2,
1
Pediatric Psychosomatic Department, Sheba Medical Center,
Tel Hashomer, Israel ; 2Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel ; 3Felsenstein Medical Research
Center, Rabin Campus, Petah Tiqva, Israel.;
Background and objective: Research in eating disorders (EDs)
suggests that outcome variables other than that of the ED per
se, such as the presence of comorbid disorders and overall
functioning at follow-up, may influence the ED condition at
that time. We sought to assess whether these different outcome
variables would be predicted by different factors. Methods:
Eighty-eight female adolescent inpatients with an ED were
assessed on admission, discharge, and around one-year postdischarge using clinical interviews and self-rating
questionnaires assessing ED and other relevant symptoms.
Results: The mean body mass index (BMI) of patients with
anorexia nervosa increased from admission to discharge and
was maintained at follow-up. Twenty-eight patients were
remitted at follow-up, whereas 48 and 12 patients had
intermediate and poor ED-related outcome, respectively.
Follow-up BMI was associated with baseline BMI.
Surprisingly, good ED-related outcome at follow-up was
associated with more lifetime suicide attempts and more severe
baseline
ED
symptomatology.
Elevated
psychiatric
comorbidity at follow-up was associated with elevated baseline
anxiety and with re-hospitalization during the post-discharge
follow-up period. Better academic/occupational and social
functioning at follow-up was associated with less lifetime
suicide attempts, less re-hospitalization and lower baseline
anxiety. Conclusion: We suggest that in EDs, diverse factors
may predict different outcome variables
High rates of prodromal negative symptoms in 22q11.2
deletion syndrome compared to Williams syndrome and to
typically developing controls
Mekori E.1,2, Guri Y.1,2, Weinberger R.1,2, Wiezman A.2,3.4,
Gothelf D.1,2,
1
The Behavioral Neurogenetics Center, The Edmond and Lily
Safra Children’s Hospital, Sheba ; 2Sackler Faculty of
23
Insights into neural mechanisms underlying late-life
depression: Impacts of chronic mild stress on affect
measures in a translational rodent model
Mernick B.1, Lotan A.1, Lifschytz T.1, Wolf G.1,
Wasserman E.1, Lerer B.1,
1
Biological Psychiatry Laboratory, Hadassah-Hebrew
University Medical Center, Jerusalem;
Late life depression (LLD) is a serious and highly prevalent
age dependent psychiatric disorder. Current evidence suggests
that an interaction between exposure to chronic stress and age
related changes contributes to the development of LLD. As part
of a comprehensive effort to gain an understanding its
neurobiological underpinnings, we have recently performed
extensive behavioral tests using a translational mouse model
that aims to recapitulate such an interaction. To model effects
of age we studied 2 vs. 18 month old C57BL/6JRccHsd female
mice. To model CMS we employed a series of mild, but
unpredictable stressors to which the animals are exposed.
Following CMS or sham exposure, the mice underwent a
comprehensive behavioral battery. Looking at overall motor
activity (distance travelled) in the open field, 2-way ANOVA
with distance travelled as the dependent variable and age and
exposure as the between-group independent variables showed a
significant effect of CMS (F=10.01, p=0.002) and a significant
interaction (F=5.2, P=0.025). Following this significant
interaction, a post-hoc analysis of the main effects revealed that
exposure type (sham vs. CMS) had an highly significant effect
on locomotion only among old mice (F1,70=15.3, P<0.0005)
without affecting the young mice (F1,70=0.380, P=0.5). These
results indicate that the old mice were significantly more
sensitive to the effects of chronic stress exposure in terms of
inducing a hyperlocomotive state, which may resemble a state
of agitation in humans, as is often the case with late-life
depression. Alongside data from additional behavioral
paradigms, the results obtained thus far provide preliminary
evidence supporting our overall hypothesis of a different effect
of stress in young and old mice. Supported by a grant # 310764 from the Israel Ministry of Science, Technology and
Space
free media increased lithium sensitivity selectively in LCLs
from NR BD patients. However no significant differences were
observed when comparing let-7c expression in LCLs from R
vs. NR BD patients. Our data support a key role for IGF-1 in
lithium resistance/response in the treatment of bipolar disorder.
The involvement of MicroRNAs in gene dysregulation in
Autistic Syndrome Disorder
Mor M.1, Elliott E.2,
Autism spectrum disorder (ASD) is a common
neurodevelopmental disorders with a complex biological
etiology. ASD is by definition a large number of disorders
characterized by social deficits, communication difficulties,
stereotyped or repetitive behaviors and interests. ASD
encompasses Rett syndrome, Asperger's and PDDNOS
(pervasive developmental disorder - not otherwise specified).
While gene transcription dysregulation has been well
characterized in the brain of individuals with ASD, there is
little knowledge of the status of microRNA patterns in the
brain of individuals with autism. Using high throughput
sequencing technology, followed by real time PCR, we
identified three microRNAs that are overexpressed in the brain
of a cohort of individuals with ASD: microRNA-21,
microRNA-451 and microRNA-142. We determined that the
transcription starting site (STT) of the microRNA-142, is
hypomethylated in the same autistic brain samples, therefore
establishing a link between epigenetic and microRNA
dysregulation in the autism brain. We also found that
microRNA-451 and microRNA-21, target the oxytocin
receptor (OXTR) gene, this was validated by luciferase assays.
We found that OXTR expression increased in these same
autistic brain samples, and microRNA-21 expression positively
correlated to OXTR expression. By using western blot analysis,
we determined that microRNA-21 expression, negatively
correlates to the production of OXTR protein, from the OXTR
transcript in our autistic brain samples. Therefore, we suggest
that Mir-21 may attenuate OXTR expression in the human
autism brain. Overall, we provide evidence that microRNAs
may play an important role in dysregulation of genes in the
autistic brain.
Insulin-like growth factor 1 differentially affects lithium
sensitivity of lymphoblastoid cell lines from lithium
responder and non-responder bipolar disorder patients
Milanesi E.1,2, Hadar A.1, Maffioletti E.3, Werner H.1,
Shomron N.2,4, Gennarelli M.3,5, Del Zompo M.6,7,
Squassina A.6,
1
Department of Human Genetics and Biochemistry, Sackler
Faculty of Medicine, Tel Aviv University; 2Department of Cell
and Developmental Biology, Sackler Faculty of Medicine, Tel
Aviv University;3Genetic Unit, IRCCS Istituto Centro San
Giovanni di Dio Fatebenefratelli, Brescia, Italy; 4Sagol School
of Neuroscience, Tel Aviv University; 5Departement of
Molecular and Translational Medicine, University of Brescia,
Brescia, Italy; 6Section of Neuroscience and Clinical
Pharmacology, University of Cagliari, Cagliari, Italy; 7Unit of
Clinical Pharmacology of the University Hospital of Cagliari,
Cagliari, Italy;
Bipolar disorder (BD) is a chronic psychiatric illness with an
unknown etiology. Lithium is considered the cornerstone in the
management of BD, though about 50-60% of patients do not
respond sufficiently to chronic treatment. Insulin-like growth
factor 1 (IGF1) has been identified as a candidate gene for BD
susceptibility, and its low expression has been suggested as a
putative biomarker for lithium unresponsiveness. In this study,
we examined the in vitro effects of IGF-1 on lithium sensitivity
in lymphoblastoid cell lines (LCLs) from lithium responder (R)
and non-responder (NR) bipolar patients. Moreover, we
evaluated levels of microRNA let-7c, a small RNA predicted to
target IGF1. We found that exogenous IGF-1 added to serum-
Locomotor effects of CB2 receptor selective agonists in the
phencyclidine model of schizophrenia
Naftaly A.1, Fride E.1, Gertsch J.2, Anavi-Goffer S.1,
1
Department of Behavioral Sciences, University of Ariel;
2
Institute of Biochemistry and Molecular Medicine, University
of Bern, Switzerland ;
Schizophrenia is one of the most important forms of
psychiatric illness, affecting young people. This disease is
associated with deficits in cognitive function, and with anxiety
and depression. These symptoms are enhanced by the
consumption of cannabis, suggesting the involvement of a
signalling system in the brain which is sensitive to cannabis
and cannabis-mimicking (cannabinoid) drugs. Alterations in
some components of the endogenous cannabinoid system have
been observed in schizophrenic patients. Recent studies have
focused on the contribution of the 'non-psychoactive'
cannabinoid CB2 receptor to disease etiology. The inhibition of
the glutamate NMDA receptor in mice induces impairment of
emotional and cognitive functions, and alterations in the
sensorimotor gating which resembles human schizophrenic
behaviour. We have shown that postnatal administration of
phencyclidine (PCP), an NMDA antagonist, leads to behaviour
paradigms relevant to anxiety and symptoms associated with
schizophrenia when animals reach adulthood. Our results
suggest that inhibition of glutamate transmission induces
cerebral lateralization in the CB2 receptor expression.
Alterations seen in the left but not in the right cortex are in line
with human studies which have detected cerebral lateralization
24
in schizophrenics using MRI imaging. Our study is now
focused around the effects of CB2 selective agonists in the PCP
model of schizophrneia. The results of this study further
support a role for the cannabinoid CB2 receptor in
schizophrenia. Acknowledgments: This study was supported
by The Institute for Psychobiology in Israel- founded by The
Charles E. Smith Family, Young Investigator Award 244-092010 to SAG. The authors are grateful to The Daniel Turnberg
UK/Middle East Travel Fellowship Scheme (to SAG), The
Irving and Cherna Moskowitz Foundation (to AN) for
supporting this study.
and long acting injections (LAIs). Given the heterogeneity of
published studies, it remains unclear which kind of
administration is superior in preventing exacerbations and rehospitalizations. Methods: We retrospectively examined the
medical records of 2,098 schizophrenia and schizoaffective
patients that were hospitalized at Geha Mental Health Center
between 2005 and 2012. We collected clinical (PANSS) and
socio-demographic data, detailed medications at discharge and
time to readmission. We compared the time to readmission in
patients treated with oral medications vs. LAIs as well as
typical vs. atypical antipsychotics. Results: Overall 902
patients (43%) were re-hospitalized within one year from
discharge. Out of 2092 patients, 661 (31.5%) were discharged
with LAIs (typical & atypical) treatment while 1437 were
discharged with oral antipsychotics. One year risk of
readmission did not differ significantly in these two groups.
Specifically, the risk for readmission following risperidone
LAI did not differ significantly either from FGA LAIs
(zuclopenthixol decanoate, haloperidol decanoate, fluphenazine
decanoate) or from oral risperidone. There were no significant
differences with regard to age at first admission, total number
of hospitalizations and PANSS score at admission. The patients
under FGA LAIs had longer total illness duration (p< 0.05) and
higher PANSS score at discharge (p< 0.05). Conclusions:
Among hospitalized schizophrenia patients, as a whole, LAIs
were not superior to oral antipsychotics regarding the risk for
readmission. Risperidone LAI was not superior either to FGA
LAIs or to oral risperidone.
