Lecture 11 Reading

Question 1

Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis

What are systemic stressors and how are they relayed to the PVN?

What are processive stressors and how are they relayed to the PVN?

What do functional and neuroanatomical data suggest are involved in inappropriate stress control?

Answer 1

Systematic stressors that involve an immediate physiological threat are relayed directly to the PVN of the hypothalamus via brainstem catecholaminergic projections ○ (catecholamines include dopamine, epinephrine, norepinephrine)

Processive stressors that require interpretation by higher brain structures are channeled through limbic forebrain circuits ○ These limbic sites connect with the PVN via interactions with GABA neurons in the bed nucleus of the stria terminalis

Functional and neuroanatomical data suggest that disease processes involving inappropriate stress control involve dysfunction of processive stress pathways

Question 2

Central coordination of glucocorticoid release: role of the PVN

If there is a lesion of the PVN what happpens?

What happens to CRH vesicles if there is stimulation of the PVN?

Answer 2

PVN neurons release ACTH secretagogues (substances that promote secretion) of CRH and arginine-vasopressin (AVP)

Lesion to PVN → reduction in ACTH and CRH levels

Stimulation of the HPA system is marked by depletion of CRH- and AVP-containing neurosecretory vesicles in the median eminence, which is indicative of ACTH release

Question 3

Initiating the stress response

What does the amydala do?

What does the bed nucleus of stria terminalis (BST) do?

Answer 3

Catecholaminergic drive appears to promote HPA secretory activity following hemorrhage, hypotension and respiratory distress, and might play a role in ACTH responses to immune challenge

HPA-excitatory information may be communicated via the amygdala

• Amygdala is known to prompt behavioral and cardiovascular responses to stress
• Stimulation of medial or cortical amygdaloid nuclei elicits corticosterone secretion

Bed nucleus of stria terminalis (BST) may also convey excitation to HPA axis

BST links regions such as the amygdala and hippocampus with hypothalamic and brainstem regions

• Ablation to this area decreases mRNA production of CRH whereas stimulation increases corticosterone release
• Activation of stress axis may be affected by ascending aminergic input from the locus coeruleus of the pons (noradrenaline) and raphé nuclei of the brainstem (5-HT, serotonin)
• But the role of these regions is up for debate

Glutamate-containing neurons and maybe acetylcholine-containing neurons also play a role in excitation of the PVN

Question 4

Limiting the stress response

What are the negative feedback routes

Answer 4

Glucocorticoids negative feedback acts at the PVN itself

Neuronal inhibitory pathways work in parallel with steroid feedback

Hippocampus displays the highest levels of glucocorticoid binding

• Lesions potentiate stress-induced glucocorticoid secretion in rats and primates, and increase the expression of CRH and AVP mRNA in parvocellular PVN neurons
• Stimulation decreases HPA activity

PFC and lateral septum damage results in enhanced HPA responsiveness to acute stress

PVN neurons receive direct inhibitory input from local hypothalamic circuits

GABA is known to inhibit the release of ACTH and corticosterone in vivo

Question 5

What are limbic stressors and what do they respond to?

What do they require?

What does excitatory outflow from the hippocampus achieve in terms of HPA activity?

How do BST, preoptic, and hypothalamic cell groups work together?

Answer 5

Limbic stress pathways are most sensitive to stressors involving higher order sensory processing

-Ex: HPA responses to restrain, fear conditioning, or exposure to a novel environment are affected by PFC, hippocampus, or amygdala lesions

Limbic-sensitive stressors are processive

• They require a sequential stimulus assembly to obtain physiologic meaning
• Key characteristic of processive stress integration: need for an intervening synapse between limbic sites and PVN

Interaction of hippocampal efferents with GABA-containing neurons from BST, preoptic area, or hypothalamus suggests a capacity for excitatory outflow from the hippocampus to achieve a net inhibitory effect on the PVN

BST, preoptic, and hypothalamic cell groups integrate limbic input with homeostatic info prior to final elaboration of the stress response

Question 6

Brain stress regulation in disease

Answer 6

GABA modulates stress-induced glucocorticoid secretion in rats and humans and has been identified as a mitigating factor in major depressive disorder

Question 7

Systemic stressors

Are these limbic sensitve or insensitive?

