31:241 Behavioral and Cognitive Neuroscience
Professor A.K. Johnson
Fall 2012
Outline
Neurobiology of Mood, Emotion and Mental Illness
11/6; 11/13; 11/15
I.
Emotion and Affect
A. Defining emotions
B. Ontogeny of emotion
C. Expression and measurement of components of emotion
II.
Theories of Emotion
A. James-Lange
B. Cannon-Bard
C. Papez-MacLean
III. Theories of Stress
A. Cannon
B. Selye
C. Mason
D. A contemporary view
IV. Stress and Pathophysiology
A. Selye's general adaptation syndrome
B. Allostasis
241-5.0a
Neurobiology of Mood, Emotion and Mental Illness
(Continued)
V.
Neural and Neurochemical Substrates of Fear and Anxiety
A.
B.
C.
D.
VI.
The defense response and the conditioned emotional response (CER)
1. Neural pathways
Neurochemistry
1. CRH
2. GABA
Anxiety Disorders
Somatic disease, stress and the defense response
Depression
A. Mood disorders introduction
B. Epidemiology and genetics of depression
C. Physiological and biochemical correlates of depression
1. Autonomic and cardiovascular changes
2. Endocrine and cytokine
3. Biological rhythms
- Seasonal affective disorder
D. Theories of Depression
1. Biogenic-amine
2. Stress and the brain–pituitary-adrenal dysfunction
3. Sickness behavior, inflammatory cytokines and depressive symptomatology
4. Stress-Impaired neurogenesis
E. Antidepressant drugs and electroconvulsive shock
241-5.0b
Key Terms and Concepts
Anhedonia
Allostasis
Allostatic load
Amygdala
Arousal
Basic emotions
Brain-deprived neurotrophic factor (BDNF)
Cannon-Bard theory of emotion
Conditioned emotional response (CER)
Corticotropic releasing hormone (CRH)
or factor (CRF)
Defense response
Electroconvulsive therapy (ECT)
Emotional response
General adaptation syndrome (GAS)
Generalized anxiety disorder
Leukocytes
MacLean's visceral brain (limbic
system) theory of emotion
Median forebrain bundle
Monamine oxidase inhibitors (MAOI)
antidepressants
Nociceptors
Nucleus accumbens
Panic disorder
Papez theory of emotion
Periaqueductal gray (PAG)
Post-traumatic stress syndrome
Simple phobia
Social phobia
Stress
Stress response
Stressor
Subjective feelings
Tricyclic/polycyclic (TCA) antidepressants
William James' theory of emotion
241-5 KTC
Examples of Lists of Basic Emotions
•
•
•
•
Surprise
Interest
Joy
Rage
• Surprise
• Happiness
• Anger
•
•
•
•
Fear
Disgust
Shame
Anguish
• Fear
• Disgust
• Sadness
241-5.1
A Scheme Proposed by Bridges
for the Development of Emotions
241-5.2
Types of Emotional Responses
Emotional
Action
Feelings
Feelings
Emotional
Expression
Subjective
Feelings
241-5.3
Darwin's Expression of the
Emotions in Man and Animals
241-5.4
Commonality of Emotional Expression
in the Faces of Animals and People
241-5.5
William James' Theory of Emotion
241-5.6
Cannon-Bard Theory of Emotion
241-5.7
The Papez Circuit Theory of Emotion
241-5.8
MacLean's Visceral Brain
(Limbic System) Theory of Emotion
241-5.9
Originators and Popularizers of the Concept of Stress
W.B. Cannon

Cannon (1920's) used the term "stress"
to characterize the physical impact of
averse stimuli on an organism much as
an engineer uses the term stress and
strain to characterize the effect of a load
placed on steel structures.
Hans Selye

Selye (1936) used the term
stress to account for the
generalized physiological
response to different averse
insults to the body.
241-5.10
Evolution of the Concept of Stress
241-5.11
Adaptive Effects of the Stress Response
 Immediate increase of metabolic fuel
 Increased oxygen intake
 Optimization of blood flow to key tissues
 Inhibition of digestion, growth immune function,
reproduction and pain perception
 Enhancement of sensory intake and memory
241-5.12
Selye's General Adaptation Syndrome (GAS)
and the Consequence of Another Stressor
Original Stress
Normal
New Stress
241-5.13
Pathological State Associated with Chronic Stress
 Fatigue, myopathy; steroid diabetes
 Hypertension
 Peptic ulcers
 Psychosocial dwarfism
 Impotence; anovulation; loss of libido
 Impaired disease resistance; cancer
 Accelerated neural degeneration during aging
241-5.14
Allostasis and Allostatic Load
 Idea evolved from concepts of
homeostasis and stress.
