Stress Sensitization Flashcards

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1
Q

Two stress response pathways?

A

Both controlled by PVN (paraventricular nucleus) of hypothalamus
1) Hypothalamic-Sympathetic-Adreno-Medullary (HSAM or SAM):
* Regulated by dorsal and ventral PVN
* Connects to brainstem
* Projections to organs of SNS
* Release of epinephrine and norepinephrine from medulla of adrenal gland

2) Hypothalamic-Pituitary-Adreno-Cortical (HPAC or HPA):
* Regulated by medial PVN
* Connects to pituitary (release ACTH)
* Release of cortisol from the cortex of adrenal gland

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2
Q

Feed-forward processes?

A
  • Each part must dynamically adjust to inputs from the other parts.
  • Frontal lobes —> limbic system —> Hypothalamus —> Brainstem.
  • All parts contribute to the type and intensity of response.
  • Response will vary depending on appraisals, motivations, arousal, and mood.
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3
Q

Hormones in Harmony: HSAM vs HPAC

A

HSAM (sympathetic activation) - short-term response:
* Epinephrine and norepinephrine regulation (Two types of catecholamines).
* Adrenergic (related to adrenaline).
* Aminergic (made from amino acids).

HPAC (HPA axis) - long-term response:
* Cortisol regulation
* Steroid hormone (made from cholesterol)
* Glucocorticoids are cortisol (in humans) and other similar hormones (corticosterone in rats)

The two systems work in harmony…. They talk to each other…and increase each other’s effects (sympathetic and HPA axis stronger impact on body)

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4
Q

Stress Hormones list?

A
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5
Q

Stress Hormones: Aminergic?

A

Made from amino acids
* Catecholamines (made from the amino acid tyrosine): Epinephrine, Norepinephrine, Dopamine.
* Serotonin (made from the amino acid tryptophan): Melatonin is derived from serotonin.

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6
Q

Steroid hormones?

A
  • Made from cholesterol
  • Glucocorticoids (has impact on most of the cells, tissues in the body):
    1) Cortisol (in humans), Corticosterone (in rats).
    2) Has effects on most cell types in the body.
  • Mineralocorticoids (Mainly involved in regulating balance of water and electrolytes).
  • Sex hormones (Estrogen, testosterone, progesterone).
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7
Q

Two Major Stress Hormones

A

1) Epinephrine (adrenaline):
* Sympathetic activation (prime HPA axis to become active)
* Short-term stress response for immediate action
* Epinephrine at pituitary stimulates ACTH release
* ACTH in blood stimulates release of cortisol

2) Cortisol:
* Involved in normal metabolism (diurnal cycle)
* Does not initiate the stress response
* Regulates and maintains the stress response
* Make sympathetic nervous system more responsive to epinephrine

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8
Q

The Adrenergic Hormones?

A

Epinephrine (adrenaline) vs. Norepinephrine (noradrenaline)

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9
Q

Epinephrine vs. Norepinephrine (similarities and differences)

A
  • Similar effects
  • Both act as excitatory neurotransmitters (in CNS and PNS):
    1) Norepinephrine involved in general arousal (in brain)
    2) Epinephrine limited function as neurotransmitter (in brain)
  • Both released from the adrenal medulla
  • Both increase heart rate, force of heart contractions
  • Both increase metabolic energy (Increase blood sugar and release of fat stores)
  • Epinephrine more impact on heart and lungs
  • Norepinephrine more impact on blood vessels
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10
Q

Organs of the sympathetic nervous system contain what and activated by?

A
  • Contain adrenergic receptors
  • Activated by adrenaline/epinephrine or noradrenaline/norepinephrine
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11
Q

Adrenergic receptors are?

A

Alpha receptors and beta receptors

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12
Q

Alpha receptors?

A
  • More activated by norepinephrine
  • Typically leads to Vasoconstriction (squeeze the blood vessels)
  • Can quickly increase blood pressure
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13
Q

Beta receptors?

A
  • More activated by epinephrine.
  • Typically leads to Vasodilation (relax the blood vessels).
  • Increases heart rate (more blood go through).
  • Beta receptors on vagus nerve ultimately connect to amygdala.
  • Amygdala gets feedback from sympathetic activation (tell amygdala that adrenaline is going up).
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14
Q

Cortisol is part of? Circadian rhythm?

A

Cortisol is part of regular metabolism:
* Circadian rhythm (physical, mental, and behavioral changes that follow a 24-hour cycle) for cortisol production.

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15
Q

Cortisol permissive VS productive role

A

1) “Permissive” – normal levels of cortisol lets things happen
* “Maintain regularly scheduled program”

2) “Productive” – high levels of cortisol makes things happen
* “Shift focus to emergency tasks”
* Certain metabolic functions get prioritized over others

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16
Q

Cortisol is regulated by and part of?

