THE STRESS RESPONSE Flashcards
Which two nuclei release VSP? What
Magnocellular and parvocellular neurons in the Supraoptic and PVN. Parvocellular important for acute stress, magnocellular for water homeostasis.
How does AVP travel?
Magnocellular: AVP then travels down the axon through the infundibulum in neurosecretory granules that are found in Herring bodies (localized swellings of the axons and nerve terminals). Stored in the posterior pituitary until release.
Parvocellular in the PVN: released into the median eminence, then through the hypophyseal portal circulation to the anterior pituitary
What happens to VSP in anterior pituitary?
It works synergistically with the CRH to release ACTH from corticotrophin cells.
What is stress?
A change in the internal or external environment which the organism perceives as a threat to homeostasis. It is physical or anticipatory
What is the general adaptation syndrome?
Alarm, resistance - coping, exhaustion - illness
What are consequences of stress?
- Adrenal hypertrophy of the cortex, producing more glucocorticoid
- Thymic atrophy
- Ulcers
- HT and cardiovascular dysfunction
- Behavioural issues
Describe Cushings and an important note
- Immunosuppression
- Hypertension- can occur when the glucocorticoids act on the mineralocorticoid receptor in the kidney. This is normally prevented as cortisol is inactivated in the kidney to cortisone through 11bhsd2.
- Steroid diabetes
- Centropetal obesity but in other tissues you get lipolysis
- Muscle wasting. Cortisol is a catabolic hormone to provide a substrate for metabolism
- Impaired cognitive function
- Emotional lability
- Neurodegeneration
- Osteoporesis
- Impaired growth
- Impaired reproductive function
That people with stress related disorders do not have Cushing’s
What are general functions of the glucocorticoids?
- Regulation of innate/acquired immunity
- Cell growth and differentiation
- Metabolism – energy mobilisation: increases blood glucose. Largely catabolic actions – hepatic glycogenolysis, gluconeogenesis/proteolysis, lipolysis (in some tissues, but centripetal obesity i.e. re-distribution of fat), inhibition of glucose uptake in peripheral tissues
- Cardiovascular function
- Bone turnover
- Cognitive function
What 3 ways could you say glucocorticoids deal with stress?
Permissive, adaptive and protective
What are examples of permissive?
At low physiological levels cortisol maintains or primes the defence mechanisms to enable the organism to respond appropriately to stress by for example augmenting expression of:
- Pro-inflammatory cytokine receptors
- β-adrenoceptors and phenylethanolamine methyl transferase
What about adaptive?
- Energy mobilization
- Hepatic gluconeogenesis, raised blood sugar
- Mobilisation of fatty acids and amino acids
- Increased mental alertness
What are protective functions?
- Inhibition of the synthesis and release of pro-inflammatory mediators, e.g. IL-1β, IL-6, prostaglandins, leukotrienes
- Impaired translocation of the glucose transporter, GLUT-4, to the cell membrane; hence reduced glucose uptake by cells.
- Suppression on non-vital functions, e.g. growth and reproduction.
What factors influence circadian rhythm?
Through the suprachiasmatic nucleus
What are factors affecting cortisol excretion?
- Neural - CRH and AVP neurones posses ionotropic glutamate and alpha – 1 adrenoceptors (stimulatory) and GABAa receptors (inhibitory)
- Humoral – cytokine, chemokine – circumventricular organ
- Local – prostaglandins (produced from pain
- Hormonal feedback
How does stressed induced activation of the axis occur? Diagram
Through the limbic system (amygdala and hippocampus) to the PVN. The environmental and higher stressors go via the cortex to the limbic system. Finally homeostatic mechanisms go via the NTS to the PVN or limbic system. Cortisol is produced in relation to ACTH but there is a slight delay as it has to be synthesised (hence acth levels go down initially)
What are experimental end points for measuring stress?
- Plasma ACTH and/or corticosterone – increasingly using repeated measures over time to examine hormone pulsatility. Also, following stress ACTH granules are released meaning levels rise very quicky and there is then a delay in cortisol release. One measurement at a specific time might therefore not be representative
- CRH and AVP in portal blood (very difficult).
