Exam
Written exam will take place on Monday June 22, 2015, at 10 – 12 AM, in the room 0.03a
After written exam one should sign up for an oral exam, which will take place on June 23-24,
2015, in the room 4.64 (Laboratory Room of Biomedical Physics)
Central systems
Central systems – cells and circuits that mediate functions necessary for the coordinated
behavior of the whole organism
The hypothalamus
The hypothalamus regulates basic life processes by
three main mechanisms.
I.First, the visual inputs are used by the
suprachiasmatic nucleus to synchronize the internal
clock mechanism to the day-night cycle in the external
world.
II.Second, the hypothalamus compares sensory
information with biological set points. There are set
points for a wide variety of physiological processes,
including blood sugar, sodium, osmolality, and
hormone levels.
III.Finally, when the hypothalamus detects a deviation
from a set point, it adjusts an array of autonomic,
endocrine, and behavioral responses to restore
homeostasis. E.g., if the body is too warm, the
hypothalamus shifts blood flow from deep to
cutaneous layers and increases sweating, to increase
heat loss through the skin. Meanwhile, the
hypothalamus activates coordinated behaviors, such as
seeking to change the local ambient temperature or
seeking a cooler environment.
Pituitary gland
The master neurohemal organ (i.e., organ that releases stored neurosecretory substances
into the blood ) in vertebrates is the pituitary gland.
The hypothalamus controls the endocrine
system through the pituitary directly and
indirectly.
The pituitary consists of an endocrine and a
neural part. The endocrine (anterior) part is
called adenohypophysis and neural
(posterior) part is called neurohypophysis.
Direct control:
The neurohypophysics contains axons
terminals (5) releasing two peptide
hormones: oxytocin and vasopressin.
Indirect control:
Hypothalamic axons terminals (1-4) secrete
regulatory hormones into the local
circulation, which are carried by blood
vessels into the anterior pituitary. These
regulatory hormones control the synthesis
and release of anterior pituitary hormones
into the general circulation.
Hypothalamic – pituitary system
Pituitary
Hypothalamus
Cells in different
regions (hypothalamus
and other sites) all
send axons to the
median eminence.
Discharge of these
neurons release so
called releasing
factors (RF). Their
action on pituitary
cells are to stimulate
immediate release as
well as to induce long
term synthesis of
hormones.
Neuroimmune circuits
The main route of neural immunoregulation is
the hypothalamic-pituitary-adrenal cortical axis
(HPA) (oś podwzgórze – przysadka – kora
nadnerczy).
Within the immune system organs phagocytic
(phag) and B and T lymphocytes proliferate in
response to antigenic (Ag) stimulus.
Low concentrations of corticosteroids (CS) and
adrenocorticotropic hormone (ACTH) stimulate
immunological response (+). High
concentrations of CS and ACTH (thick arrows)
suppresses immunological response (-).
The substances of the immune system regulate
the immune response but also act to block the
actions of other substances at different levels of
the HPA axis (black bars).
The immunosupression in people suffering
depression or stress is related to suppression of
the immune response by CS and ACTH.
Neuroimmune circuits
The time course of the antibody response of the immune system to an antigenic
stimulus (above) and corticogenic response of HPA axis (below). There is clear
correlation between the two responses. Between the graph, mechanism correlating the
two systems are postulated.
Immune system – membrane properties
A variety of substances can affect the immune response implying the presence of
appropriate membrane receptors.
Immune cells have a number of receptors which are involved in neural – immune interactions. A. Ligand-gated
channels. B. Voltage-gated channels. Because of the many receptors present, some researche suggested that the certain
cells of immune system may serve as „free-floating nerve cells”, and collectively may represent a mobile brain. It
could serve as a sensory organ („sixth sense”) for stimuli such as bacteria, viruses and tumor cells.
Central systems
Central systems – cells and circuits that mediate functions necessary for the coordinated
behavior of the whole organism
Specific transmitter-defined systems
Glutamate
Distribution of neurons using glutamate as a
neurotransmitter in the rat brain.
Most prevalent neurotransmitter
with a primarly excitatory action.