A

1) Cortisol is part of regular metabolism
* Circadian rhythm for cortisol production.
* Regulated by sleep-wake cycle, influenced by hours of “daylight”.
Wake up - cortisol levels high (peaks in morning) and then decreases throughout the day; low cortisol - when we sleep, drops in cortisol help you fall asleep.

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17
Q

Circadian Rhythm of Cortisol Regulation? Which parts of brain?

A
  • Suprachiasmatic nucleus (SCN) of hypothalamus
  • Receives visual info from thalamus
  • Day-night cycles detected from light exposure
  • SCN regulates daily activity of PVN
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18
Q

Functions of Cortisol? Why its needed?

A

Cortisol is called a stress hormone, but is needed for normal homeostatic functioning:
* Has a wide range of effects.
* Cortisol does not trigger a stress response. It regulates the stress response.
* The presence of cortisol by itself should not be considered a sign of stress.

(Cortisol levels should never get high because of negative feedback mechanisms.)

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19
Q

Negative Feedback Loops With Cortisol

A

Cortisol is released into the bloodstream:
* Detection of cortisol reduces production of cortisol
At the pituitary:
* Detection of cortisol, reduces production of ACTH
At the hypothalamus:
* Detection of cortisol in cerebrospinal fluid (third ventricle)
* Reduces activity of the medial PVN
At the hippocampus:
* Hippocampus can increase or decrease PVN activity, but….
* Detection of cortisol decreases PVN
* Hippocampus important inhibitor of HPA axis

20
Q

Cortisol During Stress

A

Stress decreases effects of negative feedback
* Increased cortisol should decrease production of CRF in the hypothalamus

BUT…there’s other players involved….
* Amygdala
* CRF Feedback system
* …others including the immune system

21
Q

There’s More (ways to regulate cortisol)?

A

“Normal” Cortisol regulation:
* Daily cycles of cortisol release
* Negative feedback regulation

Stress-induced cortisol regulation:
* Produced by extreme or prolonged stress
* When HSAM and HPAC remain simultaneously active
* Not easily regulated with negative feedback
* Allows cortisol levels to increase beyond “normal” levels

22
Q

Two ways to the HPA: Two different types of CRF neurons in PVN of hypothalamus?

A

1) Parvocellular (smaller cells)
* Parvo-cellular means “small cells”
* Release CRF alone
* Normal homeostasis
* Less effect on ACTH release
* More responsive to negative feedback (turns off when cortisol is detected

2) Magnocellular (bigger cells)
* Magno-cellular means “big cells”
* Releases CRF with Vasopressin (CRF-AVP)
* Causes more ACTH release
* Ten times less responsive to negative feedback

23
Q

The Paraventricular Nucleus (PVN) of the Hypothalamus function

A
  • Regulates the stress response
  • Controls both sympathetic activation and HPA axis
24
Q

Autonomic functions?

A
  • Dorsal and ventral projections from PVN
  • Projects to brain stem and spinal cord
  • Regulates sympathetic/parasympathetic activity
25
Q

Endocrine functions?

A
  • Medial and lateral projections from PVN
  • Connects to pituitary
  • Regulates the HPA axis
26
Q

Two ways of regulating HPA

A

Parvocellular neurons of the PVN (CRF neurons):
* Smaller neurons in the paraventricular nucleus
* Controls normal level of cortisol secretion
* Release CRF into pituitary —> pituitary releases ACTH
* Easily regulated by negative feedback loops

Magnocellular neurons on the PVN (CRF-AVP neurons):
* Bigger neurons in the paraventricular nucleus
* Release CRF with Vassopressin
* Connections to pituitary to release ACTH
* Connections to brainstem (aminergic nuclei)
* Triggered by sympathetic activation (for short period of time when less stress and vice versa)
* Not easily regulated by negative feedback loops

27
Q

activation of what?

Minor Stressors

A

1) A typical, short-term stressor (minor):
* Sympathetic activation (threat or challenge)
* SAM signals activation of the HPA
* If stress is short-term, sympathetic turns off quickly
* HPA regulation returns to “normal” circadian cycle (HPA return to baseline takes longer than SAM return to baseline)

28
Q

Major Stressors

A

2) Extreme or extended stressor
* SAM and HPA may remain simultaneously active for extended time
* Effects of both are intensified
* Increased activation of CRF feedback system throughout brain
* CRF released in combination with Vassopressin
* More ACTH is released
* Increased activation of Magnocellular (CRF-AVP) neurons of the PVN
* PVN and HPA activity less responsive to negative feedback

29
Q

Negative feedback loop?!!

