Nov 13 Neurobiology of Stress and Anxiety

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Nov 13Neurobiology of Stress and Anxiety
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• Limbic Structures
• Amygdala fear-conditioning etc
• Hippocampus puts conditioned fears in
  appropriate context
• If you get mugged along a particular route, you
  develop a conditioned fear to stimuli associated
  with mugger (gun, face, voice) amygdala does
  that.
• Development of a fear to the route itself and
  future avoidance of it is mediated by the
  hippocampus. Makes fears location-specific.
• In PTSD, these boundaries are lost. (Hear a
  plane fly overhead in their driveway, dive for
  cover). PTSD is accompanied by hippocampal
  damage/dysfunction in response to large and
  prolonged doses of stress hormones.

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• Limbic Structures
• Amygdala fearful stimuli
• Hippocampus related context
• Hypothalamus mediates the autonomic arousal
  associated with many emotional states (heart rate
  inc, facial flushing, stress hormone release,
  etc)
• helps coordinate the physical events necessary
  to take action fight or flight reactions
• Hypothalamus and amygdala have many connective
  pathways.
• 4. Medial forebrain bundle - midbrain to
  hypothalamus.
• Pleasure - electrical brain stimulation studies
  (self-stimulation)
• Dopamine is important neurotransmitter.

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Brain centers relevant to emotion A. Limbic
Structures B. Cortex 1. Prefrontal cortex 2.
Parietal Cortex
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• Prefrontal Cortex (when rest intact)
• Extensive connectivity between limbic structures
  and prefrontal cortex pathways mostly one way
  so hard to cognitively control strong emotions
• Orbitofrontal cortex (OFC)
• Provides updated info. to the amygdala that
  allows the extinction of fear conditioning
• Evaluates reward and punishment contingencies in
  specific place and time situational
  appropriateness of behavior

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• Prefrontal Cortex (when rest intact)
• Extensive connectivity between limbic structures
  and prefrontal cortex
• Orbitofrontal cortex (OFC)
• b. Dorsolateral region of the prefrontal cortex
• Positive, pleasant, approach states are
  associated with greater left side activation.
  Expression of positive emotions controlled by
  left side.
• Unpleasant states, emotions, show more activation
  on the right side. Expression of negative
  emotions controlled by right side.
• Damage right (remove negative) gtgt may produce
  pathological laughter (cheerful manic)
• Damage left gtgt pathological crying (depressed))

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Brain centers relevant to emotion A. Limbic
Structures B. Cortex 2. Parietal cortex
processing of non-verbal expressions of emotion
(especially right parietal) Emotional tone of
voice Nonspeech sounds screams shrieks
laughing, crying Emotional faces Emotional
content of visual scenes
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Stress a state of emotional arousal that may
interfere with performance and coping Stress
complex response to environmental demands Stress
a response of the body to a stimulus or stimuli
that alters normal physiological equilibrium
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• Factors that influence how stressful we rate a
  particular situation
• familiarity - less familiar, the more threatened
  you may feel. Ex 1st test vs 2nd traffic in LA
  vs Boston
• controllability - if under our control, less
  stressful. Ex Traffic jam - stress take
  alternative route - just as long but less stress.
• Drive not fly more dangerous, but under our
  control more

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- controllability The Executive Monkey Studies -
2 monkeys - one can press bar to terminate
shock the other cannot. Get identical shocks
for same amount of time - one has control, the
other does not. (yoked control) Monkey with no
control gtgt more stress
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• Factors that influence how stressful we rate a
  particular situation
• predictability - more predictable, less
  stressful.
• Executive Monkey Studies - for one monkey, light
  warns that shock is coming for other, no
  warning.
• More signs of stress in monkey who gets no
  warnings. (Ex. unexpected shots pop quizzes)

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• Factors that influence how stressful we rate a
  particular situation
• predictability
• appraisal of situation - personal interpretation
  of situation
• Individual differences - reactions to flying
  blind dates surgery exams death, fights, Sept
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• Stress is in the eye of the beholder

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Responses to Stress 1. Emotional responses -
anger, annoyance, anxiety, apprehension, grief,
sadness. Strong emotional arousal can interfere
with performance and coping. Optimal arousal
level below or beyond that, performance
impaired. (inverted U) test anxiety
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Responses to Stress 1. Emotional responses 2.
Behavioral responses - involve some type of
coping - healthy or unhealthy.
Striking out at others
venting emotion giving up
indulging oneself - eating shopping
Getting involved.
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Responses to Stress 1. Emotional responses 2.
Behavioral responses 3. Physiological responses
- immediate response may be emotional long term
stress may impact health.
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• Physiology of Stress Response
• activation of hypothalamic-pituitary-adrenal
  axis leading to release of stress hormones
  (cortisol)
• activation of the sympathetic nervous system
  which increases release of norepinephrine and
  epinephrine (within brain and peripheral nervous
  system)

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• Physiology of Stress Response
• Glucocorticoids (cortisol) - steroid hormones
  released from the adrenal cortex in response to
  stress.
• Put body in state that mobilizes energy for
  action.
• increase glucose availability and use
• increase blood flow to muscles
• increase heart rate and blood pressure
• _____________________________________
• suppress immune function
• suppress response of gonads to sex steroids (LH)