A novel herbal treatment: identifying the most effective
antianxiety and antidepressant herb component
Navot H.1, Feldman S.1, Rehavi M.2,3, Doron R.1,4,
1
School of Behavioral Science the Academic College Tel Aviv
Yaffo; 2Department of Physiology and Pharmacology, Sackler
Faculty of Medicine, Tel Aviv University; 3The Dr. Miriam and
Sheldon G. Adelson Chair and Center for the Biology of
Addictive Diseases; 4Dept. of Education and Psychology, The
Open University;
Depression & anxiety disorders are a major public health
concern. Finding adequate treatments for these disorders is at
utmost importance. Conventional pharmacological treatments
such as selective serotonin reuptake inhibitors (SSRIs) are
associated with a wide variety of side effects. Thus, the search
for an alternative treatment such as herbal medicines is
necessary. We have recently studied a novel herbal treatment
(NHT) that can substitute the conventional treatment for
anxiety & depression disorders. The NHT was prepared from
four herbal food components: Crataegus pinnatifida (i.e. Shanzha), Fructus Zizyphi Jujubae (i.e. Da-zao) Triticum aestivu
(i.e. Fu-xiao-mai), Lilium brownie (i.e. Baiha) and was found
to be effective in reducing depressive- and anxiety-like
behaviors in ICR mice following exposure to unpredictable
chronic mild stress (UCMS). The first aim of the present study
was to examine the anxiolytic and antidepressant effects of
NHT and each of its four components in comparison to SSRI
(escitalopram). Anxiety- and depressive- like behaviors were
measured in elevated plus maze (EPM) and in the tail
suspension test (TST), respectively. Secondly, we aimed to
investigate the impact of the three most prevalent side effects
knows in SSRI's (i.e. low activity level, sexual dysfunction and
weight changes) within the substances reached significance
influence. Activity level of mice was measured in the novel
open test (NOT). Our results replicate our previous findings
showing that the NHT is an efficient candidate for treating
anxiety and depression. Further, our results show that the ShanZha herb is the only component found to significantly reduce
both anxiety and depressive- like behaviors. By comparing the
three known side effects between the three significantly
effective substances (i.e. Shan-Zha herb, NHT, SSRI), we
revealed that decreased activity level, decreased sexual
behavior and increased weight gain were found only in the
SSRI- treated mice.
Effects of menstrual cycle phase on social perception –
preliminary results
Oren C.1, Richtman M.1, Linkovsky L.1, Shamay-Tsoory S.1,
1
Department of Psychology, University of Haifa;
Women's fertility changes profoundly across the menstrual
cycle. Increasing evidence suggests that there are outward
changes across the menstrual cycle in terms of social behavior,
voices and physical appearance. Furthermore, research shows
changes in different functions throughout the menstrual cycle
such as creativity and emotion recognition. Previous research
shows that during the follicular phase of the menstrual cycle,
facial emotion recognition is more accurate. Here we
investigated whether the menstrual cycle phase affects complex
social understanding abilities and particularly perception of
social relationships. 16 healthy women, not using hormonal
contraceptives, underwent the Interpersonal Perception Task
which assesses accuracy of social judgments. The task involves
identification of relationships between individuals in video
clips divided to categories: kinship, competition, status and lie.
The task was completed twice; during ovulation and during the
luteal phase (phase detection was assured by a reliable
commercial ovulation kit). We hypothesized that the menstrual
cycle phase influences women's accuracy of social perception,
so that accuracy will be higher during ovulation as compared to
the luteal phase. In line with our hypothesis, we found a
general effect of the menstrual cycle phase on improving
accurate perception of social interactions. Specifically,
improvement in identifying lies was observed during ovulation.
These results demonstrate that the menstrual cycle phase does
not only influence basic functions such as emotion recognition,
but also more complex understanding of social interactions. It
is possible that the hormones peaking at the ovulation phase
influence women's perceptions of social interactions, so that
they are more sensitive to social cues when ovulation occurs.
From an evolutionary standpoint, the increased sensitivity to
social cues may contribute to choosing potential mating
partners that are more competent and reliable.
The risk for readmission in schizophrenia patients treated
with Long-acting injectable (typical or atypical) vs. oral
antipsychotics
Onn R.1, Krivoy A.1,2, Weizman A.1,2,3, Valevski A.1,2,
1
Geha Mental Health Center, Petah Tikva, Israel; 2Sackler's
Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel;
3
Felsenstein Medical Research Center, Campus Rabin, Sackler
Faculty of Medicine, Petah Tikva;
Background: Antipsychotic treatment is the main contributor in
minimizing the frequency of hospitalizations in schizophrenia
patients. There are several types of pharmacological
treatments, including first and second generation
antipsychotics. Each group consists of both oral medications
25
Locomotor, anxiety, and risk assessment related
phenotyping and striatal transcriptome analysis in four
autism mouse models
Oron O.Elliott E.
1
Bar-Ilan Faculty of medicine;
In recent years, multiple ASD mouse models have been
produced for the purpose of gaining insight into the complex
behavioral and molecular etiology of this phenomenon. Our
aim was to gain high-impact information on behavioral and
molecular phenotypes which are in common in several models,
and therefore more directly involved in autistic behavior. We
performed behavioral and motor-related experimentation on the
following ASD models: Shank3 KO, CNTNAP2 KO,
Chr16p11.2del and BTBR. In addition we performed RNAseq
on the striatum of the models. In the motor-related tests the
BTBR, Caspr2 KO and Chr16p11.2del animals expressed
hyperactivity while Shank3 KO animals expressed hypoactivity
in the OF and rotorod test. We also found that the BTBR
expressed anxiogenic behavior, while the Chr16p11.2del model
expressed anxiolytic behavior. The Caspr2 KO and Shank3 KO
expressed anxiolytic behavior in the DL and EPM and less
risk-assessment and anxiogenic behavior in the OF. The
RNAseq data revealed 31 genes that were commonly
dysregulated in the BTBR, Shank3 KO and Chr16p11.2del
models. Using Gene Ontology analysis, we found that
developmental processes are dysregulated in the Shank3 KO
and Chr16p11.2del models, while in the BTBR the
dysregulated processes were mostly immunologically-related.
All mouse models displayed dysregulations in locomotive
activity, highlighting the importance of motor function in
autistic behavior. In addition all genetic mouse models
displayed a similar behavioral profile in the EPM and DL
mazes, demonstrating a shared behavioral outcome to several
genetic mutations in ASD. The profile suggests anxiolytic
behavior, which may be explained by less risk assessment. The
RNAseq data suggests that there might be a developmentallyrelated molecular basis for the behavioral commonalities
observed in the Shank3 KO and Ch16p11.2del models while in
the BTBR the underlying cause could be immunologicallyrelated, which is an important field in ASD research
We have shown that ITGB3 expression was upregulated after
in vitro chronic treatment in human lymphoblastoid cell lines
with SSRI, while miR-221 and miR-222, which are predicted
to target ITGB3 were down regulated. We recently
demonstrated that a Novel Herbal Treatment (NHT) reduced
depressive-like behaviors in the brain of chronically stressed
mice. The aim of the present study was to evaluate the
behavioral and biological AD effects of NHT in this mouse
model. ICR mice were exposed to postnatal maternal
separation, followed by 4 weeks of unpredictable chronic mild
stress starting at the age of 4 weeks. Subsequently, mice were
treated with NHT or with vehicle for 3 additional weeks.
Depressive and anxiety-like behaviors were evaluated in
Elevated Plus Maze (EPM) and in Open Field Test (OFT). We
analyzed the expression of miR-221/222 and their predicted
target gene ITGB3 in the prefrontal cortex (PFC) using qPCR.
NHT reduced depressive and anxiety-like behaviors in EPM
and OFT. Moreover, ITGB3 expression in the PFC of the NHT
mice was significantly higher compared with the control group.
In addition, we observed a corresponding decrease in the
expression of miR-221/222. Overall, we have shown that
similar to ADs, NHT reduces depressive and anxiety-like
behaviors via miR-221/222 regulation on ITGB3.
A novel herbal treatment reduce anxiety, sickness behavior,
and TNF-alpha plasma responses to LPS in mice
Paley S.1, Rivkin I.2, Franko M.2, Ben-Eliyahu S.1, Doron R.2,3,
1
Department of Psychology, Tel-Aviv University, Ramat-Aviv,
Tel Aviv, Israel; 2School of behavioral science, College of TelAviv Yaffo, Israel; 3Department of education and psychology,
The Open University, Ra’anana, Israel;
Previous studies in our laboratory showed anti-depressive
effect of a Novel Herbal Treatment in animal subjected to
unpredictable stress.The purpose of this study was to examine
potential beneficial effects of the NHT on TNFalpha plasma
levels and sickness behavior in mice subjected to LPS
challenge.Two experiments were conducted employing ICR
mice that were randomly assigned to an NHT treatment group
I.P 30mg/kg/day,a conventional pharmacological treatment
group the selective serotonin reuptake inhibitor SSRI
ecitalopram 15 mg/kg/day,or a vehicle control group saline +
1% DMSO.The injections were performed daily for 3
week.Biological and behavioral indices were observed in
responded to i.p. injections of either LPS 5 μg/mouse or
vehicle. In the first experiment,blood was drawn from
periorbital venous sinus at 5 time points: 0, 2, 4, 6, and 24
hours,and Elisa test was used to measure TNFalpha plasma
levels.The results show that treatment with NHT changed the
pattern of TNFalpha levels compared to the control groups
with increased levels 2 hours after LPS and decreased levels at
6 hours. The second experiment was conducted to test immune
responses manifested through sickness behavior at 5 time
points: 0, 2, 4, 6, and 24 hours.Sickness behavior was
evaluated by measurements of changes in body weight, food
consumption, sucrose 2% solution and water intake at 0, 2 4, 6,
and 24 hours after LPS/vehicle injection.Mice treated with
NHT demonstrated significant increase in sucrose
intake,moderate increase in water intake and body weight
gain.No differences in food consumption were evident. Taken
together these finding indicate that pre treatment with NHT
induce effective coping compared to conventional treatment or
no treatment. Although,NHT animals responded faster to LPS
their clinical signs were reduced and their recovery was
faster.These results indicate positive NHT impact on immune
responses,and the potential clinical use of this treatment in
infectious challenges
A novel herbal treatment reduces depressive and anxietylike behaviors and increases ITGB3 levels in the prefrontal
cortex of stressed mice
Oved K.1,2, Versano Z.3,4, Franko M.3, Rehavi M.4,5, Gurwitz
D.1,6, Shomron N.2,6, Doron R.3,7,8,
1
Department of Human Genetics and Biochemistry, Sackler
Faculty of Medicine, Tel-Aviv University; 2Department of Cell
and Developmental Biology, Sackler Faculty of Medicine, TelAviv University; 3School of Behavioral Sciences, Academic
College of Tel Aviv-Yaffo; 4Department of Physiology and
Pharmacology, Sackler Faculty of Medicine, Tel-Aviv
University; 5The Dr. Miriam and Sheldon G. Adelson Chair in
the Biology of Addictive Diseases Tel-Aviv University; 6Sagol
School of Neuroscience, Tel-Aviv University; 7Department of
Education and Psychology, The Open University of Israel,
Raanana; 8School of Health and Life Sciences, Hadassah
Academic College, Jerusalem;
Selective serotonin reuptake inhibitors (SSRIs) are the first-line
treatment for major depression. However, treatment resistance
occurs in >30% of patients which requires switching to another
antidepressant (AD). The link between inhibition of serotonin
reuptake and remission from depression remains controversial:
in spite of the rapid onset of serotonin reuptake inhibition,
remission from depression takes several weeks, presumably
reflecting synaptogenesis/neurogenesis and neuronal rewiring.