A

The hypothalamus secretes corticotrophin-releasing hormone (CRH) which stimulates the anterior pituitary gland to secrete adrenocorticotrophic hormone (ACTH). ACTH travels via the bloodstream and stimulate the secretion of cortisol from the adrenal glands. As the cortisol levels rise, this blocks the release of CRH from the hypothalamus and ACTH from the anterior pituitary gland. As a result, the reduction in CRH and ACTH levels lead to reduced cortisol levels.

30
Q

Amygdala involved in regulating both HSAM and HPAC

A

1) HSAM regulation (by the amygdala)
* Monitors sympathetic activity through vagus nerve
* Vagus nerve (connects to amygdala) has beta-adrenergic receptors that detect epinephrine

2) HPAC regulation (by the amygdala)
* Cortisol passes blood-brain barrier, so amygdala can directly monitor levels of cortisol

3) Amygdala “knows” when HSAM and HPAC are both higher than normal

31
Q

Cortisol Receptors? Which brain areas?

A

1) Type 1 (MR - mineralocorticoid) Cortisol receptor:
* Sensitive to low levels of cortisol
* Regulates daily cycle of cortisol

2) Type 2 (GR - glucocorticoid) Cortisol receptor:
* Much less sensitive to cortisol
* Only active when cortisol levels are high
* Regulation of stress responding
* Can alter gene expression

  • Hippocampus and hypothalamus contain both Type 1 and Type 2
  • Amygdala and frontal lobe areas contain mostly Type 2
32
Q

Sensitization to Stress

A

1) High levels of stress can make the nervous system more responsive to future stressors.
* More of a positive feedback loop than negative feedback loop

2) Type 2 Cortisol receptors only activated by high cortisol levels:
* Type 2 can alter gene expression (Increases release of CRF with vasopressin).
* Increased CRF in amygdala —> more ACTH and Cortisol release (increased stress reactivity)
* Increased CRF in locus ceruleus (more epinephrine release) —> increased arousal and alertness (hypervigilance)

33
Q

Amygdala which memory? Function?

A

1) Amygdala responsible for “emotional memories”:
* Classical conditioning
* Basolateral area of amygdala

2) Amygdala can “learn” which stimuli or context produced elevated stress
* Associations or conditioning can be learned without conscious awareness

3) After amygdala has “learned” what caused elevated stress….
* …the stress response will be BIGGER the next time it happens * Hyper-reactive stress response

34
Q

Long-term Effects of Stress Sensitization

A

1) Sensitization of amygdala
* Increased CRF expression in amygdala
* Enhanced fear responses, increased HPA activity

2) Increased CRF expression in central feedback system * Increased arousal and alertness (via norepinephrine)

3) Greater reactivity of the HPAC
* More ACTH and Cortisol

4) Greater reactivity of the HSAM
* Cortisol stimulates increased catecholamine synthesis
* Cortisol increases sensitivity of adrenergic receptors
* More epinephrine and norepinephrine made
* Greater response to epinephrine and norepinephrine

35
Q

CRF feedback system (Central Feedback system)?

A
  • CRF acts as ”stress” neurotransmitter active throughout the brain
  • CRF feedback system integrates sensory information with emotional states and behavioral responses
36
Q

What CRF does….

A

1) In HPA —> release ACTH —> Release cortisol
2) In other brain areas:
* CRF —> Frontal lobes (alters attention and working memory)
* CRF —> Amygdala (emotional memory, classical conditioning)
* CRF —> Hippocampus (enhance long term memory)
* CRF —> Locus ceruleus (activate norepinephrine circuits)
* CRF —> Ventral Tegmental Area (VTA) (activate dopamine circuits)
* CRF —> Raphe Nucleus (activate serotonin circuits)
* CRF —> Immune system —> trigger inflammatory response

37
Q

Locus Coeruleus?

A

Brainstem nucleus in reticular formation
* Norepinephrine arousal system
* Activation increases arousal, alertness
* Inactive during sleep

38
Q

CRF in the LC?