Answer 7

HPA responses to physiological threats (e.g. hypoxia, lack of oxygen) are not affected by lesions to the limbic system

-In these situations, rapid relay of an excitatory signal to the PVN occurs via the brainstem, bypassing the need for cognitive processing

Limbic-insensitive stressors are systemic

-These stressors are of immediate survival value and do not require interpretation by higher order brain structures

Question 8

Do all processive and systemic stressors do use the same mechanisms?

Answer 8

All stressors within the two classes do not use identical circuitry i.e. Specific processive stressors should elicit characteristic patterns of limbic activation

NO!

Question 9

The Sympathetic Nervous System

Answer 9

The sympathetic nervous system (SNS) is the most important system associated with the stress response

-Fight or flight

Adrenaline released from adrenal medulla and noradrenaline from sympathetic nerves results in an increase in heart rate, peripheral vasoconstriction, and energy mobilization

PVN helps integrate stress signals

This system is activated in response to physical threats and in reaction to bodily events (e.g. injury, infection)

System returns to normal once the source of stress is terminated

Question 10

HPA Axis basics

Outline of hormones

Timeline from start to finish

Answer 10

HPA axis becomes activated when threats and negative consequences are anticipated, even well before they have occurred

System can be active over longer periods of time, even if the event never occurs (e.g. an important deadline, exam)

More reactive to psychosocial stressors

CRH from hypothalamus → ACTH from pituitary → glucocorticoids from adrenal cortex (cortisol in humans, corticosterone in rats)

Time between stress onset and peak in secretion of cortisol is 15-30 mins

Cortisol levels return to baseline about on hour after a stressor stops

Question 11

Subjective emotional experience of stress in the CNS

What did Lazarus argue?

How might individual differences influence this?

What brain regions play a part?

Answer 11

Cognitive factors determine the initial appraisal of a situation as stressful

Lazarus argued that an individual’s appraisal of a situation as threatening, which is determined by a comparison of the significance and demand of the situation with the available resources, will cause the individual to perceive a situation as stressful and initiate the physiological and endocrinological responses to stress

Psychological factors (e.g. self-esteem, coping style) and activated memories of past threats play a role in the perception of stress

Regions that have been identified to be involved in this process -Anterior cingulate gyrus

• Ventromedial PFC
• Orbitofrontal cortex
• Amygdala (and the medial temporal lobes in general)

Question 12

Assessment of the subjective emotional stress experience (how do we do it?)

How does this combine with other psychometrics?

Answer 12

Includes measures of perceived stress and cognitive appraisal ○ Primary appraisal secondary appraisal scale

• COPE inventory
• Profile of mood states

Can be combined with measures of key personality traits such as -Self-esteem

• Extraversion
• Neuroticism

Question 13

Assessment of the SNS (how do we do it?)

6 things

Answer 13

Can look at catecholamine release, heart rate, blood pressure, galvanic skin response

Cardiac imaging

Measure salivary alpha-amylase

Question 14

Measurement of HPA axis activity

What is the most common measure?

Is there a weakness with this?

Answer 14

ACTH and cortisol measured from blood plasma

Most common technique: salivary cortisol

• Easy to obtain samples from participants
• But it is really only a fraction of the final product of the activation of the HPA axis, perhaps not getting the whole picture by using this measure

Question 15

THE INTERPLAY BETWEEN THE SYSTEMS INVOLVED IN STRESS PROCESSING

Why is there incongruence?

Answer 15

“Response coherence”: the idea that the initial stressor causes a coordinated response at the level of the subjective emotional experience, and the behavioral, physiological, and endocrine systems

Would expect that being exposed to a stressful situation leads to a perception of that situation, and the activation of both the SNS and HPA THIS DOES NOT HAPPEN!

Several factors could play a role in this incongruence -Individual’s appraisal of their own emotional reaction

-Individual might possess specific personality characteristics that would make it more difficult to accurately be aware of emotions resulting in distorted self-perception and reporting ○ Interaction between systems might be different from coherence hypothesis

Question 16

Bio psycho social model of stress

What is the limitiation of the theory?