The expression levels of several genes and their controlling
microRNAs (miRs) were implicated in the mode of action of
ADs. miRs are short RNAs that can silence gene expression.
26
NAlysis and RDoC projects
Peled A.
1
Rappaport Faculty of Medicine, Technion, Israel Institute of
Technology, Haifa, Israel;
The NIMH with its RDoC project declares DSM non-relevant
for research; DSM5 is criticized for being biased and nonvalid. Nick Craddock, from Cardiff UK, is quoted, “What is
needed for psychiatry is a game-changer: a truly new approach
to diagnostic classification that better reflects the underlying
functions and dysfunctions of the brain and that, hence, maps
more readily onto the experiences of patients.” “NAlysis” is a
theoretical framework and a strategic plan for discovering
brain-disturbances causing mental disorders and curing them
by targeting NAlysis-related brain network systems. The
theoretical framework is titled NeuroAnalysis and outlines a set
of integrated testable predictions for formulating mental
disorders as brain disturbances. NAlysis assumes that mental
disorders are best understandable at the network “Connecom”
level, and are related to Global Brain disturbances i.e.,
Globalopathies. Thus NAlysis assumes that 1) schizophrenia
spectrum disorders are disturbances to connectome stability
caused by related disturbances to connectivity and hierarchy
imbalances, 2) mood and anxiety disorders are associated with
altered plasticity that reduces brain optimization dynamics and
3) that personality disorders are developmental disturbances of
the Default-Mode, Resting-State neuronal networks of the
brain. NAlysis strategic plan suggests that psychiatrist, team-up
with a brain imaging lab and vice versa. Feel free to use CBP
to generate testable predictions of personalized brain-related
disturbances to each of the patients in the study group. You
will need to include System-Analysts for signal processing in
order to try and validate NeuroAnalytic hypothesis, or any
other NeuroAnalytic-like hypothesis. It is recommended to use
sensor phenomenology extraction to maximize reliability of
CBP entries, Deployed Sensors technologists can be
instrumental toward this end. For more information visit:
http://neuroanalysis.org.il/
depicting touch as more emotional\moving than under placebo.
The results suggest that oxytocin may play a role in AM of
inanimate objects' touch and further supports the social salience
hypothesis of altering perceptual salience of social cues.
Moreover, the results suggest that oxytocin may have a
normalizing effect on AM in autism, and may contribute to
improving their mentalising skills.
Perceived sleep and history of sexual abuse among former
opiate addict’s women with and without methadone
maintenance treatment
Peles E.1,2, Hacohen S.2, Sason A.1, Lamberg S.3, Adelson M.1,
1
Adelson Clinic for Drug Abuse, Treatment & Research. TelAviv Medical Center; 2Sackler Faculty of Medicine Tel-Aviv
University; 32MABAT, Haifa Drug Abuse Treatment Center;
Aims: To study sleep indices and sexual abuse history and its
relation to opiate addiction treatment modalities we compared
women from Methadone Maintenance Treatment (MMT) and
from MABAT a medication-free in-patient rehabilitation
treatment. Methods: Women from Adelson MMT clinic and
MABAT rehabilitation center were compared using Sleep
quality (PSQI), Daily Sleepiness (EPSS score), Depression
(Hamilton), Clinical-OCD (Y-BOCS), dissociation (DES), and
sexual, emotional, physical and neglect abuses questionnaire.
Results: Mean PSQI was highest (poorer sleep) among 38
MMT-sexually abused (10.4±4.2) followed by 24 sexually
abused from MABAT rehabilitation treatment (8.1±4.5), and
lowest among 12 MMT non-abused (6.3±4.8, p=0.03), with no
differences in daily sleepiness (7.2±4.8, 7.9±3.7 and 5.7±4.2
respectively, p=0.4). Sexual abused score was most severe
among MABAT sexual abused (16.3±3.9), followed by MMT
sexual abused (14.1±4.3) and lowest among MMT non-abused
(10.6±3.7, p=0.001). Depression score was higher among the
two sexual abused (MMT and MABAT) groups (15.0±6.3 and
15.2±6.7) than the non-abused (10.5±6.3, p=0.08). Dissociation
was highest among the MABAT sexual abused (25.1±19.2)
followed by the MMT sexual abused (11.8±10.5) and the nonabused (6.0±6.1, p<0.0005). OCD score was 13.8±9.8 among
MABAT, and 12.2±10.7 among the MMT sexual abused, and
lowest among the non-abused (6.5±7.0, p=0.1). PSQI linearly
correlated with depression (Hamilton score R=0.6, p<0.0005),
with OCD (Y-BOCS score R=0.3, p=0.04), with total abuse
score (R=0.29, p=0.03) and as a trend with sexual abused score
(R=0.26, P=0.054). Conclusion: Sleep quality was not related
to methadone treatment. Poor sleep was found to be highly
related to depression, which characterized the women who
severely been abused from both MMT and MABAT. Adequate
intervention for depression may improve sleep quality as well,
and is highly recommended.
Oxytocin induces anthropomorphic traits for inanimate
objects
Peled L.1, Shamay-Tsoory S.1,
1
Department of Psychology, University of Haifa, Haifa;
For symposium:“Understanding the neural basis of social
behavior: from animal models to clinical trials”
Anthropomorphism (AM) is the tendency to ascribe human
characteristics to non-human agents. Converging evidence
suggests that AM is mediated by several neural systems which
are repeatedly involved in the processing of social behavior,
therefore we reasoned that the oxytocinergic system may have
a role in AM. The administration of oxytocin has been shown
to modulate several social cognitive processes in
humans, specifically in the autism spectrum. One of the leading
hypotheses regarding the mechanism underlying the social
effects
of
oxytocin
is
the
'social
salience
hypothesis', suggesting that oxytocin alters the perceptual
salience and/or processing of social cues. In this study we
explored whether intranasal administration of oxytocin
modulates AM traits of inanimate objects. Furthermore,
impairments in mentalising ability, as evident in autism, would
be expected to affect the ability to attribute mental states to
inanimate objects. Thus, we divided our subjects into high and
low autistic traits according to their performance in the autism
quotient (AQ) survey. We presented 54 subjects with photos
depicting two inanimate objects either touching or not touching
and asked participants to rate how emotional\moving are the
photos. The results show that oxytocin had an effect on
emotional ratings only in the photos which depicted touch but
not in the non-touch conditions. Following oxytocin
administration, the high autistic traits group rated photos
Multi-parameters Neuro-markers for psychiatric and
neurologic disorders
Peremen Z.1, 2, Reches A.1, Shani-Hershkovich R.1, Laufer I.1,
Weiss M.1, Or-ly H.1, Mesika D.1, Haor D.1, 3,
1
ElMindA; 2Tel Aviv University; 3Ben Gurion University;
Changes in EEG functional connectivity reflecting the
spatiotemporal dynamics of brain network responses over time
or following treatment are crucial in assessing brain disorders
including psychiatric and neurologic conditions. BrainNetwork-Activation (BNA), is a novel non-invasive image
technology for the visualization and quantification of specific
brain functionalities. The BNA technology allows visualization
in high resolution of the complex interconnections of the
human brain at work, to enable accurate and objective clinical
decision making for significantly improved diagnosis and
treatment of brain disorders and injuries in parallel to the
traditional subjective measure. BNA can quantify the networklevel dynamics implicated in specific healthy or pathological
brain functions and enables to analyze raw EEG data and
27
transform it into a coherent map of network activation. The
novel technology is highly suitable to capture the
spatiotemporal evolution of brain networks since it depicts the
evolving network dynamics in time, location amplitude and
frequency. This multidimensional tool may be used to help
predict treatment effectiveness, monitor treatment response and
evaluate the effectiveness of various therapeutic options. Thus,
BNA may provide recommendations regarding treatment
regimens, help to adjust the treatment protocol (closed loop
treatment) and contribute for follow-up and decide whether
additional treatment is needed. In accordance with the NIMH
Research Domain Criteria (RDoC) framework that encourages
researchers to focus on functioning and quantification, we now
examine the integration of neuromarkers from different
domains to better characterize brain activity. Thus, we are
developing a composite score that enables the assessment of
multiple dimensions of brain activity in parallel. In the
presentation we will cover the usage of different BNA
parameters related to several brain disorders such as mTBI,
ADHD and chronic pain.
for in gambling tasks in order to disentangle risk attitude and
suboptimal decision making. People with ADHD reported
higher engagement in risky behaviors. On the gambling tasks,
people with ADHD did not choose the risky options more often
than controls when expected values of alternative were equal.
However, when expected values differed, they chose the less
favorable alternative, whether or not it was the risky one. These
findings challenge the notion that ADHD is associated with
risk seeking.
The therapeutic impact of Exendin-4 on mice subjected to
blast traumatic brain injury
Rachmany L.1, Rubovitch V.1, Tweedie D.2, Greig N.H.2,
Pick C.G.1
1
Dept. of Anatomy and Anthropology, Sackler Faculty of
Medicine, Tel-Aviv University; 2Drug Design and Development
Section, Laboratory of Neurosciences, Intramural Research
Program, Natio;
Traumatic brain injury (TBI) is a major cause of disability and
death worldwide associated with high morbidity and mortality
yet without specific therapeutic treatment. Blast-TBI (bl-TBI)
is a form of TBI associated with the detonation of improvised
explosive devices in regions of conflict. This type of injury
affects both military personnel and civilians, causing acute and
long-term cognitive, emotional and behavioral disturbances.
We have developed a mouse bl-TBI model that mimics
essential elements of human exposure to detonation to define
the acute and chronic impact of bl-TBI on the brain and aid the
development of clinical treatment strategies. Anesthetized mice
were exposed to a controlled detonation 7m from the blast
source creating intensity of 2.5 PSI. The therapeutic action of
the long-acting GLP-1R agonist, exendin-4 (Ex-4), was
assessed as it has demonstrated consistent neuroprotective
actions in cellular and animal models of neurodegeneration.
Previous research from our lab has shown that Ex-4
administration ameliorates cognitive deficits that were found
after bl-TBI in mice. TBI was previous found to involve
oxidative stress and glutamate toxicities, hence, we tested the
effect of Ex-4 on neuronal cell cultures. Ex-4 significantly
ameliorated H2O2-induced and glutamate toxicities.
Immunofluorescence double-staining with Fluoro Jade B and
anti-NeuN revealed a decrease in the degeneration of neurons
in mice treated with Ex-4 before or after blast exposure
compared to untreated injured mice. Staining with
synaptophysin also revealed more synapses in the brains of Ex4 treated blast mice than blast mice that did not receive the
drug. In synopsis, our mouse bl-TBI model effectively mimics
key elements of human exposure allowing characterization of
cellular pathways that underpin ensuing cognitive deficits and
their treatments such as Ex-4.
What can be learned about human behavioral disorders
from dominant-submissive interactions in mice?
Pinhasov A.
Ariel University, Ariel, Israel
Personality formation and development, education, family life,
as well as career opportunities, all involve social interactions,
characterized by hierarchical relationships in which one
member of a given pair achieves dominant status, while the
other is relegated to submissiveness. Beyond binary
relationships, dominance and submissiveness have been
identified as two opposite poles of the behavioral spectrum,
measurable by priority of access to resources like food, water,
territory or sexual partners. Several studies have examined the
parallels between dominant submissive behavior in animals
and a range of behavioral disorders in humans. Subordinate
animals, similarly to depressed humans, show increased
defensive behavior, weight loss and major alterations in sleep,
eating and sexual behaviors.