Low and moderate glutamate levels,
activate AMPA receptors
High glutamate concentrations
activate NMDA receptors
Distribution of NMDA receptors in the rat brain. Highest
receptor concentration include the olfactory bulb (OB),
hippocampus (Hi), cerebellum (Cb). Intermediate
receptor densities are seen in the cerebral cortex (Cx),
striatum (St), thalamus (Th).
g-Aminobutyric Acid (GABA)
Distribution of GABAergic neurons. There are short
tracts from striatum to substantia nigra and in
cerebellum. The long pathway projects form
hypothalamus to cerebral cortex. Most GABAergic
neurons are local interneurons in cortex, olfactory
bulb, hippocampus, cerebellum and retina.
Most prevalent neurotransmitter with a
primarly inhibitory action. There are two
classes of GABA receptors: GABAA and
GABAB. There are numerous subunit
isoforms for the GABAA receptor. The
subunit composition determines which
ligands may bind and modulate the
receptors besides GABA itself. Examples:
Barbiturates (hypnotics e.g. phenobarbital),
Benzodiazepines (relaxants e.g. Valium),
Ethanol (alcohol).
Isoforms of GABAA receptors in different brain areas. Each region,
subregion and layer has its unique combination of subunits.
Glycine
Traditionally, glycine has been localized mainly to the
brainstem and spinal cord. Recent years have brough the
evidence of a widespread distribution of glycine in the
brain. Glycine is an inhibitory neurotransmitter.
Distribution of the b subunits of the glycine. High density
of receptor is visible in the olfactory bulb (OB),
hippocampus (CA3), cerebellum (Cb), cerebral cortex
(Cx), striatum (St) and thalamus (Th).
The detection of glycine in the interstellar medium has been debated.
Kuan YJ, Charnley SB, Huang HC, et al., Interstellar glycine, Astrophys J (2003), 593(2): 848-867
„Glycine was probably formed when ices containing simple organic molecules were exposed to ultraviolet light” – if
amino acids exsist in outer space than there might be proteins and life as well!
Later, Kuan’s results were called into question:
Snyder LE, Lovas FJ, Hollis JM, et al., A rigorous attempt to verify interstellar glycine, Astrophys J (2005), 619(2):
914-930.
In 2008, the glycine-like molecule aminoacetonitrile was discovered in a giant gas cloud near the galactic center in the
constellation Sagittarius by the Max Planck Institute for Radio Astronomy.
In 2009, glycine sampled in 2004 from comet Wild 2 by the NASA spacecraft Stardust was confirmed.
Miller-Urey experiment (1953)
Jupiter’s atmosphere – methane
(CH4), ammonia (NH3), hydrogen
(H2), helium (He).
Simulations of the conditions of the early Earth’s
atmosphere: water (H20), methane (CH4), ammonia
(NH3), hydrogen (H2), carbon monoxide (CO).
Experimental setup of MillerUrey experiment - replication at
NASA.
At the end of two weeks of
continuous operation 10–15% of the
carbon within the system was in the
form of organic compounds. Two
percent of the carbon had formed
amino acids that are used to make
proteins in living cells, with glycine
as the most abundant.
Recent results: "old" genes, defined
as those that are found to be common
to organisms from several widely
separated species are enriched in
those amino acids that are also most
readily produced in the Miller–Urey
experiment.
Miller S. L. (1953). "Production of Amino Acids Under Possible Primitive Earth Conditions". Science 117: 528.
Dopamine
•Loss of DA synapses in the striatum (in basal
ganglia) is primary cause of movement disorders
(e.g. Parkinson disease).
• In hypothalamus DA influences the release of
the hormones, mainly prolactin.
•In the limbic system DA is implicated in the
reward system responsible for biological drives
(feeding, drinking, sex) and motivation.
Dopamine is important for immediate pleasant
rewards and for arousal effects that are predictive
of impending rewards.
Distribution of dopamine-containing neurons.
The two main projection neuron groups are located in
substantia nigra (SN) and ventral tegmental area
(VTA). Besides there are short axon DA cells in
olfacory bulb, hypothalamus, retina.
Main projections reach the limbic structures (septum,
amygdala, prefrontal cortex) and are implicated in
emotion and agression; prefrontal cortex is crucial for
some of our highest cognitive functions.
Dopamine
•Almost all addictive
substances (eg. cocaine,
opiates (morphine, heroin),
nicotine or alcohol) increase
the DA level in NA.