Answer 16

Biopsychosocial model of stress: first model to make predictions about the differential involvement of these various stress systems

• Focused on the interaction of the cognitive process (appraisal) and the physiological consequences
• If an individual engages in a situation where the demands exceed to the individual resources, then increases of both catecholamine (SNS) and cortisol secretion (HPA) can be observed. If the stressor stops, then increased cortisol secretion is observed but catecholamine secretion decreases
• Limitation: does not take into account the natural variation in the stress response system itself

Question 17

Biological sensitivity model (BSC)

Orchids/thistles

Answer 17

Biological sensitivity model (BSC): first stress reactivity by environment interaction model that showed differential health consequences depending on the magnitude of the stress response and the environment the individual was living in ○ Researchers who proposed this model found that children with low reactivity to stressors had similar rates of respiratory illness in both low and high adversity settings; highly biologically responsive children exposed to high adversity environments had substantially higher illness incidences; highly responsive children living in lower adversity conditions had the lowest illness rates

More biologically responsive children would experience unusually poor outcomes in high-stress, unsupportive social conditions but would benefit the most under low-stress, nurturing, predictable conditions Thistles and orchids

Question 18

Adaptive calibration model (ACM)

4 patterns

what is the bias?

Answer 18

Adaptive calibration model (ACM): individual differences are the result of conditional adaptation, the ability of an organism to modify its developmental trajectory

• Extends BSC by making direct claims as to the origins of interindividual differences in stress reactivity
• Takes sex differences into account
• Four patterns of stress responsivity are proposed

Sensitive stress pattern: moderate SNS responsivity and high HPA axis reactivity

Buffered pattern: moderate SNS and HPA axis reactivity

Vigilant pattern: high SNS and HPA responsivity

Unemotional pattern: decreased responsivity in all systems

Male-biased

Question 19

Problems with old models (2)

Answer 19

All of the models possess limitations

• Detailed explanations are provided as to how individual differences in stress responsivity might develop, but explanations as to how these differences translate to disease are missing
• Assume a coherence of the stress systems (as proposed by Lazarus)

Question 20

Empirical evidence on the nature and direction of the interaction between the stress systems

Class material about TSST

ELA and TSST responses

Answer 20

Several rodent studies have looked at the central interactions between glucocorticoid and noradrenergic systems

• These studies have emphasized the cognitive effects found in association with either HPA or SNS activations
• Some evidence points to an inverse relationship between the SNS and HPA after they have been triggered by CNS components in the presence of a stimulus that has been perceived as stressful

Several studies have looked at the effects of manipulation of SNS on HPA axis - administering propranolol (which causes an adrenergic blockade and prevents partial activation of SNS despite stimulation) leads to an increase in cortisol levels following stress exposure, 2 possible explanations

• Direct inhibitory effect of SNS activation on the adrenal cortex could be in place, attenuating cortisol release
• Increase in adrenaline production is due to propranolol blocking noradrenergic binding to receptors

Study from Andrews’ lab (author of this review paper)

• Gave participants dexamethasone (an anti inflammatory corticosteroid) or a placebo and administered the Trier Social Stress Test (TSST)
• Those who received the drug had higher TSST scores and higher heart rates throughout the experiment
• Results suggest an interaction between the two systems such that the SNS activity may be elevated in the presence of a suppressed HPA axis response
• Gordis et al study: reported greater asymmetry between baseline and reactive salivary alpha-amylase (sAA) and cortisol levels in response to a laboratory stress task in youths with histories of maltreatment and abuse
• Related back to the idea that subjects exposed to some form of early life adversity (ELA) might experience a change in regulation of their stress systems (adaptive calibration model)

Study by author’s lab again: investigated whether the ratio of sAA over cortisol would show a stronger relationship to ELA than the ratio of cortisol over sAA, or either marker alone, and whether there is a systematic link between this marker and other phenotype variables

The ratios were more strongly related to ELA than either measure alone; among the two measures, the sAA over cortisol ratio seemed to be most strongly associated with signs of ELA

High ELA can lead to a blunting of the HPA axis stress responsivity

-Seems to be complemented by a stronger SNS activity

Evidence points to a compensatory interaction between the endocrine and the physiological stress systems, which also seems to be related to specific phenotype variables

Question 21

What happens if you dysregulate one system?

What conditions fo you see lower/higher HPA activation in?

Answer 21

The dysregulation of one system will have significant (psycho)pathological consequences

• In PTSD and panic disorder, lower activation of the HPA axis in response to stress is often observed
• Hyperactivity of the HPA is frequently reported in depression ○ According to the coherence/compensation model, a reduced SNS activation in response to a stressor could potentially contribute to a hyperactive HPA, increasing the risk for development of depression Recommendations for future studies

Should include measures of all systems together in the same study

Not always easy to do but critical for examining interactions between the systems