The formation of hierarchal relationships between mice
allowed us to develop unique animal populations with strong
and stable features of dominance and submissive. We
developed these populations using selective breeding based
upon the Dominant-Submissive Relationships (DSR) food
competition test. By employing further behavioral,
pharmacological, we characterized and established the
construct and face validity of this model. Particularly, we
found that dominant and submissive mice react differentially to
stressogenic triggers and to pharmacological agents.
Furthermore, Sub mice display innate anhedonia, as well as
heightened activation of the HPA axis, after exposure to
chronic mild stress that did not affect their Dominant
counterparts. Thus, our accumulating evidences suggest that
animals possessing strong dominant and submissive
phenotypes represent a valuable tool for studying human
behavioral abnormalities.
Methylphenidate administration before trauma exposure
attenuates anxious reactions to a reminder one month later
Ritov G.1,3, Boltyansky B.1,3, Richter-Levin G.1,2,3,
1
Neurobiology and Etiology Department, University of Haifa,
Israel; 2Psychology Department, University of Haifa,
Israel; 3The Institute for the Study of Affective Neuroscience
(ISAN) ;
Background: Long-term reactions to trauma are quite diverse.
Some people exposed to an extreme traumatic event exhibit
only time-limited distress, yet others, exposed to the same
event, might continue to intrusively re-experience it and
qualify for a diagnosis of posttraumatic stress disorder (PTSD).
One theoretical explanation for this diversity suggests that
dissociative states during the traumatic experience
fundamentally affect the phathogenesis of PTSD. According to
this, dissociative states at the time of trauma distort the
perception and encoding of the event and generate fragmented
representations of the experience. In the long-term, these
Risk taking and risk attitude in people with ADHD
Pollak Y.1, Oz A.2, Nave O.2, Raber H.2, Tal N.2, Shoham R.2,
1
School of Education, The Hebrew University of
Jerusalem; 2Dept. of Psychology, The Hebrew University of
Jerusalem;
The present research aims to examine whether individuals with
ADHD tend to show risky behavior and whether differences in
risk attitude underlie this tendency. In a series of studies,
adolescent and adults, with and without ADHD, completed a
self-rating scales probing risk behavior, and performed
different gambling tasks, in which they had to choose between
safe and risky options. Notably, expected value was controlled
28
1
fragmented
memories
incite
irrepressible
traumatic
recollections and perpetuate the intrusive re-experiencing
symptoms in PTSD (David Spiegel, 1997). Methylphenidate
(MPH) is a psychostimulant which is frequently prescribed to
reduce attention distortions. Its administration may thus reduce
encoding distortions and memory fragmentation, and by this
reduce trauma-related pathology. In order to examine the above
hypothesis in rodents we administered MPH before or after
trauma exposure, and evaluated the impact of distress
symptoms one month later. Results: Oral administration of
low-dose Methylphenidate (MPH; 0.5mg/kg) 1hr prior to
underwater trauma exposure attenuated anxious-like reactions
to a contextual reminder a month later. In contrast to that,
administration of MPH 1hr after exposure to trauma
exacerbated anxious-like reactions to the reminder.
Conclusions: The results reinforce the hypothesized
involvement of traumatic memory fragmentation in
perpetuating long-term anxious reactions. Conducted one
month after trauma exposure, this study demonstrates the
possible therapeutic benefits of pre-trauma administration of
low-dose Methylphenidate for long term pathologies such as
PTSD. This work was supported by A DOD award number
W81XWH-11-2-0111 to GRL.
The Matta and Harry Freund Neuropsychiatric Tourette
Clinic, Schneider Children’s MC of; 2New School of
Psychology, Interdisciplinary Center, Hertzlia, Israel;
Tourette Syndrome [TS] and its common comorbidities can be
a major impediment to normal childhood development.
Previous research demonstrated that TS is associated with
significantly compromised quality of life, in part due to the
decrease in ability to deal with stress. However, the
mechanisms through which these pathological developments
occur have so far remained unidentified. Our work focuses on
the parents’ substantial influence on their child’s childhood
onset chronic syndrome. We identify two interrelated areas that
have not been addressed yet regarding TS: the characteristics
of parent-child relationship and the significance of selfrepresentation and emotion-regulation abilities. In the study of
these areas we employ insights from Attachment Theory,
which proved a useful framework for understanding parentchild relationships under conditions of stress in other life
settings. By assessing certain psychological characteristics of
the parents as well as the child, we illustrate the relations
between parental attachment styles, care giving, experience of
parental functioning, emotion-regulation abilities, the ability to
confront the Syndrome and the child’s psychological
functioning. Our findings—which show significant correlations
between parental attachment style, the parents’ experience of
the child and the child’s self-esteem — pave the way for
designing new clinical interventions for the parents as well as
the child with TS. We will discuss the potential of these
interventions for handling common comorbidities, promoting
benefits from existing “tic target” treatments and securing the
healthy mental development of the child with TS.
The Myth of medical models of psychopathology
Rofe J.1,
1
Bar Ilan University;
This abstract is based on a book, entitled Insanity & Madness:
Indefensible Defense, which I have almost completed, attached
herewith. The book demonstrates the inadequacy of traditional
theories of psychopathology and suggests an alternative theory,
The Rational-Choice Theory of Madness (RCTM), which is a
revised version of the rational theory of The Rational-Choice
Theory of Neurosis (see Rofé, 2010; Rofé & Rofé, 2013). The
book shows that RCTM is the only theory that can integrate the
relevant research and clinical data concerning the development
and treatment of neurosis and schizophrenia into one coherent
system. The aim of this abstract is to relate to several data that
expose the inadequacy of medical models to explain and treat
psychological disorders, including schizophrenia. For example,
these models would have difficulty to explain 1) The strike
differences in the positive symptoms of schizophrenic patients.
How can brain impairments cause schizophrenic patients, such
as Prof. Kaczynski (the Unabomber), to become a serial killer
(Graysmith, 1996), Prof. Joan Nash to develop non-violent but
meaningful delusions (e.g., describing himself as the left foot
of God or Emperor Antarctica; see Naser, 1998), and Jennifer
Plowman (see Schwartz, 2000) to develop disorganized speech.
2) Why sometimes psychological interventions, such as
psychoanalysis (Karon, 2008) or CBT (Bradshaw (1998)
succeed to cause full recovery of schizophrenia after failure
intervention of medical treatment. 3) How is it that prolonged
treatments with antipsychotics can cause serious psychological
and bodily damage, including sexual dysfunction, decrease in
cognitive functioning, metabolic syndrome (e.g., comprising
obesity, dyslipidemias, glucose intolerance, insulin resistance),
sudden cardiac attack, progressive brain tissue volume
reductions and a risk for Alzheimer's disease (for references
see the attached Rofé's book, pp. 250-251). RCTM already
proved its ability to
The loss of chromatin organizer protein CTCF in the
hippocampus leads to impaired memory and dysregulation
of memory genes
Sams D.1, Nardone S.1, Getselter D.1, Raz D.2, Tal M.2,
Hakim O.2, Elliott E.1,
1
Bar Ilan University Faculty of Medicine; 2Bar Ilan University
Department of Life Sciences;
CTCF is a DNA-binding protein that is primarily responsible
for three dimensional chromatin structure. Recently, genetic
studies have discovered de novo mutations in CTCF in humans
with intellectual disabilities. However, the role of CTCF and
CTCF-mediated chromatin organization in the brain is
unknown. Our aims were to determine the role of CTCF in
mammalian behavior and the molecular mechanisms through
which CTCF mediates behavioral changes. To determine the
role of neuronal CTCF in behavior, we developed a conditional
CTCF knockout (cKO) mouse model, which lacks CTCF
specifically in forebrain neurons. In addition, we used an
adenoviral system to deplete CTCF specifically in the
hippocampus, a brain area that is crucial for learning.
Behavioral analysis determined the effect of CTCF depletion
on learning and memory, histological analysis determined
effects on synapse formation, real time PCR analysis
determined effects on gene expression, and 4C chromatin
capture determined the role of CTCF in 3-dimensional
structure in neurons. CTCF cKO animals display a dysfunction
in learning and memory function, as detected in multiple
behavioral tests. Specific lentiviral ablation of CTCF in the
hippocampus also induced deficits in learning and memory.
CTCF cKO animals displayed deficits in synaptic density
specifically in the CA1 region of the hippocampus. In
molecular studies, CTCF cKO animals display differential
expression of the learning genes BDNF, Reelin, and PP1C after
a learning paradigm. Current studies are aimed at
understanding how CTCF regulates the 3D-genome structure
of these genes. We have mapped the long-range structure of the
promoters of these genes, and are comparing the chromatin
Parenthood and Tourette Syndrome: The Interface
between Attachment, Stress, Emotion Regulation and the
Child’s Experience of Self – Designing a Protocol for
Working with Parents
Ruhrman D.1, Ben aroya-Milshtein N.1, Mikulincer M.2,
Steinberg T.1, Apter A.1,
29
patterns between WT and KO mice. Our results indicate that
CTCF plays a primary role in learning and memory processes
in the hippocampus of the mammalian brain, and that
regulation of synapse structure and specific gene expression
may be a mechanism for this effect.
MSC treatment resulted in increased BDNF levels in the
hippocampus (35.9% increase, P<0.05). MSC treatment also
induced an increase in hippocampal neurogenesis as indicated
by 34.1% increase in Ki67-positive cells (P<0.001) and 18. 7%
increase in doublecortin-positive cells (P<0.001). Conclusions:
Intracerebroventricular MSC transplantation improves core
autisitic behaviors in a mouse model of ASD. We suggest that
increased BDNF levels accompanied by enhanced
neurogenesis in the MSC treated group, might underpin the
behavioral improvement. Our study presents a novel
therapeutic approach which may be translatable to ASD
patients.
Identifying Potential Genes Involved in the
Pathophysiology of Childhood Onset Schizophrenia (COS)
Schechter Tanya 1, Ben Dreiman1, Sagiv Shifman2 and Yoav
Kohn1,3
1
Jerusalem Mental Health Center, Eitanim Psychiatric
Hospital; 2 Genetics Department, Hebrew University,
Jerusalem; 3 Hebrew University-Hadassah School of Medicine,
Jerusalem
Introduction: Childhood Onset Schizophrenia (COS) is a
severe form of the disorder that is characterized by presentation
before the age of 12. It is far more chronic in nature than Adult
Onset Schizophrenia (AOS), development and functioning are
more severely impaired and it is less responsive to treatment.
The prevalence rate is 2:100,000. It has been shown that COS
has a much stronger genetic loading than AOS. Only a few
groups world-wide have studied the illness. Genetic studies
found mainly that AOS genes were also associated with COS.