•Addiction involves positive
reinforcement related to
increase of DA release and
negative visceral side-effects
related to drug withdrawal.
Brain-reward circuitry in the rat
•In people in the state of
romantic love there is strong
activation of dopaminergic
pathways of the VTA; love is
rather a motivation system
than an emotion.
Acetylocholine
ACh acts on either nicotinic receptors (producing
brief synaptic potentials) or muscarinic receptors
(producing slow synaptic potentials).
It is the only neurotransmitter used as an excitatory
neurotransmitter at neuromuscular junctions in
skeletal muscles.
Acetylcholine is one of many neurotransmitters in the
autonomic nervous system. In cardiac tissue
acetylcholine has an inhibitory effect, which lowers
heart rate.
Distribution of cholinergic cell groups and their
projections in the rat brain. Main projections are from
habenula (HAB), septum (SEP), striatum (STR), basal
nucleus (BN).
It produces both excitatory and inhibitory responses
in the brain.
ACh has an important role in the enhancement of
sensory perceptions when we wake up and in
sustaining attention.
Damage to the cholinergic (acetylcholine-producing)
system in the brain has been shown to be associated
with dementia (Alzheimer’s disease).
Norepinephrine
The terms noradrenaline (from the Latin) and
norepinephrine (from the Greek) are
interchangeable.
Norepinephrine (NE) or noradrenaline (NA) has
neuromodulatory action and is setting levels of
central neural activity for different behavioral
states.
It is released by Locus Ceruleus (LC) neurons to
almost every regions of the CNS.
Distribution of norepinephrine containing neurons.
The widespread patterns of projections suggest that
these neurons are involved in adjustments of global
neuronal excitability.
NE neurons act like a central autonomic nervous
system, to complement the peripheral autonomic
system and its release of epinephrine (andrenaline)
into the bloodstream.
Serotonin
Serotonin (5HT) is released by neurons in
Raphe Nuclei, which project widely to
many brain regions, alike the NE neurons.
Like the NE system, the 5HT system exerts
widespread influence over arousal, sensory
perception, emotion and higher cognitive
functions.
Serotonin is thought to be a contributor to
feelings of well-being and happiness.
Several antidepressive drugs inhibit the
reuptake of serotonin, making it stay in the
synaptic cleft longer.
Distribution of neurons releasing serotonin.
serotonin
lysergic acid
diethylamide
The psychedelic drugs psilocin/psilocybin,
dimethyltryptamine (DMT), mescaline, and
LSD act as partial agonists at postsynaptic
serotonergic receptors. They bind to 5HT
receptors but their presence prevents
serotonin from sending neural messages. It
is redirected to other brain areas and causes
psychedelic hallucinations.
Peptides - substance P
Peptides are short chains of amino acid monomers linked by peptide bonds. Polypeptides are long,
continuous, and unbranched peptide chains. Proteins consist of one or more polypeptides arranged
in a biologically functional way.
Substance P is an important element
in pain perception. The sensory
function of substance P is thought to
be related to the transmission of pain
information into the CNS.
Substance P has been associated with
the regulation of mood disorders,
anxiety, stress, reinforcement,
neurogenesis, respiratory rhythm,
neurotoxicity, nausea/vomiting.
Distribution of substance P containing neurons.
Free nerve endings
The simplest type of sensory receptor in the skin is the free nerve ending. They respond to:
- mechanical stimuli (mechanoreceptors)
- heating and cooling (thermal receptors)
- noxious stimuli (nociceptors – pain receptors)
Activation of receptors mediating pain. Recording of the compound action potential from a
peripheral nerve in response to a single electric shock, showing different components of fast
conducting (Aa, b), medium conducting (Ad) and slow conducting (C) fibers. The immediate
sharp pain is mediated by Ad fibers, the subsequent constant aching is mediated by the C fibres.
Peptides - somatostatin
Somatostatin regulates (inhibits) the
secretion of growth hormone in anterior
pituitary gland.
Somatostatin is also secreted in several
locations in the digestive system:
stomach, intestine and pancreas.
Distribution of somatostatin containing neurons.
Somatostatin analogues are used to
treat acromegaly.
Endorphin and enkephalin
The short chain penta-peptides are called
ekephalins whereas the longer chain
compounds are called endorphins. The term
endorphins may be used to refer to both.