Bruce McEwen
 P. Sterling and J. Eyer were the
originators of the concept.
 Allo – prefix meaning variable.
 Allostasis = maintaining stability
through change; the active process
of maintaining a physiological
function in the face of a challenge by
old control systems adjusting level
of function or "new" systems being
activated.
 Systems involved in the stress
response show dramatic responses.
 Allostatic load = wear and tear on the
body that results from repeated or
sustained activation of processes
that maintain homeostasis.
Popularizer of Allostasis
and Allostatic Load
241-5.15
The Cardiovascular Defense Response
241-5.16
Brain Stimulation-Induced Defense Response
Behavioral
• Piloerection
• Hissing
• Halloween Posture
Cardiovascular
•
•
•
•
•
 Cardiac Output ( HR)
 Blood Pressure
 Skeletal Muscle Blood Flow
 Renal Blood Flow
 Mesenteric Blood Flow
241-5.17
The Conditioned Emotional Response (CER):
A Rat Undergoing Fear Conditioning
241-5.18
Neural Pathways Mediating the
Cardiovascular (A) and the Behavioral
(Freezing) (B) Components of the Defense Response
241-5.19
The Amygdala and Fear
241-5.20
Stress Pathways and the Control of Glucocorticoids
241-5.21
The Physiological Effects of CRF
241-5.22
Putative CRF Pathways and CRF1 (a) and
CRF2 (b) Receptor Localization
241-5.23
Effects of Amygdala Lesions on the CRF
Enhancement of the Startle Response
241-5.24
The Projections of the Amygdala That Mediate
Behavioral, Physiological and Endocrine
Responses to Fear Stimuli
241-5.25
There is a Key Role for GABA in
Controlling Activity of the Amygdala
241-5.26
The GABA Synapse
241-5.27
GABA Synthesis
COOH
COOH
CH2
CH2
Glutamic Acid
CH2
H2N
+ CO2
Decarboxylase
CH
COOH
Glutamic Acid
CH2
H2 N
CH2
GABA
241-5.28
The Interplay Between Neurons
and Glia in GABA Metabolism
241-5.29
Schematic Model of the GABAA Receptor Complex
BDZ, benzodiazepine
241-5.30
Anxiety Disorders
241-5.31
The Defense Response as an Inducer of
Chronic Hypertension
Björn Folkow
Hypothalamic Stimulation
Producing the Defense Response
and Chronic Hypertension
 About 50 years ago, Folkow hypothesized that sustained or repeated
activation of the defense response predisposes towards developing
chronic hypertension.
241-5.32
Multiple Environmental
Stressor-Induced Hypertension
241-5.33
Mood Disorders
241-5.34
Major Depression
• Major depression is the leading cause of
disability in the U.S. and worldwide.
• Depressive disorders affect an estimated 9.5%
of adult Americans ages 18 and over in a given
year, or about 18.8 million people in 1998.
241-5.35
Distribution of Mood Disorders in the U.S. Population
241-5.36
Symptoms and Signs of Major Depression*
• Must include either pervasive depressed mood
(verbal report) or pervasive loss of ability to
experience pleasure or interest in other things
(anhedonia).
• Must include at least five of the following:
- Depressed mood (require verbal report)
- Feelings of worthlessness or guilt (require verbal report)
- Diminished concentration (require verbal report)
- Recurrent thoughts of death or suicide (require verbal report)
- Weight change  
- Sleep disturbance  
- Psychomotor agitation or retardation  
- Fatigue or loss of energy
- Loss of pleasure (anhedonia) or interest
*Adapted form DSM-IV-RT
241-5.37
DSM-IV-RT Diagnostic Criteria for Dysthymic Disorder
A.
B.
C.
D.
E.
F.
G.
H.
Depressed mood for most of the day, for more days than not, as indicated either by subjective
account or observation by others, for at least 2 years. Note: In children and adolescents, mood can
be irritable and duration must be at least 1 year.
Presence, while depressed, of two (or more) of the following:
• Poor appetite or overeating
• Insomnia or hypersomnia
• Low energy or fatigue
• Low self-esteem
• Poor concentration or difficulty making decisions
• Feelings of hopelessness
During the 2-year period (1 year for children or adolescents) of the disturbance, the person has never
been without the symptoms in Criteria A and B for more than 2 months at a time.