The current study seeks to identify novel genes that are
involved in the etiology of COS in Israeli patients. The goal of
the present study is to recruit as large of a sample as possible of
individuals affected with COS. This will serve the current
genetic study as well as setting a foundation for future basic
and clinical research on the disorder. Methods: Subjects with
COS were identified in psychiatric inpatient and outpatient
units across Israel. Participants were interviewed with a
structured tool and provided demographic and clinical data as
well as DNA samples. Whole Exome Sequencing was
performed for a number of the subjects affected with COS and
their unaffected parents in order to identify de-novo genetic
mutations. Results: Preliminary clinical and genetic results
will be presented. Discussion: Identifying COS genes and
clarifying their role will provide a basis for understanding the
pathophysiological mechanisms of COS and will improve
diagnosis and treatment.
Comparative blood microRNA expression profiling in
PTSD
Shalev A.1, Benarroch F.1, GOLTSER DUBNER T.1, 2,
CANETTI L.1,2 , Segman R.2, GALILI-WEISSTUB E.1
,1The Herman-Danna Division of Pediatric Psychiatry,
Department of Psychiatry, Hadassah - Hebrew Univ; 2,
2Molecular Psychiatry Lab. - Dept. of Psychiatry, Hadassah Hebrew Univ. Med. center, Jerusalem;
Background: Childhood trauma exposure has been suggested
to result in epigenetic reprogramming with a persisting
systemic pro inflammatory state, and an increased propensity
to develop Posttraumatic Stress Disorder (PTSD) upon adult
trauma exposure. Exposure to trauma and the development of
PTSD may result in epigenetic changes in mononuclear cells
that reset the immune inflammatory response, and may be used
as diagnostic and prognostic markers.
Aim: Toidentify long term expression changes in epigenetic
markers among mononuclear cells and their relationship to the
development of PTSD in victims of terrorism. Methods: From
a large database of children and adolescents who came to the
Emergency Department after a terrorist attacks over the
previous decade, we thus far ascertained 43 subjects comparing
those who developed chronic PTSD and those who remained
resilient and did not develop the disorder despite a comparable
life-threatening trauma exposure. The
groups will be phenotyped to compare levels of microRNA in
mononuclear cells isolated from peripheral blood in order to
characterize alterations in the epigenetic regulation of the
immune system and assess the impact of intermediate variables
such as early adverse childhood experiences and early parental
attachment styles.
Preliminary Results: So far, 43 participants have been
ascertained and grouped into those with current\past and
full\partial PTSD, and resilient trauma exposed control
subjects. Recruitment is ongoing to allow performing
molecular assays on an extended sample.
Study Relevance: Identifying differences in the epigenetic
expression in white blood cells may enable the usage of
diagnostic /prognostic biomarkers and potentially elucidate
mechanistic involvement of the immune system in PTSD.
Mesenchymal Stem Cell Transplantation Promotes
Neurogenesis and Ameliorates Autism Related Behaviors in
BTBR Mice
Segal H.1, Karvat G.2, Barak N.2, Barzilay R.1, Ganz J.1, Edry
L.2, Aharony I.1, Offen D.2,
1
Felsenstein Medical Research Center, Sackler Faculty of
Medicine, Tel-Aviv University; 2Department of Neurobiology,
Weizmann Institute of Science;
Background: Autism spectrum disorders (ASD) are
neurodevelopmental disorders characterized by social
communication deficits, repetitive stereotyped behaviors and
cognitive rigidity. Mesenchymal stem cells (MSC) are known
for their regenerative effect in brain disorders. In the current
study, we evaluated the beneficial effect of MSC
transplantation on behavioral and biochemical endophenotypes
manifested by the BTBR mouse model of ASD. Methods: 6-8
weeks old BTBR mice were transplanted with human MSC
into the lateral ventricles (n=14) and compared to shamoperated littermates (n=13) in a set of autism-related behavioral
tests. Tissue analysis included evaluation of BDNF protein
levels and hippocampal neurogenesis. Results: MSC
transplantation resulted in reduced stereotypical behaviors
manifested by 46% decrease in digging duration (P<0.01) and
60% decrease in self-grooming duration (P<0.05). In addition,
MSC treatment induced an improvement in social behavior and
a decrease in cognitive rigidity observed in improved
performance in the 3-chamber social test (P<0.01) and the wet
T-maze (P<0.001), respectively. ELISA analysis revealed that
Decoding social behavior in mice – an ethological approach
Shemesh Y.1, 2, Forkosh O.1, Anpilov S.1,2, Chen A.1,2,
1
Department of Neurobiology, Weizmann Institute of Science,
Rehovot, Israel; 2Department of Stress Neurobiology and
Neurogenetics, Max Planck Institute of Psychiatry, Munich,
Ger;
Disturbed social behaviors are at the core of complex
psychiatric disorders such as autism and schizophrenia. Such
multicomponent illnesses are affected by complex genetic
networks as well as by the environment. Much like the variety
of factors that affect susceptibility to these disorders the social
phenotypes are diverse and they differ between disorders as
well as between patients suffering from the same disorder. The
wealth of genetic tools available for mice makes them ideal
animal models for studying the molecular and neuronal
31
mechanisms that underlie social behaviors. However, many
social tests focus on the interaction of no more than two
animals, often under artificial conditions. While the use of a
highly controlled environment can help minimizing the
variability in an experiment, it lacks an appropriate ethological
context. We present a system for tracking a group of mice in a
semi-natural, ethologically relevant context, which allows us to
quantify their social behavior and infer the social structure of
the group. We also show how advanced methods such as
optogenetics can be incorporated into group behavior
experiments. Finally we discuss the challenges of upgrading
the group tracking prototype into a multi-arena system with
automated and efficient data analysis.
Evaluating the side effects of fast onset treatment for
depression and anxiety compared to SSRI
Simon N.1, Gdalia H.1, Doron R.1,2,
1
School of Behavioral Science, the Academic College of TelAviv Yaffo, Israel; 2Department of Education and Psychology,
The Open University, Ra'anana, Israel;
Current anxiolytic and antidepressant treatments such as SSRIs
display a delayed onset of therapeutic action and are commonly
accompanied by side effects. A recent study in our laboratory
found that treatment with a Japanese herb (JH) alone or in
conjunction with other forms of treatment proved to be
therapeutically efficient after a 7 day treatment period. The aim
of this study was to assess the side effects generated by JH
after a 1 week treatment period, namely sexual dysfunction and
weight gain. Treatments were compared in no' of mounts on
females, latency till first mounting, 2 independent blind judges
evaluation of sexual behavior, and weight. The study
comprised of 3 stage. In the first stage, ICR male mice
commenced Unpredictable Chronic Mild Stress (UCMS)
paradigm for 4 weeks. In the second, mice were treated for 1
week. Mice were randomly divided into 7 groups of treatment
(n=15): [1] Vehicle [2] escitalopram [3] herbal mixture (NHT)
[4] Only JH [5] One constituent herb from NHT with JH [6]
NHT with JH [7] escitalopram with JH. In the third stage mice
were weighed and behaviorally assed for sexual dysfunction.
Mice were placed in a cage with 2 females for a duration of 30
min'. Variables recorded were total no' of mounting attempts,
time in minutes before first mount attempt (latency) and judges
grades for overall impression of sexual behavior. All
treatments including JH showed significantly higher mounting
attempts and significantly higher averaged judges scores
compared to control. Only the group treated with JH in
conjunction with SSRI showed significantly shorter latency
compared to control. No significant difference could be found
in weight changes between groups, suggesting that neither
form of treatment induces weight gain within 1 week of
treatment. These findings show JH to be a promising direction
for future research and treatment, both alone in its own right
and as an augmentative supplement.
Regulation of gene expression during psychiatric diseases
Shomron N.
1
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;
Genome-wide pharmacogenomic studies for developing
targeted therapies offer the advantage of hypothesis-free search
for tentative drug response biomarkers eventually leading to
personalized medicine treatments. However, they require large
patient cohorts and are therefore laborious and quite costly.
Here we present our experience with an alternative approach,
based on genome-wide transcriptome profiling of olfactory
epithelium (OE) or a panel of human lymphoblastoid cell lines
(LCLs). The expression of biomarker genes and microRNAs
were measured in OE or LCLs. We applied the OE expression
on schizophrenia patients and the LCLs on SSRI
antidepressants, seeking biomarkers or drug response
biomarkers, respectively. Our studies demonstrate that
surrogate cells such as OE and LCLs are a powerful and costeffective tool for searching for future biomarkers for
personalized medicine in psychiatry.
Cannabinoids prevent the effects of exposure to trauma
and trauma reminders on extinction and plasticity
Shoshan N.1, Segev A.1, Abush H.1, Akirav I.1,
1
Department of Psychology, University of Haifa;
The formation of a fear memory following a traumatic event is
an important mechanism for the subsequent development of
anxiety disorders, such as PTSD. The consequences of
exposure to trauma are affected not only by aspects of the
event itself, but also by the frequency and severity of trauma
reminders. There is a growing body of data pointing to a
therapeutic potential of cannabinoids for the treatment of
PTSD. Here we aimed to test the long term effects of a single
traumatic event followed by contextual reminders on avoidance
and extinction of the traumatic event as well as on hippocampal
plasticity. We also tested whether cannabinoid agonists prevent
the effects of these stress-induced alterations via CB1 receptors
(CB1r) and glucocorticoid receptors (GRs) in the brain's fear
circuit. Rats were exposed to a single foot shock followed by
exposure to three contextual 1-minute reminders of the shock
on days 7, 14, and 21 after the trauma. The CB1/2 agonist
WIN55,212-2, the FAAH inhibitor URB597 or vehicle were
injected IP following trauma exposure on day 1. One month
after the initial trauma, exposure to reminders exacerbated the
effects of the trauma and rats demonstrated persistent
avoidance from the context of the trauma, impaired extinction,
as well as impaired LTP and up regulation of CB1r and GRs in
the hippocampus. The cannabinoid enhancers administered
following the traumatic event prevented the effects of the
trauma and reminders on avoidance, extinction, plasticity and
the protein expression of CB1r and GRs in the CA1. These
results demonstrate that acute enhancement of cannabinoid
signaling following a traumatic event is effective in preventing
the detrimental effects of trauma and reminders and that these
effects are mediated by hippocampal CB1r and GRs.
High prevalence of vitamin D deficiency and insufficiency
in adolescent inpatients diagnosed with eating disorders
Stein D.1,2, Levy-Shraga Y.2,3, Pinhas-Hamiel O.2,3, Kochavi
B.1, Enoch-Levy A.1, Vered I.4, Modan-Moses D.2,3,
1
Pediatric Psychosomatic Department, Sheba Medical Center,
Tel Hashomer, Israel ; 22Sackler Faculty of Medicine, Tel-Aviv
University, Tel-Aviv, Israel; 3Pediatric Endcrinology Unit,
Sheba Medical Center, Tel Hashomer, Israel; 4Institute of
Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel.;
Background and Objective: Previous studies assessing vitamin
D status in adolescents with eating disorders showed
inconsistent results. The aim of the current study was to assess
vitamin D status in adolescent inpatients with eating disorders
(EDs) and its relation to bone mineral density (BMD) and
depression. Method: 25-hydroxyvitamin D (25OHD), calcium,
phosphorus, and alkaline phosphatase levels as well as BMD
and depression were assessed on admission in 87 inpatients
with eating disorders [anorexia nervosa (AN)=64; bulimia
nervosa (BN)=5; eating disorders not otherwise specifiedbinge/purge type (EDNOS-B/P)=18]. Results: Mean 25OHD
levels were 24.1±7.5ng/ml (25.0±7.6, 25.4±9.9 and 22.0±9.9
ng/ml in AB, BN and EDNOS-B/P patients, respectively).