Endorphins ("endogenous morphine”) are
produced by the pituitary gland and the
hypothalamus during exercise, excitement,
pain, consumption of spicy food, love and
sex. They resemble the opiates in their
abilities to produce analgesia and a feeling
of well-being.
Distribution of endorphin containing neurons.
Capsaicin is the chemical which give rise to the heat of chillies.
When eaten, it stimulates body's production of endorphins.
Endorphins act on the μ1 opioid receptors,
which are are presynaptic, and inhibit
neurotransmitter release; through this
mechanism, they inhibit the release of the
inhibitory neurotransmitter GABA, and
disinhibit the dopamine pathways, causing
more dopamine to be released.
Opioids are among the world's oldest known
drugs (opium).
Emotion and feeling
“The value of life can be measured by how many times your soul has been deeply
stirred.”
Soichiro Honda
The beginnings of studies of emotions
Darwin’s dog, displaying the contrasting expressions of hostility and affection. From: The Expression of Emotions in Man and
Animals, Charles Darwin.
Darwin first pointed out in 1872, that fearful, angry, and happy facial expressions are
universal. The Expression of Emotions in Man and Animals, Charles Darwin, 1872
Emotion and feeling
An emotional state has two components, the one is a characteristic physical sensation and the other
is a conscious feeling. The term emotion sometimes is used to refer only to the bodily state (i.e., the
emotional state) and the term feeling is used to refer to conscious sensation.
Conscious feeling is mediated by the cerebral cortex, in part by the cingulate cortex and by the
frontal lobes. Emotional states are mediated by a family of peripheral, autonomic, endocrine, and
skeletomotor responses. These responses involve subcortical structures: the amygdala, the
hypothalamus, and the brain stem.
stimulus
Model of the basic neural systems that control emotions. The particular emotion experienced is
a function of cross-talk between neocortical and subcortical structures, as well as feedback from
peripheral receptors.
First theories of emotions
James-Lange:
Emotions are
cortical
interpretation of
feedback
information from
the periphery.
Cannon-Bard:
Emotional
experience
and
physiological
arousal are separate
and are both
triggered by
subcortical activity.
Traditionally, it was assumed that emotions are initiated by cognitive activity. James – Lange (1884) proposed the opposite view, that the
cognitive experience of emotion is secondary to the physiological expression of emotion. He suggested that when we encounter a potentially
dangerous situation, we act instinctively by running away and then consciously explain our action and the changes in our body (the increase
in heart rate and respiration) as “driven by fear.”
Experimental support for the James-Lange theory exists. 1) objectively distinguishable emotions can be correlated with specific patterns of
autonomic, endocrine, and voluntary responses. 2) patients with the spinal cord transection, whom lack feedback from the autonomic
nervous system appear to experience a reduction in the intensity of their emotions. The James-Lange theory also have shortcomings: for
example, one often continues to be emotionally aroused even after the physiological changes have subsided.
According to Cannon and Bard (1915), the physiological responses to emotionally significant stimuli are too undifferentiated to convey to
the cortex specific, detailed information about the nature of an emotional event. They showed that intense emotion triggered an emergency
reaction—a fight-or-flight response —in anticipation of additional behavioral responses and expenditure of energy. Cannon suggested that
this flight-or-fight response was mediated by the sympathetic component of the autonomic nervous system and that it acted as a whole,
almost in an all-or-none way, independent of the specific emotionally significant stimuli that elicited it. They proposed that perceived
stimulus (by the thalamus) triggers both physiological response (mediated by the hypothalamus) and emotional experience (mediated by the
cortex); physiological arousal does not have to precede emotional experience.
The Schachter’s theory
Schachter proposed (1960s) that the cortex actively translates peripheral signals into specific feelings. He suggested that the cortex
creates a cognitive response to ambiguous peripheral information consistent with the individual's expectations and social context.
Experimental support: Schachter injected volunteers with epinephrine; some subjects were informed of the side effects (eg, pounding
heart), others were not. All of the subjects were then exposed either to annoying or amusing conditions. The subjects who had been
warned about the side effects of epinephrine exhibited less anger or less pleasurable feelings.