No Major Depressive Episode has been present during the first 2 years of the disturbance (1 year for
children and adolescents); i.e., the disturbance is not better accounted for by chronic Major
Depressive Disorder, or Major Depressive Disorder, In Partial Remission. Note: There may have been
previous Major Depressive Episode provided there was a full remission (no significant signs or
symptoms for 2 months) before development of the Dysthymic Disorder. In addition, after the initial 2
years (1 year in children or adolescents) of Dysthymic Disorder, there may be superimposed episodes
for Major Depressive Disorder, in which case both diagnoses may be given when the criteria are met
for a Major Depressive Episode.
There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode, and criteria have
never been met for Cyclothymic Disorder.
The disturbance does not occur exclusively during the course of a chronic Psychotic Disorder, such
as Schizophrenia or Delusional Disorder.
The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a
medication) or a general medical condition (e.g., hypothyroidism).
The symptoms cause clinically significant distress or impairment in the social, occupational, or other
important areas of functioning.
Specify if:
Early Onset: if onset is before age 21 years
Late Onset: if onset is age 21 years or older
Specify (for most recent 2 years of Dysthymic Disorder):
241-5.38
With Atypical Features
Criteria for Manic Episode
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood,
lasting at least 1 week (or any duration if hospitalization is necessary).
B. During the period of mood disturbance, three (or more) of the following symptoms have
persisted (four if the mood is only irritable) and have been present to a significant degree:
• Inflated self-esteem or grandiosity
• Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
• More talkative than usual or pressure to keep talking
• Flight of ideas or subject experience that thoughts are racing
• Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external
stimuli)
• Increase in goal-directed activity (either socially at work or school, or sexually) or
psychomotor agitation
• Excessive involvement in pleasurable activities that have a high potential for painful
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions,
or foolish business investments)
C. The symptoms do not meet criteria for a Mixed Episode.
D. The mood disturbance is sufficiently severe to cause marked impairment in occupational
functioning or in usual social activities or relationships with others, or to necessitate
hospitalization to prevent harm to self or others, or there are psychotic features.
E.
The symptoms are not due to the direct physiological effects of a substance (e.g., a drug
of abuse, a medication, or other treatment) or a general medical condition (e.g.,
hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic
antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy)
should not count toward a diagnosis of Bipolar 1 Disorder.
241-5.39
Male/Female Prevalence of Affective Disorders
241-5.40
Genetic Component of Behavioral/Mental Disorders
241-5.41
Confirmed Linkages in Bipolar Disorder
Genomic
Location
Principle
Report
Independent
Confirmations
18p11.2
Berrettini et al., 1994 (38)
and 1997 (39)
Stine et al., 1995 (40); Nothen et al., 1999 (41);
Turecki et al., 1999 (42)
21q22
Straub et al., 1994 (44)
Detera-Wadleigh et al., 1996 (45); Smythe et
al., 1996 (46); Kwok et al., 1999 (47);
Morissette et al., 1999 (48)
22q11-13 Kelsoe et al., 2001 (49)
Detera-Wadleigh et al., 1997 (50) and 1999 (51)
18q22
Stine et al., 1995 (40)
Mcinnes et al., 1996 (52); McMahon et al.,
1997 (53); De Bruyn et al., 1996 (54)
12q24
Morissette et al., 1999 (48)
Ewald et al., 1998 (56); Detera-Wadleigh et al.,
1999 (51)
4p15
Blackwood et al., 1996 (57)
Ewald et al., 1998 (58); Nothen et al., 1997
(59); Detera-Wadleigh et al., 1999 (51)
241-5.42
Physiological and Biochemical Signs in Depression
Vegetative
•
•
•
•
Increased heart rate
Decreased heart rate variability
Increased cardiovascular reactivity to psychosocial stressors
Increased susceptibility to heart disease
Endocrine
•
•
•
•
Increased plasma norepinephrine
Increased cerebrospinal fluid CRF
Increased plasma corticosterone
Altered cytokines in depressed mood
Circadian
•
•
•
•
•
•
Altered sleep cycles
Increased REM
Decreased REM onset latency
Sleep deprivation and depression
Altered CRF cycle
Seasonal affective disorder
241-5.43
Average Plasma Cortisol Concentrations
241-5.44
Patterns of the Stages of Sleep of a Normal
Subject and of a Patient with Major Depression
241-5.45
Changes in the Depression Rating of a Depressed Patient
Produced by a Single Night's Total Sleep Deprivation
Mean Mood Rating of Responding and Non-Responding Patients
Deprived of One Night's Sleep as a Function of the Time of Day
241-5.46
Seasonal Affective Disorder (SAD)
• Distinctive constellation of symptoms
including
- Overeating
- Oversleeping
- Carbohydrate craving
• Triggered by light deficiency
• Responds to phototherapy
• Theories accounting for the antidepressant
effects of phototherapy
- Melatonin hypothesis
- Circadian phase shift
- Circadian rhythm amplitude
241-5.47
Light Box Therapy May Ameliorate
Seasonal Affective Disorder (SAD)
241-5.48
Biological Theories of Depression
I. Monoamine Theory of Depression
•
The monoamine theory, proposed in 1965, suggests that
depression results from functionally deficient monoaminergic
(norepinephrine and/or 5-HT) transmission in the CNS.