A

CRF in the LC Increases Arousal
1) CRF in the locus ceruleus leads to norepinephrine release throughout the brain
2) CRF infused into locus ceruleus (LC) of rats:
* CRF in the LC increased norepinephrine in cortical and subcortical area.
* CRF triggered state of ”high alert”.
3) CRF regulates attention and arousal

39
Q

Sensitization as Adaptive

A

1) Sensitization allows continued stress response despite existing levels of high stress
* The stress response does not habituate
* Continues to respond
2) High levels of cortisol may indicate that the environment is dangerous
3) Sensitization increases arousal and alertness
* Hypervigilance to detect potential threats
4) Greater reactivity
* As levels of stress increase, response to stress continues to increase

40
Q

When being sensitive becomes maladaptive

A

1) In a dangerous environment, greater vigilance and stress reactivity is adaptive
* In a warzone, need to be vigilant to possible threats

2) But… the sensitization may no longer be adaptive in a safe environment
* The sensitization is long-lasting (and can be self-reinforcing)
* Hypervigilance —> Emotional appraisals of threats
* Increased stress reactivity —> more hypervigilance
* Physiological damage - Allostatic load
* Psychological and Social damage: Anxiety, irritiability, social withdrawal

41
Q

Stress and Working Memory

A

1) Cortisol also has impacts on working memory
* Requires executive functions of the frontal lobes
* Ability to concentrate and regulate attention (reduced)

2) Fronto-limbic connections between amygdala and frontal lobes

3) Experiments demonstrate that production of high cortisol levels in response to stressors impaired attentional control
* Less able to direct attention during dichotic listening task

4) High levels of cortisol impair working memory
* Poor ability to regulate attention

42
Q

Stress and Long-Term Memory

A

1) Memories of traumatic, stressful, or emotional events
* More vivid and detailed than non-emotional memories

2) Feedback mechanisms of stress hormones influence functioning of the amygdala and hippocampus
* Cortisol has direct feedback effects on amygdala and hippocampus: * Type 2 cortisol receptors in amygdala; * Cortisol negative feedback with hippocampus (decreases HPAC activity)
* Epinephrine indirect feedback mechanism through vagus nerve: * Epinephrine in blood can’t pass through blood-brain barrier; * Beta-adrenergic receptors on vagus nerve —> increase activity of basolateral amygdala; * Activation of the amygdala —> activation of hippocampus

3) Increased activation of amygdala and hippocampus promotes memory consolidation

43
Q

Memory Consolidation? Emotional memory?

A

1) Memory consolidation is the process of making memories more long-term:
* Emotional memories more likely to be consolidated
* Connections between amygdala and hippocampus

2) Experimental administration of cortisol enhances memory for emotional stimuli:
* Both positive and negative stimuli

3) High levels of cortisol generally impair long-term memory…but can enhance memory for emotional information:
* Like enhanced memory for details of traumatic events

44
Q

Prolonged Consequences of Prolonged Stress

A

1) Endocrine regulation of the stress response involves cortisol:
* Under normal conditions, cortisol regulated with negative feedback loop
* Cortisol production ultimately decreases cortisol production

2) But, an intense or prolonged stress will…
* Activate both HSAM and HPAC
* Continued activation of both increases sympathetic response and allows cortisol to reach higher than normal levels

3) The amygdala ”learns” and “remembers”:
* Higher than normal cortisol activates Type 2 receptors in the amygdala
* Type 2 receptors alter gene expression.
* Altered gene expression changes how neurons respond to the stimuli

4) Sensitization of the stress response
* Amygdala “learns” and “remembers” stimuli linked to the intense stress
* Amygdala intensifies stress response next time similar stimuli are encountered

5) In the brain…
* Increased activation of CRF feedback systems
* Greater activation of the locus ceruleus (increased norepinephrine release throughout the brain)

6) Psychologically….
* Become hypervigilant (looking for threats)
* Lose attentional control (unable to redirect focus of attention)
* Altered memory (better memory for emotional info, but worse memory overall)

7) Long-term costs for both physical and mental health

45
Q

Vulnerable to being Sensitive? Role of the hippocampus?

A

1) Individual differences in stress sensitization
* Those with a smaller hippocampus may be more vulnerable to stress sensitization

2) Role of the hippocampus
* Hippocampus stimulates the production of cortisol (under normal cycle)
* But also inhibits HPA axis when cortisol levels are high
* Individual with smaller hippocampus, more trouble regulating daily cortisol

3) Decreased volume of hippocampus is a risk factor for PTSD
* Hypervigilance and reactivity common symptoms of anxiety

46
Q

Sensitizing the Amygdala

A

1) Amygdala can be “sensitized” to stress
* Demonstrated with infusions of corticosterone into the rat amygdala

2) When glucocorticoid levels are unusually high….
* Activation of Type 2 (GR) receptors in amygdala —-> Altered gene expression in amygdala
* Neurons in the amygdala began expressing more CRF….

3) When CRF levels increase in Amygdala…
* More activation of magnocellular (CRF-AVP) neurons in the PVN
* More cortisol released…less negative feedback

47
Q

Stress-sensitization theory?

A

a traumatic event early in life can make individuals more vulnerable to mental disorders during later life stresses
* Stress responses can be re-programmed by experience