The Arnold’s theory
According to Arnold (1950 - 1970) an emotion is the product of unconscious evaluation of a situation as potentially harmful or beneficial,
while feeling is the conscious reflection of the unconscious appraisal. The physiological changes, recognized as important, accompany,
but do not initiate, the actions and experiences. Feeling is therefore a tendency to respond in a particular way, not the response itself. The
appraisal theory accounts for individual variances of emotional reactions to the same event. A finding supporting this idea is that we can
have emotional reactions to subliminal stimuli. Unlike the James-Lange theory, Arnold's view does not require that we have an autonomic
response to experience emotion.
Hypothalamus integrates autonomic and somatic components of emotional behavior
Walter Cannon and Philp Bard examined behavior of cats with both cerebral hemispheres (cortex, white matter, basal
ganglia) removed. The animals exhibited angry behavior with autonomous (increase of blood pressure and heart rate,
dilatation of pupils, erection of the hairs on the back and tail) and somatic motor components (arching the back, extending
the claws, snarling). This behavior was called sham rage (furia pozorna) because it had no obvious target. Cannon and Bard
showed that transection (B) removing the forebrain and leaving the hypothalamus produced sham rage, while after
transection (C) below the hypothalamus the sham rage response was lost. Additionally it was shown that electrical
stimulation (A) of discrete sites in the hypothalamus of awake, freely moving cats could also lead to a rage response, and
even to attack behavior.
Bard suggested that whereas the subjective experience of emotion might depend on an intact cerebral cortex, the expression
of coordinated emotional behaviors does not necessarily entail cortical processes.
Agressive behavior
Selective stimulation of sites in the hypothalamus may induce two basic types of attack. In affective attack
(above) the animal displays sympathetic arousal, emotional exciment and rage. In quiet biting (below) the cat
shows no emotion but proceeds to caputre the rat and bite it.
Papez circuit for emotions
According to Papez (1937) neural circuit underying emotions
involves the limbic system. It starts with the mammilary body
of the hypothalamus as the site of output for expression of the
emotions (1). Collateral fibers pass to the thalamus (2) and
cingulate gyrus (3). Here, it was proposed that conscious,
subjective emotional experience arises. The cingulate gyrus
project to the hippocampus (4). The hippocampus integrates
different inputs and projects them to the mammilary body (5).
A neural circuit for emotion extended by Paul MacLean. The
circuit originally proposed by Papez is indicated by thick lines;
more recently described connections are shown by fine lines.
Known projections of the fornix to hypothalamic regions
(mammillary bodies and other hypothalamic areas) and of the
hypothalamus to the prefrontal cortex are indicated. A pathway
interconnecting the amygdala to the hypothalamus is shown.
Finally, reciprocal connections between the hippocampal
formation and the association cortex are indicated.
The amygdala
The amygdala is the part of the limbic system most specifically involved with emotional
experience
Brain imaging studies (MRI + PET + fMRI) demonstrate the role of the amygdala in emotional responses
A. A series of faces shows a continuum of expression between happiness and fear. Activity in the brain of normal subjects was
recorded as they viewed these faces.
B. With the presentation of each of the faces only the left amygdala activation was found to vary in a systematic fashion.
C. The mean regional cerebral blood flow (rCBF = PET or fMRI) shows that the responses in the amygdala were significantly
greater to fearful expressions than to happy expressions. These results are consistent with recording and ablation experiments
on animals that suggest the amygdala has a critical role in emotions, particularly in fear.
Fear conditioning
The amygdala mediates both inborn and acquired emotional responses. The best studied example of a learned emotional state
is the classical conditioning of fear. In this form of learning an initially neutral stimulus, such as a sound that does not evoke
autonomic responses, is paired with an electric shock to the feet, which produces pain, fear, and autonomic responses. After
several pairings the sound itself elicits a fearful reaction, such as freezing in place or changes in heart rate or blood pressure.
Bilateral lesions of the basolateral complex of the amygdala in experimental animals abolish this learned response to fear.
Amygdala activation in affective disorders
In unipolar depression, abnormal patterns of blood flow are apparent in the “triangular” circuit
inter- connecting the amygdala, the mediodorsal nucleus of the thalamus, and the orbital and medial
prefrontal cortex.