•
The theory was based on the ability of known antidepressant
drugs (TCA and MAOI) to facilitate monoaminergic
transmission, and of drugs such as reserpine to cause
depression.
•
Other pharmacological evidence fails to support the
monoamine hypothesis.
•
Biochemical studies on depressed patients do not, in general,
support the monoamine hypothesis, except that consistently
low concentrations of 5-HIAA in the CSF are found.
•
Though the monoamine hypothesis in its simple form is no
longer tenable as an explanation of depression,
pharmacological manipulation of monoamine transmission
remains the most successful therapeutic approach.
241-5.49
Pharmacological Evidence Relating to the
Monoamine Hypothesis of Depression
Drug
Principal Action
Effect in
Depressed Patients
Effects consistent with the hypothesis
Reserpine
Inhibits NE and 5-HT storage
Mood 
Tricyclic
antidepressants
Block NE and 5-HT re-uptake
Mood 
MAO inhibitors
Increase stores of NE and 5-HT
Mood 
-methyltyrosine
Inhibits NE synthesis
Mood ; calming of manic patients
Methyldopa
Inhibits NE synthesis
Mood 
Electroconvulsive
therapy
Increases CNS response to
NE and 5-HT
Mood 
241-5.50
Pharmacological Evidence That Does Not Support
the Monoamine Hypothesis of Depression
Drug
Principal Action
Effect in
Depressed Patients
Amphetamine
Releases NE and blocks
re-uptake
None. Euphoria in normal subjects
Cocaine
Inhibits NE re-uptake
None. Euphoria in normal subjects
Tryptophan
(5-hydroxytryptophan)
Increases 5-HT synthesis
Mood?  but only in some studies
- and -adrenoceptor
antagonists
Blocks actions of NE
Mood slightly ↓ with -adrenoceptor
antagonists; No effect on manic
patients
Methysergide
5-HT receptor antagonist
None
L-dopa
Increases NE synthesis
None
Iprindole
No effect on amine
metabolism
Mood 
241-5.51
Stahl's Hypothesis for Specific Syndromes Associated
with Different Kinds of Monoamine Deficiencies
Norepinephrine Deficiency Syndrome
•
•
•
•
•
•
•
Depressed mood
Impaired attention
Problems concentrating
Deficiencies in working memory
Slowness of information processing
Psychomotor retardation
Fatigue
Serotonin Deficiency Syndrome
•
•
•
•
•
Depressed mood
•
Food craving; bulimia
Anxiety
Panic
Phobia
Obsessions and compulsions
241-5.52
Biological Theories of Depression
II. Evidence for a CRF-HPA Theory of Depression
 Corticotropin-releasing factor (CRF) in cerebrospinal fluida,b
Blunted adrenocorticotropic hormone (ACTH) -endorphin to CRF stimulationa
 Density of CRF receptors in frontal cortex of patients who commit suicide
Pituitary gland enlargement in depressed patientsb
Adrenal gland enlargement in depressed patients and patients who commit suicideb
 Cortisol production during depressiona
Plasma glucocorticoid, ACTH, and -endorphin non-suppression after
dexamethasone administrationa
 Urinary free cortisol concentrations
aState-dependent
bSignificantly
correlated to post-dexamethasone cortisol concentrations
241-5.53
Biological Theories of Depression
III. Macrophage Theory of Depression
-- R.S. Smith Medical Hypotheses 35:298-306, 1991
Seven Lines of Support
1. Volunteers given monokines (IL-1; INF-; TNF) develop symptoms of a
major depressive episode.
