Lecture 1 - The stress response, the impact of chronic stress and stress in critical stages of development Flashcards
What is the stress response?
Represents an integrated reaction to stressors, broadly defined as real or perceived threats to homeostasis or well-being
What does HPA stand for in the HPA axis?
Hypothalamic-pituitary-adrenal
What is the ‘hallmark’ of the stress response?
HPA activation - it is the primary hormonal response to a stressor
What does the HPA axis do?
Mobilises energy reserves insuring an organism can respond to an actual or anticipated threat
What is the input to the HPA axis?
- Signals (visceral afferents) from all over the body are received by brainstem noradrenergic neurons
- These stimulate (innervate) the paraventricular nucleus (PVN) of the hypothalamus
What is the output of the HPA axis?
- Glucocorticoid receptors (GR) mediate mobilisation of energy stores (liver, fat, muscle) - inflammation and neural function
- Mineralocorticoid receptors (MR) important for basal circadian and ultradian rhythms
What are the two sub-sections of the motor (efferent) division of the peripheral nervous system (PNS)?
- Autonomic nervous system (ANS)
- Somatic nervous system
What are the two sub-sections of the Autonomic Nervous System (ANS)?
- Sympathetic
- Parasympathetic
What does the sympathetic nervous system do?
Mobilises body systems during activity (fight or flight)
What does the parasympathetic nervous system do?
Conserves energy and promotes ‘housekeeping’ functions during rest
What occurs when a stressor appears to release adrenaline and noradrenaline?
- The peripheral nervous system sends the signal to the central nervous system (specifically the brain)
- The signal is sent to the hypothalamus
- The sympathetic division of the ANS is activated to create the fight or flight response
- A signal is sent from the sympathetic nervous system to the adrenal medulla to release adrenaline and noradrenaline
What occurs when a stressor appears to allow glucocorticoids to release cortisol?
- The peripheral nervous system sends the signal to the central nervous system (specifically the brain)
- The signal is sent to the hypothalamus
- CRH is released which causes ____
- ACTH is released which _____
- The adrenal cortex sends a signal to the glucocorticoids to release cortisol
What are the two processes involved in shutting the stress response down?
- Passive steroid ‘clearance’
- Negative feedback
How does the stress response get shut down?
- GR binding to the PVN leads to endocannabinoid release and reduction in ‘drive’ to CRH neurons
- GR and MR in ventral hippocampus and prefrontal cortex (role for glutamergic projections to GABAergic PVN projecting neurons)
What is chronic stress?
- The result of repeated or prolonged exposure to a stressor
- Chronic central ‘drive’ to the neurons controlling the stress response
What is allostatic load (McEwan & Stellar, 1993)?
Mediators of the stress response promote adaptation in the aftermath of acute stress, but also contribute wear and tear on the body and brain that result from being ‘stressed out’
What is allostasis?
The adaptive processes that maintain homeostasis through the producdtion of mediators such as adrenalin, cortisol and other chemical messengers
How can chronic stress be a cumulative process?
- Adrenal cortex frequently increases in size and becomes more sensitive to ACTH meaning that cortisol responses to stressors are amplified
- Glucocorticoid-sensitive immune organs undergo cell death and involution (shrinkage)
- Loss of glucocorticoid feedback control of the HPA axis, associated with decrease GR in regions such as the hippocampus and prefrontal cortex - as well as the PVN
How does habituation to a ‘homotypic’ stressor occur?
- Repeated exposure to the same stressor results in decreasing cortisol response over time
- Despite reduced response, the organism is still undergoing repeated stress
- Decrement in HPA drive requires the MR
- Some degree of habituation is evident following exposure to varying (heterotypic) stressors
How does facilitation to stressor occur?
- HPA axis stress response to a new stressor is either maintained or increased
- Exposure to stressor 1 facilitates the cortisol response to stressor 2
- Overall faster onset of cortisol release and higher peak cortisol levels
- Facilitation involves circuits connecting with the PVT
What is the feedback model of stress?
Closed feedback loop - allostasis:
- Stressor occurs and behavioural action is carried out to bring HPA back to baseline
Open loop - allostatic load:
- Stressor occurs but the behavioural action is not appropriate and thus the HPA remains elevated
What are some perceptions of control?