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The hypothalamic-pituitary-adrenal axis Stress
stimulates neurons in the hypothalamus to release
corticotropin-releasing factor (CRF) CRF
stimulates limbic system- emotional response CRF
stimulates anterior pituitary to release
adrenocorticotrophic hormone (ACTH). ACTH
stimulates release of glucocorticoids from the
adrenal cortex (cortisol).
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Physiology of Stress Response High
glucocorticoids in blood --gt neurons in
hypothalamus stop releasing CRF. No CRF --gt
ACTH not released and glucocorticoids not
released.
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• Physiology of Stress Response
• activation of the sympathetic nervous system
• Within brain, more NE and E released
• Sympathetic nervous system increases the release
  of epinephrine (adrenalin) and norepinephrine
  from the adrenal medulla (part of adrenal gland
  that is itself on top of kidneys).
• Mobilizes fight-or-flight response

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Selyes General Adaptation Syndrome (1950s) Stage
1 - Alarm - arousal Stage 2 - Resistance -
arousal continues, but may level off
somewhat. Stage 3 - Exhaustion - diseases of
adaptation This started all the work on stress
and health.
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• Chronic Stress and Disease
• decreased immune functions increase risks for
  disease --gt infections cancer
• prolonged activation of cardiovascular system
  --gt high blood pressure heart disease
• prolonged excess glucose availability --gt Type
  II diabetes
• reduced recovery from illness

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• Role of stress hormones in fear, anxiety and
  psychopathology
• glucocorticoids, norepinephrine and epinephrine
  all released during stress also CRF
• many receptors for these hormones in
  hippocampus, septum, amygdala, hypothalamus, and
  pituitary
• activation of these systems - important role in
  learning relationships between stimuli and fear
• memories help predict the next similar
  experience and maximize the likelihood of
  survival

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• What about intense experiences?
• may prime the memory systems so much that the
  individual remains sensitized to stimuli
• fear conditioning that does not extinguish
  (amygdala sprouts new connections)
• hippocampus may be unable to connect (confine?)
  events within appropriate location
• (relevant to Post-Traumatic Stress Disorder)

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• What about chronic stress and activation of
  stress hormones?
• with prolonged activation, some receptor
  activity adjusts through down-regulation
  reduced numbers of receptors reduced sensitivity
  of receptors
• In pituitary, reduced sensitivity to CRF occurs
  (so not as easily triggered to produce ACTH). In
  hypothalamus, reduced sensitivity to
  glucocorticoids. Both effect feedback
  regulation.
• In hippocampus and frontal cortex, reduced
  sensitivity to glucocorticoids and norepinephrine
  and serotonin develops
• Result is withdrawn, anxious, or depressed
  behavior

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• Anxiety Disorders
• (dysfunction in normal regulatory mechanisms for
  stress)
• Generalized Anxiety Disorder
• Panic disorder
• Obsessive Compulsive Disorder
• Post traumatic stress disorder
• Phobias
• Collectively, affect 10-15 of population.

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Animal models of generalized anxiety disorders
emphasize GABA - has inhibitory actions on
neurons in many brain areas, including limbic
system Low in GABA receptors, more stress and
anxiety.
High in GABA receptors, less stress
and anxiety. (more related to generalized
anxiety disorder) SEROTONIN inhibitory in many
pathways excitatory in others Reduced levels or
receptor response may lead to reduced inhibition
of arousal mechanisms and increased withdrawal or
consummatory behaviors (grooming food hoarding)
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Drugs used in Treatment of Anxiety
Disorders Benzodiazepines - class of drugs used
to treat anxiety disorders (anxiolytics) work
on GABA Selective Serotonin Reuptake Inhibitors
Prozac, Paxil, Zoloft Other serotonergic drugs
Clomipramine BuSpar
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• Benzodiazepines - class of drugs used to treat
  anxiety disorders (anxiolytics)
• act by potentiating the action of GABA at one of
  its primary receptors (GABA A receptor)
• main BZPs used to treat anxiety disorders
• Valium, Ativan, Klonopin, Xanax, Serax, Librium,
  Restoral, Verstran, Tranxene
• known to act at cortical and limbic sites

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• SSRIs also used to treat anxiety disorders
• act by blocking reuptake of serotonin at certain
  sites - this makes more serotonin available
  also helps down-regulate the hyptothalamic-pituita
  ry-adrenal system of control of stress hormones
• main SSRIs used to treat anxiety disorders
• Paxil, Prozac
• known to act at cortical, limbic, and brainstem
  sites

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• Panic Disorder
• unexpected, uncued panic attacks
• marked by sudden anxiety - increased heart rate
  increased respiratory rate shortness of breath
  sweating fear
• occur in 1-2 of population

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Biology of Panic Disorder 1. 50-70 of people
with panic disorder can be triggered to have
attack by injecting lactate. lt10 of healthy
subjects can Lactate is a potent respiratory
stimulant. 2. Carbon dioxide sensors in medulla
monitor levels in air. Too much in air, we
experience anxiety/panic. People with panic
disorder are unusually sensitive. Levels of
CO2 that cause panic in 8 of controls, cause
panic in 50-80 of people with PD.
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Biology of Panic Disorder 3. May have dysfunction
in serotonin system - PD people have lower
threshold for panic reaction to elevated
serotonin levels mCPP is a serotonergic receptor
agonist that can induce anxiety and panic in some
normal individuals. Among panic disordered,
reaction occurs at a lower dose and among high
percentage of people. Similar for fenfluramine,
a drug that causes release of serotonin lower
dose induces panic in panic-disordered than in
normals. Lower threshold indicated.
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Biology of Panic Disorder 4. People with PD are
less sensitive to benzodiazepines - drugs that
potentiate neuronal reaction to GABA (GABA has
calming and relaxing effects) PD require higher
dose to get these effects. 5. Caffeine
(inhibits action of adenosine at receptor
adenosine induces sleep) Too much caffeine makes
anyone anxious. People with PD panic at lower
dose than others. Caffeine also enhances taste
sensitivity this too occurs at lower dose in
panic disordered than normals. So not just an
anxiety category effect