2. IL-1 can account for hormonal abnormalities (e.g.,  ACTH;  GH).
3. Diseases and cohorts characterized by macrophage activation are
associated with high rates of depression.
4. Brain macrophages (microglia) secrete monokines.
5. Estrogen increases IL-1 secretion by macrophages.
6. Eicosapentaenoic acid suppresses macrophages, whereas linoleic
acid activates them.
7. Substantial epidemiology is consistent with this hypothesis.
241-5.54
Biological Theories of Depression
IV. Stress-Induced Neurodegeneration
241-5.55
Drugs Used in Affective Disorders: Antidepressants
Reuptake Inhibition
Drug Name
Generic (Trade)
Sedative
Activity
Tricyclic Compounds
Imipramine (Tofranil)
Moderate
Desipramine (Norpramin)
Low
Trimipramine (Surmontil)
High
Protriptyline (Vivactil)
Low
Nortriptyline (Pamelor, Aventil) Moderate
Amitriptyline (Elavil)
High
Doxepin (Adapin, Sinequan)
High
Clomipramine (Anaframil)
Low
Second-Generation (Atypical) Compounds
Amoxapine (Asendin)b
Low
Maprotiline (Ludiomil)
Moderate
Trazodone (Desyrel)
Moderate
Bupropion (Wellbutrin)
Low
Venlafaxine (Effexor)
None
Serotonin-Specific Reuptake Inhibitors
Fluoxetine (Prozac)
None
Sertraline (Zoloft)
None
Paroxetine (Paxil)
None
Citalopram (Celexa)
None
Fluvoramine (Luvox)
None
Dual-Action Antidepressant
Mirtazapine (Remeron)
High
MAO Inhibitors: Irreversible
Phenelzine (Nardil)
Low
Isocarboxazid (Marplan)
None
Tranylcypromine (Parnate)
None
MAO Inhibitor: Reversible
Moclobemide (Aurorix)d
None
Norepinephrine-Specific Reuptake Inhibitor
Reboxetine (Edronax)
None
Anticholinergic
Activitya
Elimination
Half-Life (hr)
NE
Serotonin
Dopamine
Moderate
Low
Moderate
Moderate
Low
High
High
Low
10-20
12-75
8-20
55-125
15-35
20-35
8-24
19-37
++
+++
+
+++
++
++
++
++
++
+
+
+
++
++
++
++++
0
0
0
0
0
0
0
0
Moderate
Moderate
Low
Low
None
8-10
27-58
6-13
8-14
3-11
++
+++
0
0/+
++
+
0
++
0/+
++++
0
0
0
++
0
None
None
None
None
None
24-96
26
24
33
15
0
0
+
0
0
++++
++++
++++
++++
++++
0
0
0
0
0
Low
20-40
++
++++
0
None
None
None
2-4c
1-3c
1-3c
0
0
0
0
0
0
0
0
0
Low
1-3c
0
0
0
Low
13
++++
0
0
aAnticholinergic side effects include dry mouth, blurred vision, tachycardia, urinary retention, and constipation.
bAlso has antipsychotic effects due to blockage of dopamine receptors. cHalf-life does not correlate with clinical
effects. dNot available for use in the US. 0=no effect; +=mild effect; ++=moderate effect;
+++= strong effect; ++++=maximal effect.
241-5.56
Changes in Adrenergic Receptors and in
Norepinephrine Synthesis and Release with Chronic
Antidepressant Treatment (Reuptake Inhibitors)
241-5.57
Selective Serotonin Reuptake Inhibitors
Drugs
• Fluoxetine
• Sertraline
Advantages
• Fewer anticholinergic and cardiovascular
side effects
• However relatively new and long-term
effects need to be evaluated
241-5.58
Changes Induced with Chronic Treatment with
Selective Serotonin Reuptake Inhibitors
241-5.59
Long-Term Adaptations to Antidepressant Treatment
241-5.60
Progression of Changes in the Pharmacological
Treatment of Major Depressive Disorder
241-5.61
Electroconvulsive Therapy (ECT)
• 1900's observed that spontaneous seizures
improved psychiatric state
• Early seizures induced with camphor and oil
• 1938 ECT
• ECT generally used on depressed patients
unresponsive to pharmacotherapy
• Its efficacy is 80% to 90% which is higher than
conventional therapies
• Technically difficult and expensive
• Must be administered several times a week for
several weeks
• Mood changes are due to cortical seizures and not
to peripheral results
• Mechanisms are not known
241-7.62