Areas of increased blood flow in the left amygdala, orbital, and medial prefrontal cortex (A) and in a location in the left medial
thalamus (B) from a sample of patients diagnosed with unipolar clinical depression. The “hot” colors indicate statistically
significant increases in blood flow, compared to a sample of nondepressed subjects.
Cortical Lateralization of Emotional Functions
Emotionality is lateralized in the cerebral hemispheres in at least two ways. (1) The right
hemisphere is in general more concerned with both the perception and expression of emotions than
is the left hemisphere. The right hemisphere is especially important for the expression and
comprehension of the affective aspects of speech. (2) The left hemisphere is more importantly
involved with what can be thought of as positive emotions, whereas the right hemisphere is more
involved with negative ones.
Asymmetrical smiles on some famous faces. Studies of normal subjects show that facial expressions are often more quickly
and fully expressed by the left facial musculature than the right. The left lower face is governed by the right hemisphere, what
suggests that the majority of humans are “left-faced,” in the same general sense that most of us are right-handed.
Facial expression - muscles
Dermal muscles of the human face as portrayed in Darwin’s book (1872). In higher mammals and
especially in humans facial muscles have become adapted for the expression of emotions.
Pathways for facial muscles control
There are two anatomically and functionally distinct sets of descending projections responsible for
control of the muscles of facial expression. Volitional smile is driven by the motor cortex, which
communicates with the brainstem and spinal cord via the pyramidal tracts. The genuine smile is
mediated by accessory motor areas in the prefrontal cortex and the basal ganglia that access
brainstem nuclei via “extrapyramidal” pathways.
Social (Pan-Am) smile
Spontaneous smile
Facial expression - evolution
Comparison of human expression of smiling and laughter with bared-teeth displays of lower primates and primitive
mammals. Friendly human smile evolved from more aggressive display of teeth.
The prefrontal, cingulate and parahippocampal cortices
ACG – cingulate gyrus
OFC – orbitofrontal cortex
PFC – prefrontal cortex
Cingulate gyrus has numerous connections to a variety of cortical and subcortical structures. It may act as a control
center between these structures. Cortical mechanisms provide a means by which memory and imagination, not just
external stimuli, can evoke emotional feelings and they enable us to use emotional information generally in cognitive
processing. Cortical structures also provide the means by which conscious thought can suppress reflex emotional
responses.
The frontal cortices - Phineas Gage and hazard
The executive functions of behavior—judgment, long-term planning, and holding and organizing
events from memory for prospective action take place in the anterior association area (prefrontal
cortex).
The ventromedial frontal cortex is thought to provide source of cognitive control of emotional
responses by predicting their consequences.
Lesions to the ventral sector of the frontal lobe result in disinhibition of inappropriate behavior in
social situations.
A
B
C
D
Insights into the function of cortical association areas
have come from the case of Phineas Gage. An iron bar
was driven through his frontal lobes by an explosion.
His personality was remarkably changed after the
accident. Before the accident he had been reliable and
calm but afterward he became unreliable and often
drank excessively. He was unable to manage his work
or personal life, and eventually became unemployed
and homeless.
+100
+100
+50
+50
-1250
-1250
-100
-100
In a “gambling experiment” a player sits draws cards from four decks
of cards, labeled A, B, C, and D. He is given a loan of $2000. The
undisclosed rules are that A and B cards yield $100 but occasionally
require the subject to repay $1250. Cards C and D yield $50 but only
require repayment of small sums (less than $100).
Normal people initially play decks A and B, but gradually, usually
within 30 of the 100 trials switch to a preference for decks C and D.
Patients with frontal lesions prefer cards from decks A and B
throughout the test despite the high penalties and the need to borrow
from the bank.
Effect of meditation on brain function and structure
Meditation increases activation and grey matter concentration in brain regions involved in learning
and memory, emotion regulation, sense of self.
Stronger brain fMRI activation in the anterior
cingulate cortex and medial prefrontal cortex in
meditators than controls for the contrast
mindfulness vs. arithmetic.
Hoelzel et al., Differential engagement of anterior cingulate and
adjacent medial frontal cortex in adept meditators and nonmeditators. Neuroscience Letters 421 (2007) 16–21
Frontal cortical areas are thicker in meditators.
Lazar et al., Meditation experience is associated with increased
cortical thickness. Neuroreport. 2005; 16(17): 1893–1897.