- ‘Easy to handle’ = active coping response = sense of control= release of noradrenaline
- Testosterone rises with success
- ‘Not easy to handle’ = more passive coping mode = behaviour less assured = loss of control - adrenaline rises
- less certainty = growing distress = adrenocorticotropic releasing hormone and cortisol levels rise
Van Holst’s Tree Shrews
- Male tree shrews competing for dominance in a large cage
- Defeated animal can feed safely in a nesting box
- Control - animal lives alone without challenge
- Dominant has full access and control
- Submissive only emerges to eat when coast is clear
- Sub-dominant occasionally tries his luck but retreats to nesting box
- Cortisol and corticosterone of the defeated submissive nearly doubled
- Testosterone only elevated in dominant animal
Human example - Students
- Task 1 = turning off a series of lights as they appeared on a board, pace demanded was out of the subject’s control
- Task 2 = same task but free to control the pace, still competitive but now rewarding
- Excretion of cortisol and adrenaline in the urine was measures
- Amount of adrenaline excreted was the same (equal amount of effort)
- Decrease in cortisol when the subject found pleasure in the task
- Increase in cortisol with forced pace task
- Extent of arousal vs. degree of distress
Study: Prenatal stress and adult offspring (RATS)
- Maternal corticosterone secretion during pregnancy on the HPA axis activity of adult offspring
- Repeated restraint during the last week of pregnancy was sued as a prenatal stressor
- Hippocampal type I and II corticosteroid receptors in male adult rats submitted to prenatal stress in utero
- Mothers: either intact corticosterone secretion or blocked by adrenalectomy with substitute corticosterone therapy
- Intact: decrease in type I hippocampal corticosteroid receptors observed in prenatally stressed adults
Study: Salm et al. 2004
- Prenatal stress and amygdala volume of adult offspring
- Pregnant females were exposed to mild stress
- Novel environment (removal from the home cage to a fresh cage)
- Handling (saline injection - at random times to avoid habituation to the stressor)
- 30% increase in volume of lateral amygdala nucleus compared to control
Lessons from the Dutch Hunger Winter 1944
- Extreme stress from starvation
- <1000 cal/day in pregnancy
- Early gestational exposure: normal birth weight, increased risk of obesity and cardiovascular disease
- Mid-gestational exposure: low birth weight, reduced renal function
- Late gestational exposure: low birth weight, smaller throughout life - lower obesity rates
What are the effects of post natal stress on ageing?
- The affects of early exposure to stress may not be evident until later life
- Stress effects evident after early stress but gone by 12 months
- Mother limited in nesting material spend less time nursing and more time off their pups (rats)
- At 4-5 months of age both early life and control rats require progressively less time to find a hidden platform in the Morris water-maze test
- By 12 months early life stress rats require significantly longer time
- Reduction in total dendritic length and arborisation in the early-stress group
What is psychosocial short stature (PSS) type II?
- AKA ‘abuse dwarfism’ and ‘psychosocial dwarfism’
- Beyond infancy failure to grow as a result of psychosocial circumstances
What is Hyperphagic short stature (HSS)?
- Excessive eating not motivated by hunger but is a maladaptive hypothalamic response to negative emotions - but BMI is normal
- Growth failure is reversible when the child is removed to a nurturing environment
Study: Orphans in WWII Germany
- Compared children in two orphanages with similar diet, medical attention and general environment - but different women in charge
- Orphanage A: woman was attentive and nurturing
- Orphanage B: woman gave minimal contact and was cold
Results:
-Children in orphanage A grew more rapidly than those in orphanage B
- When the woman from orphanage B took over the running of A, growth rates declined and growth rates in B accelerated
- Woman from orphanage B had favourites who thrived in B compared to peers and thrived even more when they moved to A with the woman
Psychosocial short stature (PSS) mechanism
- Growth hormone GH insufficiency
- Do not respond to GH treatment without psychosocial intervention
- Two legions in hypothalamic-pituitary-growth axis (reversible)
- No cortisol abnormalities