Vitamin D deficiency (32ng/ml, considered optimal by some
experts. No associations were found between 25OHD levels
and BMD or comorbid depression. 25OHD levels during
winter were significantly lower than summer levels (p<0.001).
Mean lumbar spine BMD z-score in patients with AN and
EDNOD-B/P type was low (-1.5±1.1) and correlated with
BMI-SDS (p=0.03). Discussion: Adolescents with EDs show a
31
high prevalence of vitamin D deficiency and insufficiency.
Given the risk for osteoporosis in this population, 25OHD
levels found in this group may not offer optimal bone
protection.
least partially, to NMDA receptor mediated glutamate
neurotransmission dysfunction in the brain and that AMN may
be a potential augmentation therapy for refractory OCD.
Maternal diet-induced obesity (DIO) in rats leads to
alterations in the regulation of melanocortin 4 receptor
(Mc4r) of the offspring
Tabachnik T.1,2, Marco A.1,2, Kisliouk T.4, Meiri N.4,
Weller A.3,
1
Faculty of Life Sciences; 2Gonda Brain Res Center;
3
Department of Psychology, Bar Ilan University, Ramat-Gan,
Israel 52900; 4Department of Psychology, Bar Ilan University;
5
Institute of Animal Science, ARO, The Volcani Center, Bet
Dagan;
Maternal obesity constitutes a serious health risk factor, both
for the mother and the offspring. The regulation of energy
balance is maintained by neuropeptides expressed by neurons
within nuclei located in the mediobasal hypothalamus. One of
the major anorexigenic neuropeptides, a-melanocytestimulating hormone (a-Msh), the post-transcriptional cleavage
product of proopiomelanocortin (Pomc), is expressed in the
hypothalamic arcuate nucleus (ARH). a-Msh is axonally
transported to the paraventricular nucleus (PVH), there it binds
to melanocortin 4 receptor (Mc4r), and mediating reduction of
food intake and body weight. One of the mechanisms that were
suggested to control Mc4r expression is binding of thyroid
hormone receptor Beta (TRβ) to the Mc4r promoter. TRβ is a
type of nuclear receptor that is activated by thyroid hormone
3,5,3’-tri-iodothyronine (T3). TRβ recognizes specific thyroid
response elements (TRE) in the promoter of genes and
activates or represses transcription in response to T3. We
examined the acquired alterations in hypothalamic genes
expression of offspring to DIO dams. We fed female Wistar
rats from weaning through pregnancy and lactation with either
high fat diet or chow. Pups were sacrificed at postnatal day 21
(PND21). Results: Offspring to DIO dams presented higher
body weight and plasma leptin levels compared with control
offspring. Despite the changes in leptin levels, offspring to
DIO dams ARH Pomc mRNA levels were not altered, while
their PVH Mc4r mRNA levels were lower compared to the
control offspring. The Mc4r promoter was found to be
hypomethylated, with no relation to maternal nutrition status.
Offspring to DIO dams presented higher binding levels of TRβ
to thyroid hormone response element (TRE) to Mc4r
umethylated promoter, compared to control offspring, though
they presented the same levels of TRβ mRNA in the PVH as
controls. Conclusions: These results suggest that TRβ is one of
the factors regulating Mc4r mRNA levels in the PVH
Tourette's syndrome: a developmental perspective.
Steinberg Tamar
Schneider Children’s Medical Center of Israel
Tourette's syndrome is a childhood onset neuropsychiatric
disorder that is characterized by the onset of both motor and
vocal tics before the age of 18 years. The course of the disorder
is characterized with changing symptoms as it follows the
child's development. TS is typically diagnosed around the age
of 6 years and tics reach their worst ever severity between the
ages of 10-12 years. Approximately two thirds of children
with TS will experience a substantial decrease or remission of
tics during adolescence. Identifying clinical measures that can
predict whose tic symptoms will persist into adulthood is an
area of great concern. Comorbidities such as ADHD are found
in at least one-half of clinically referred children and
adolescents with TS. The nature of the association between TS
and ADHD is still a matter of debate, but it is clear that
youngsters with TS plus comorbid ADHD usually have more
adaptive difficulties than those with tics alone. About 50% of
patients with TS also have symptoms of obsessive compulsive
disorder (OCD) TS-related compulsions are often driven by the
need to get some appearance or physical sensation 'just right'.
Sensory integration mechanisms are probably involved in the
pathophysiology of TS, we have found in a recent study that
Sensory modulation disorder SMD is more prevalent in TS
patients than in the general population. Children who suffer
from both TS and SMD have more comorbid disorders.
Amantadine Augmentation Therapy for Obsessive
Compulsive Patients Resistant to SSRIs
Stryjer R.1, Budnik D.1, Ebert T.1, Gizunterman A.1,
1
Beer Yaakov- Ness Ziona Mental Health Center; 2Sackler
School of Medicine, Tel Aviv University;
Background: Amantadine (AMN) is a dopaminergic agonist
used in the treatment of several neurological conditions.
Several studies have hypothesized that in obsessive compulsive
disorder (OCD), the glutamatergic neurons in the prefrontal
cortex are hyperactive, and have identified a glutamatergic
dysfunction in the cortico-striato-pallido-thalamo-cortical
circuits that may play a role in the development of OCD.
AMN, is a weak noncompetitive antagonist of the N-methyl-Daspartic acid (NMDA) receptor that was reported in a case
report to improve symptoms of OCD in a patient refractory to
pharmacotherapy. Methods: For study inclusion, patients were
required to meet the DSM-IV-TR criteria for OCD and, to
score above 20 points on Yale Brown Obsessive Compulsive
Scale (Y-BOCS), to be unresponsive to at least one SSRI at
anti-obsessive dose for at least 12 weeks. The study was an
open label trial of 6 weeks duration in which AMN was added
to the current SSRI regimen to which the patients were
unresponsive. Outcome measures were performed at baseline
and at the completion of the study and included the Y-BOCS.
Statistical analysis was performed using two-tailed paired t-test
comparing baseline and endpoint outcome measures. Results:
Eight patients completed the entire 6 weeks trial and were
included in the final statistical analysis. Significant reductions
were observed following 6 weeks of AMN trial in total
Y-BOCS,Y-BOCS compulsion and obsession subscales.
Conclusions: We suggest that AMN may be beneficial as
augmentation therapy in OCD patients unresponsive to SSRI
therapy. In this study we found a significant reduction in both
compulsion and obsession subscales of Y-BOCS following 6
weeks of AMN augmentation to SSRI. Therefore, our findings
support the hypothesis that OCD symptoms may be related, at
ErbB signaling inhibition ameliorate behavioral deficit
induced by phencyclidine (PCP) in mice
Tadmor H.1,2, Golani I.3, Kremer I.1,4, Shamir A.1,4,
1
Psychobiology Research Laboratory, Mazra Mental Health
Center, Akko, Israel; 2Faculty of Medicine in the Galilee, BarIlan University, Zefat, Israel; 3Department of Biotechnology,
ORT Braude College, Karmiel, Israel; 4The Ruth and Bruce
Rappaport Faculty of Medicine, Technion - Israel Institute of
Technology, Haifa;
The ErbB signaling pathway has been genetically and
functionally implicated in schizophrenia. Numerous findings
support the dysregulation of NRG and EGF signaling pathway
in schizophrenia. Higher NRG1, ErbB1 and ErbB4 expression
levels were reported in postmortem dorsolateral prefrontal
cortex of schizophrenia patients. In addition, perinatal
administration of EGF or NRG to neonatal mice, or
overexpressing the NRG1 type I isoform resulted in
schizophrenia-like behavior as abnormal social behavior,
spatial working memory and sensorimotor gating. Taken
together, these data support the idea that hyper-activation of the
32
ErbB signaling which probably triggers changes in the
dopaminergic system may underlies the role of the pathway in
the etiology of schizophrenia, and suggesting that inhibition of
the pathway might serve as a novel drug development for
schizophrenia. Herein, we studied, in mice, the capability of
blocking the ErbB signaling, in comparison with the atypical
antipsychotic drug clozapine, to counter schizophrenia-like
behavior induced by administration of the psychostimulant
PCP. We demonstrated that administration of 5mg/kg of the
pan-ErbB inhibitor JNJ28871063 (JNJ), but not 10 mg/kg,
significantly reduced the mice hyperactivity that was induced
by an acute injection of PCP as measured in the open field.
Moreover, the ability of 5mg/kg JNJ to attenuate the effect of
PCP found to be as effective as 2 mg/kg clozapine. In addition,
we showed that, like clozapine, both 5 mg/kg and 10 mg/kg
JNJ ameliorated the social deficit induced by sub-chronic
administration of PCP. Our preliminary data suggest that
treatment with JNJ attenuate abnormal behaviors induced by
PCP, and has similar effects as the antipsychotic drug
clozapine. Thus, the ErbB signaling pathway can be a novel
candidate and a new starting point for drug development for
schizophrenia.
Epigenetic yardstick for cognitively and emotionally
healthy aging
Vered R.1, 2, Atzmon G.3, 4, Richter Levin G.1, 2, 5, Kéri S.6, 7, 8,
Levy-Gigi E.2, 6,
1
1Psychology Department, University of Haifa, Israel; 22The
institute for the study of Affective Neuroscience, University of
Haifa, Israel; 3Human -biology Department, University of
Haifa, Israel; 4Medicine and Genetics Department, Albert
Einstein College of Medicine, New York, USA; 5Neurobiology
and Etiology Department, University of Haifa, Israel; 6Nyírő
Gyula Hospital, National Institute of Psychiatry and
Addictions, Budapest, Hungary.; 7Department of Physiology,
Faculty of Medicine, University of Szeged, Hungary;
8
Department of Cognitive Science, Budapest University of
Technology and Economics, Budapest,Hungary;
The aging process has been linked to the increase of risk for
cognitive and emotional decline. A genetic and epigenetic
signature for this inclined risk has been documented previously
in handful reports. However, the ability to predict gene
expression and brain function has not been fully explored. In a
pilot study aimed to test possible cognitive mechanisms that
may underlie the elevated depressive symptoms in older adults,
141 individuals (ages 32-85), with no evidence of general
cognitive impairments were tested on a novel reversal
paradigm and underwent clinical interviews to assess levels of
depressive and anxiety symptoms. We found that oldest- older
adults have a selective impairment in reversal learning from
negative to positive. This impairment positively correlated with
levels of depressive symptoms. The results suggest possible
cognitive mechanisms that link between impaired ability to
reverse negative outcomes and elevated depressive symptoms
in older age. While our pilot study demonstrated the ability to
perform the psychological side on this project we will combine
our epigenetic skills to design the epigenetics yard stick. We
will focus on epigenetic modifications involving cytosine
methylation, which have been associated with cognitive
decline. And utilize state-of-the-art technology (i.e. HELPtag)
to obtain significant information on epigenomic changes in
methylation with aging. These data will be analyzed by
assessing the occurrence of age-related cognitive and
emotional decline and its interaction with either supportive or
adverse environments (i.e. epigenetic influence). Our aims are
1) Cross sectional examination of epigenetic methylation
changes across age and their impact on cognition and emotion;
2) Longitudinal examination of epigenomic changes coupled
with cognitive and emotional decline or protective adaptations;
3) Establishing an Epigenetic-Cognitive (EPI-COG) yardstick
for evaluation of cognitive and emotional health of the elderly.
Attitudes regarding herbal treatment for depression and
anxiety
Toledano R.1, Sagiv-Schifter T.1, Doron R.1,2,
1
School Of Behavioral Science the Academic College, Tel Aviv
Yaffo; 2Dep. Of Education and Psychology, the Open
University.;
Depression and anxiety disorders are major public health
concerns worldwide, which are known to cause considerable
emotional and physical suffering along with social as well as
economic
consequences.
While
the
conventional
pharmacotherapies SSRIs are the front-line approach, they are
characterized by a low success rate and are associated with a
wide variety of side effects. In recent years, there has been a
significant increase in the efforts invested by researchers to
develop herbal medicines for anxiety and depression. However,
little attention has been given to the attitudes towards these
herbal medicines. The present study sought to examine the
attitudes and beliefs of health care consumers regarding herbal
medicines compared to conventional drugs for depression and
anxiety. Data was collected using a self-administered
structured questionnaire designed for the purpose of this study.
A total of 54 participants completed the questionnaire that was
published on a mental health forums and social networks.
Preliminary findings indicate that the majority of respondents
expressed preference for the use of herbal medicines over
conventional medications, if it was to offer similar therapeutic
effect. The findings of this study also provide information
about the relationship between mental health condition and
attitudes regarding psychiatric drugs. It seems that healthy
people in comparison to people diagnosed with anxiety and
depression are more influenced by the positive label of herbal
medicines namely, that it's perceived as safer and holds less
side effects in comparison to conventional drugs, but also are
more affected by the negative label of herbal medicines
specifically for not being supported by scientific research. In
contrast, it appears that patients who suffer from depression
and anxiety are less affected by these characteristics, and are
simply seeking a solution to their distress, with main interest
that the drug–whether conventional or herbal–will work
Cannabis, emotional disorders, psychosis and the brain
Weinstein A.1,
1
University of Ariel;
Cannabis is the most popular illicit drug in the Western world.
Many people use it for recreational purpose especially at young
age. Despite its growing popularity, there is an increasing
number of users who report adverse effects of the drug
including anxiety, depression, panic attacks and psychotic
experiences. Many cannabis users especially the young ones,
use it to alleviate the emotions of anxiety and depression.
However, anxiety and depression are often exacerbated when
regular users try to stop using the drug. This often results in the
cannabis withdrawal syndrome. There are currently no
effective medications for treatment of the cannabis withdrawal
syndrome. Furthermore, some cannabis users report psychotic
experiences especially when they started using before the age
of 15 and there is evidence for genetic vulnerability to
cannabis-induced psychosis. In this talk, the pharmacological
and brain mechanisms that may be responsible for the
33
interaction between cannabis, anxiety,
psychosis will be described and discussed.
depression
and
manic) can effectively prevent the emergence of a wide range
of neuropathological changes and domains of psychopathology
seen after different early insults in the absence of intervention.
We will also show that the period of effective early
intervention is time-restricted. Collectively, these data
reinforce the concept that adult-onset disorders are preceded by
a period of developmental plasticity that can be harnessed for
halting brain pathology and the emergence of “symptoms”.
Intracranial pancreatic islet transplantation attenuates
behavioral dysfunction, and promote brain insulin and
growth factors reserve in rats exposed to
hypoglutamatergic insult (MK801).
Weizman A.1, Gil-Ad I.1, Vardi P.2, Tarasenko I.1,
Vanichkin A.3, Taler M.1, Bloch K.2,
1
Laboratory of Biological Psychiatry; 2Laboratory of Diabetes
and Obesity Research; 3Laboratory of Transplantation
Felsenstein Medical Research Center, Sackler School of
Medicine, TAU;
Background: Recent reports suggest that brain insulin signaling
plays an important role in the pathogenesis of several brain
disorders, mainly Alzheimer's disease. Intracranial pancreatic
islet transplantation is an optional tool for promoting insulin
and islets hormones levels in the brain. Aims: 1. Evaluate the
capacity of intracranial grafted islets to attenuate behavioral
dysfunctions in rats exposed to MK-801 2. Determine the
effect of the grafted islets on insulin, glucagon and growth
factors levels and expression in the brain. 3. Determine the
effect of the grafted islets on peripheral glucose homeostasis.
Protocol and Results: The syngeneic pancreatic islets were
grafted into the cranial subarachnoid cavity of rats. Rats under
basal conditions or following MK-801 administration were
examined in the open field (OF) and the Morris Water Maze
(MWM) tests. 60 days after transplantation rats were
euthanized. We found well vascularized grafted islets
expressing insulin, glucagon and somatostatin onto the
olfactory bulb and prefrontal cortex (PFC). Higher levels of
insulin were detected in the hippocampus (H) and PFC of the
transplanted rats. Higher levels of BDNF were found in the H
of transplanted rats. The peripheral glucose homeostasis
remained intact in all animals. OF test revealed that shamoperated rats, exposed to MK-801 showed hyperresponsiveness in motility parameters and augmented center
field activity compared to intact controls, these effects were
antagonized by the grafted islets. Moreover, in the MWM,
sham-operated rats treated with MK-801 showed larger
impairment of spatial memory, which was partially corrected
by the grafted islets. Conclusion: Islet transplantation leads to
increased expression of islet hormones in the brain and
attenuates behavioral dysfunction in rats exposed to MK-801
without altering the peripheral glucose homeostasis. These data
suggest a potential neuroprotective effect of intracranially
grafted pancreatic islets.
Alteration in serum klotho levels in inpatients with
anorexia nervosa
Wolf I.1,2, Shahmoon S.1, Ziv S.3, Hemi R.4, Kanety H.4,
Rubinek T.1, Modan-Moses D.2,5,
1
Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel; 2Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel ; 3Pediatric Psychosomatic Department, Sheba
Medical Center, Tel Hashomer, Israel ; 4Institute of
Endocrinology, Sheba Medical Center, Tel Hashomer, Israel ;
5
Pediatric Endocrinology and Diabetes unit, Sheba Medical
enter, Tel Hashomer, Israel;
Background and objective: Klotho is a trans-membrane protein
which can be shed to act as a hormone; its blood levels can be
regulated by the GH/IGF-1 axis. Klotho deficient mice may
exhibit decreased fat and muscle mass, osteopenia, and
impaired fertility. As anorexia nervosa (AN) is characterized
by malnutrition and GH resistance, we hypothesized that
klotho levels would be altered in AN. Our aim was to assess
klotho levels in undernourished AN patients and following
weight rehabilitation. Methods: Blood samples were obtained
on admission and after weight restoration in 19 female
adolescents hospitalized because of AN. Weight and height
were recorded on admission and discharge. Bone mass density
(BMD) was assessed on admission Results: Klotho levels on
admission were lower than expected for age, and correlated
with lumbar spine BMD Z-score (r=-0.81, p<0.001) and
alkaline phosphatase levels (r=0.66, p=0.003) but not with age,
height-SDS, weight-SDS, BMI-SDS, and serum calcium,
phosphorus and IGF-1 levels. Both IGF-1 and klotho increased
significantly during hospitalization (IGF-1: 44±17nmol/l to
53±11nmol/l,
p=0.008;
klotho:
1061±421pg/ml
to
1519±781pg/ml, p=0.008). Conclusions: Klotho levels are low
in the acute stage of AN and increase with nutritional
rehabilitation. Low klotho levels on admission may be
secondary to low IGF-1 and may contribute to the clinical
manifestations of AN. The role of klotho in the
pathophysiology of AN and as a novel marker of disease
severity should be further explored.
Early Intervention in the Prevention of Schizophrenia: an
animal model perspective
Weiner I.
School of Psychological Sciences and Sagol School of
Neuroscience, Tel-Aviv University
The
growing
recognition
that
major
adult-onset
neuropsychiatric disorders such as schizophrenia originate
early in development and are preceded by periods of brain and
functional deterioration, has raised the exciting yet highly
challenging and controversial possibility of early intervention
in psychiatry. While these challenges must be met at the level
of clinical research, model rodents based on developmental
disruptions have aided considerably in redefining issues at the
proof-of-concept level, offering the possibility of identifying
neuropathological changes
across development
and
demonstrating causally that early interventions prevent the
emergence of specific schizophrenia phenotypes in the adult
animal. We will present evidence from well established
neurodevelopmental rodent models of schizophrenia that periadolescent interventions with a wide variety of compounds
(anti-anxiety, anti-inflammatory, anti-psychotic and anti-
Differential Age-Related Effect of Chronic Mild Stress on
Hippocampal-Dependent Learning: Insights from
preliminary results of young and old female mice
Wolf* G.1, Lifschytz* T.1, Lotan A.1, Mernick B.1, Wasserman
E.1, Lerer B.1,
1
Biological Psychiatry Laboratory, Hadassah-Hebrew
University Medical Center, Jerusalem;
Chronic stress is related to decreased volume of hippocampal
formation, as well as to impaired hippocampal-dependent
learning. Moreover, the elderly might be more sensitive to the
effects of stress compared with younger population. It was
previously demonstrated that exposure to chronic stress in
rodents induced longer latencies in the MWM test, reflecting
impaired spatial learning. The present study was designed to
gain a comprehensive understanding of the age-related effects
of chronic stress. To model effects of age we studied 3 vs. 20
month old C57BL/6JRccHsd female mice. To model CMS we
employed exposure to a series of mild, unpredictable stressors.
Following CMS or sham exposure, the mice underwent a
behavioral battery, assessing cognitive and affective aspects.
Looking at the averaged latency to platform area in the RAWM
34
test, 2-way ANOVA with repeated measures revealed a
significant effect of testing day (F(1,72) = 5.245, p<0.025) as a
within-subject factor and significant effect of age (F(1,72) =
13.395, P<0.001) as a between-subject factor, indicating that
although all groups displayed shorter latencies in the second
day of the test the younger mice located the platform more
quickly compared with the older mice. Also, ANOVA that
treated combined treatment group as independent variable
revealed a significant treatment by testing day interaction
(F(3,72) = 5.586, p<0.002). Post-hoc comparisons indicated
that the latencies of old CMS mice were significantly longer
compared with the latencies of young CMS mice (p<0.001).
No such difference was found comparing the latencies of old
and young sham mice (p<0.535). These results indicate that the
old mice were significantly more sensitive to the effects of
chronic stress exposure in terms of inducing cognitive
impairments, especially in hippocampus-dependent tasks, an
effect that was previously demonstrated in elderly humans. *
equal contribution Supported by a grant #3-10764 from the
Israel Ministry of Science
Tourette syndrome (TS) is a childhood-onset disorder
characterized by motor and vocal tics. In most cases, tics
decline or even disappear by late teenage years, and only 20%
of cases will continue through adulthood. It was suggested that
reduced inhibition in the sensory and limbic areas lead to an
inability to suppress the premonitory urges whereas reduced
inhibition in motor cortical areas leads to inability to control tic
expression. Response inhibition is widely accepted as one
feature of the executive functions (EF). EF system is a complex
cognitive processing mechanism requiring the coordination of
several sub processes to achieve a particular goal. EF include
other abilities such as set shifting, planning, and effective
performance. While some studies examined EF in TS showed
no differences between TS to normally developing subjects,
other studies found EF impairments in TS patients. Contrary to
these findings, recent studies reported increased levels of
cognitive control in a group of young TS patients compared to
a control group. These findings led to the speculation that some
young TS patients show reorganization of pre-frontal areas to
allow enhanced EF as a compensation mechanism. In the
current study, we are following the EF development in 30
young patients diagnosed with TS. A battery of specific EF
tasks is administrated once every 6 months for each subject, as
well as tic severity assessment. Preliminary results show a
correlation between observed improvements in some EF
abilities to tics reduction. This finding led us to speculate that
the unique pattern observed in young TS patients may have a
role in the symptoms reduction observed in adulthood. Based
on these findings, we propose a future intervention aiming to
reduce tics observed in TS.
Early intervention prevents both schizophrenia- and
depression-like behavioral abnormalities in the offspring of
dams exposed to post-partum immune stimulation
Wolff N.1, Jacobovich E.1, Doron R.2, Weiner I.1,
1
School of Psychological Sciences and Sagol School of
Neuroscience, Tel Aviv University, Israel; 2School of
Behavioral Science, the Academic Col. of Tel-Aviv Yaffo,
Israel;
Background: Over the past two decades, a paradigmatic shift in
preventive psychiatry has allowed the prospective
identification of subjects at high risk for psychosis and
affective disorders and attempts at early intervention. A critical
assumption is that treatment at earlier (asymptomatic) stages is
associated with better response and prognosis, and is
transdiagnostic. Although some success has been achieved,
studies in humans face grave practical, methodological, and
ethical problems. Animal models can aid considerably in
demonstrating feasibility of prevention at the PoC level. This
study used a novel neurodevelopmental model in which
lactational exposure to the viral mimic poly-I:C leads to sexspecific schizophrenia and depression phenotypes, to: 1. test
the concept that treatment can be transdiagnostic and highly
effective when given at an asymptomatic stage 2. Establish
efficacy of a novel herbal treatment (NHT), mood stabilizer
drug (lithium) and anti-psychotic drug (risperidone) as early
intervention. Result: Adult male offspring of Poly I:C treated
dams exhibited cognitive perseveration as manifested in
persistent latent inhibition (LI) mimicking negative/cognitive
symptoms of schizophrenia, while female offspring exhibited
depressive-like despair as manifested in increased immobility
in the forced swim test (FST). Both abnormalities were
prevented by NHT, lithium or risperidone given during
adolescence (postnatal day 34-47). Conclusion: Early treatment
with three mechanistically different drugs can prevent
behaviors modeling cognitive\negative symptoms of
schizophrenia as well as behavior modeling symptoms of
depression, supporting the concept that early intervention can
be drug-nonspecic and transdiagnostic.
The microglial biology of cognitive and emotional processes
Yirmiya R.1,
1
Department of Psychology, The Hebrew University of
Jerusalem;
Recent studies led to a shift in our understanding of microglial
functioning under normal, physiological quiescent conditions,
demonstrating that in their "resting" state microglia participate
in the development of neural circuits, normal synaptic
functioning, experience-dependent plasticity, and neurogenesis.
Furthermore, research in my laboratory and others recently
provided direct evidence that microglia also play important
roles in cognitive and emotional processes. For example,
microglial number, morphology and secretion of interleukin
(IL)-1 is altered by learning and by environmental enrichment,
and these cellular/molecular alterations are critical for the
memory consolidation as well as the enhanced neuroplasticity
and neurogenesis induced by these conditions. In contrast, the
morphological and functional alterations in microglia and their
cytokines during pathological/neuroinflammatory conditions
are causally associated with cognitive impairments and
emotional disturbances. For example in a model of Alzheimer's
disease we found that microglial activation and overproduction of IL-1 mediate at least some of the memory
impairments and reduced neurogenesis, which can be rescued
by intra-hippocampal transplantation of neural-precursor cells
with transgenic over-expression of IL-1ra as well as
pharmacological treatment with IL-1ra. Furthermore, during
exposure to chronic unpredictable stress microglia are first
over-activated, but subsequently undergo apoptosis, decline
and dystrophy. These changes are causally associated with the
development of depressive-like symptoms and suppressed
neurogenesis, evidenced by the ability of microglial modulators
to rescue the depressive symptoms. Together these findings
indicate that deviation of microglia from their homeostatic state
(i.e., either over-activation or decline), which disrupts the
normal physiological roles of these cells, is causally related to
neuro-behavioral pathology.
Executive functions in Tourette syndrome
Yaniv A.1,2, Benaroya-Milshtein N.3,4, Steinberg T.3,4, Ruhrman
D.3,4, Apter A.3,4, Lavidor M.1,2,
1
Department of Psychology, Bar-Ilan University, Ramat-Gan,
Israel; 2 Gonda Multidisciplinary Brain Research Center, BarIlan University, Ramat-Gan, Israel; 3The Matta and Harry
Freund Neuropsychiatric Tourette Clinic, SCMCI; 42Sackler
Faculty of Medicine, Tel Aviv University, Tel Aviv;
35
New approach for treating addiction using novel deltaopioid peptides
Zada M.1,2, Hevroni Y.3, Barnea R.1,2, Bareli T.1,2, Firer M.3,
Yadid G.1,2,
1
The Mina and Everard Goodman Faculty of Life Sciences,
Bar-Ilan University, Ramat-Gan, Israel.; 2The Leslie and
Susan Gonda Multidisciplinary Brain Research Center, BarIlan University, Israel.; 3The Department of Chemical
Engineering & Biotechnology, Ariel University of Samaria,
Israel.;
One of the major challenges in cocaine addiction is controlling
the high rate of relapse to drug usage. Cue-induced cocaine
craving intensifies, or “incubates”, during the first few weeks
of withdrawal and persists over extended periods of time. Most
studies relate the µ opioid receptor to the addiction process.
However, our previous studies showed a critical role for the
delta opioid receptor and its endogenous and potent ligand, βendorphin, in the control of heightened craving; however, βendorphin can not penetrate the BBB. In this study, we used a
commercial, recombinant Phage M13 in which 12mer peptides
of combinatorial sequence are displayed at the end of the tail
protein PIII to identify peptides that specifically bind the delta
opioid receptor. Bound phages were eluted from cells
expressing the receptor and 15 phages from isolated plaques
were collected randomly. Two phage clones showed a
significant decrease in their binding to the target cells in the
presence of a specific agonist to delta opioid receptor, DSLET,
whereas a specific agonist to µ opioid receptor,DAMGO, did
not change the binding of the two phages to the cells. We
examined the specific binding by Flow cytometry and its
functionality by cAMP assay. In a second stage of the work,
rats were trained to self-administer cocaine (0.75 mg/kg, 10
days, 6 h/day), followed by either a 1-day or a 30-day period of
forced abstinence. Subsequent testing for cue-induced cocaineseeking behavior showed minimal cue-induced cocaineseeking behavior, on day 1 of forced abstinence, with increased
cocaine seeking behavior at day 30. Injections of the peptides
into the NAc on day 30 of forced abstinence demonstrated a
significant decrease in active lever presses. Altogether, these
results demonstrate a novel approach for treating incubation of
cocaine craving through the delta opioid receptor.
and only a small proportion were against it. Conclusion: The
results of the surveys suggest that clinicians found the available
nomenclature system dissatisfactory and many times confusing
for them and the patients. The proposed 4 axis template seeks
to up-end current usage by placing pharmacology rather than
indication as the primary axes. Based on the results the authors
envision that the primary usage would relate to Axis 1Pharmacological Target and Mode of Action, Axis 2 –
Approved Indications and Axis 3 – Efficacy and side effects.
The other Axis 4- Neurobiology - being optional and largely
depending upon the extent to which the clinician seeks to dig
into the scientific base.
Cell-Free DNA (CFD) levels – a potential Bio-marker for
Blast wave-induced minimal traumatic brain injury
(mTBI) and post-traumatic stress disorder (PTSD) in an
innovative rat model
Zuckerman A.1, Ram O.2, Sadot O.2, Matar M.1, Kaplan Z.1,
Douvdevani A.3, Cohen H.1,
1
Department of Anxiety and Stress Research Unit, Beer-Sheva
Mental Health Center, Ministry of Health ; 2Department of
Mechanical Engineering Ben-Gurion University of the Negev,
Beer Sheva, Israel.; 3Department of Clinical Biochemistry,
Soroka University Medical Center and Faculty of Health
Sciences;
Blast wave-induced minimal traumatic brain injury (mTBI) and
post-traumatic stress disorder (PTSD) have become one of the
most frequent injuries in the military and civilian health care
sectors since the increase in worldwide terrorism and warfare.
Although those injuries are usually defined as “minor” injuries,
they tend to become chronic injuries in the absence of early
diagnosis and intervention. Moreover, accurate diagnosis and
the initial care of those injuries are a complex challenge
especially in the events of mass casualties, and may led to
delay the necessary therapeutic intervention. Therefore, early
identification of the affected (high-risk) population is of great
clinical importance for aid in diagnosis, treatment planning,
and rehabilitation assessment for patients. Accordingly, a
number of potential biomarkers have been proposed, but none
of them have yet been established as a broadly applicable
marker. Recently, Prof. Douvdevani and other researchers from
Soroka Medical Center, reported that Cell-Free DNA (CFD)
levels in the serum, increased significantly following various
pathologies and injuries. Circulating CFD appears following
cell damage. DNA is release and its levels significantly
increased in various pathologies and following injuries. In
order to evaluated this method as a potential Bio-marker for
Blast-wave injuries, non-anesthetized rats were exposed to
visual, auditory, olfactory, low pressure blast-wave (25kPa),
and serum samples were taken for determination of the CFD
level. Simultaneously, combining of cognitive-behavioral
paradigms were used in order to determine the rats' anxiety and
learning abilities (as markers for PTSD-like and/or mTBI-like
behavioral response). CFD levels were significantly increased
in the blood of all rats, 2 hours after exposure to low-pressure
blat-wave (from 473140 to 689186 ng/ml, P<0.0002). 30
days after the blast exposure the blood CFD levels remained
elevated only in those rats whose behavior...
Why we have not updated our naming of psychotropics in
the last 60 years?
Zohar J.1,
1
Tel Aviv University, Israel;
Objective:Current
psychopharmacological
nomenclature
remains wedded to earlier period of scientific understanding,
failing to reflect contemporary developments and knowledge,
does not help clinicians to select the best medication for a
given patient, and tending to confuse patients as they are being
given a drug with a different name compared to their identified
diagnosis (e.g. "Antipsychotic" for depression). A four-axis
pharmacology based nomenclature template as a potential
system which refresh current nomenclature by using
contemporary scientific concepts of neuroscience will be
presented.
Methods:
Four
major
colleges
of
Neuropsychopharmacology (ECNP, ACNP, Asian CNP, and
CINP together with IUPHAR) proposed a new template
comprising
a
multi-axial
pharmacologically-driven
nomenclature. The template comprises of four axes: 1—
Pharmacological Target and Mode of Action; 2-Approved
Indications; 3-Efficacy and side effects; and 4- Neurobiology.
Several surveys in four different continents were conducted in
order to examine satisfaction with the current
psychopharmalogical nomenclature, as well as test the fouraxis template. Results: A significant proportion of the
participants in the surveys were in favour of the proposed
system, a similar number wanting to consider the idea further,
36