- Hypothalamic CRH and AVP mRNA and peptide (note CRH and AVP protein levels are reduced in the median eminence after stress as stores have been released; delayed increases in CRH and AVP mRNA levels occur and serve to restore the depleted protein levels.
- Immediate early gene activation in the brain (usually cfos) mRNA or protein)
- Expression of CRH, AVP and glucocorticoid (GR and MR) receptors
- In vitro studies
What is coping?
- Rapid mobilization of effector systems and effective feedback mechanisms.
What happens in acute stress and what are the mediators?
Raised cortisol - Magnitude and duration of rise depend on the stress and the individual. Designed to mobilize and redirect energy stores, prime immune system, arousal, maintain blood pressure and inhibit HPG axis. Rapid activation (‘fight or flight response) closely followed by resolution/recovery phase = effective stress coping response. Principal effectors of the stress system: CRH, AVP, nor-adrenaline, adrenaline, glucocorticoids
In chronic stress, what do adaptive responses depend on?
– Adaptive responses dependent on
• the stress and its predictability
• the individual and his/her ability to cope as well as their previous experiences
What are the chronic responses to stress?
- Raised morning cortisol
- Blunted circadian rhythm
- Exaggerated or prolonged cortisol responses to novel stress. HYPER EXCITABILITY OF THE HPA AXIS
- Overall tissues experience a more continuous exposure of glucocorticoids
What happens in repeat homotypic stress?
– Animals become habituated and the HPA response on each repeated stress exposure is attenuated
– Responses to novel stressors may be exacerbated.
What happens in the onset of progressive disease?
– Development of HPA over-activity parallels the onset and severity of disease
– AVP becomes the primary driver of ACTH secretion. CRH Decreases significantly, neurons downregulated. AVP may be responsible for the hypersensitivity of the axis.
What is chronic progressive disease characterised by?
- Downregulation of CRH mRNA in the parvocellular PVN
- Downregulation of CRH receptor binding in the anterior pituitary
- Sustained upregulation of AVP mRNA in the parvocellular PVN. No increase in the number of cells expressing AVP mRNA, but an increase in the amount of AVP mRNA per cell.
- Increase in V1b receptor mRNA and AVP receptor binding levels in the anterior pituitary
What happens in chronic variable stress? What did the animal study show
Adaptive changes: increased CRH expression and impaired glucocorticoid feedback. Tissues may experience overall greater glucocorticoid exposure.
There is an increase in the number of cells expressing CRH as well as an increase in sympathetic inputs. This reflects the increase in stimulatory glutaminergic and noradrenergic inputs (measured through synaptophysin)
– Thymus weight unchanged (at very high levels of glucocorticoid would expect a decrease in weight)
– There is impaired negative feedback and a downregulation of glucocorticoid receptors in the hypothalamus and a downregulation of hippocampal MR and GR
– Rat experiment: Characterised by a modest but sustained hypersecretion of corticosterone, ACTH (the weight of the adrenal gland increases), prolactin (unknown the reason behind this, perhaps to modulate the immune system
What are the neuroplastic responses to stress?
Atrophy of regions with inhibitory influences on HPA & ANS responses to acute stress and hypertrophy of excitatory regions
What happens in the inhibitory neuroplastic responses?
• Hippocampus & mPFC
• Retraction of apical dendrites & reduced dendritic spine density (sites of excitatory glutamataergic input) in response to chronic restraint.
• Decreased GR expression
Net: chronic GC elevations (decreased GC feedback); impaired memory & reward
What happens in excitatory neuroplastic responses?
Hypertrophy/up-regulation in regions with excitatory influences on HPA & ANS responses to acute stress
• Basolateral amygdala (psychogenic stress/HPAA) - Increased dendritic branching & stress excitability
• Central amygdala (systemic stress/ANS activation) - Increased CRH expression and release
• Hypothalamic PVN: Increased CRH & AVP expression & release
• Decreased GR expression
Net: increased excitability to novel stress (GCs & emotionality) & decreased reward
What do all stresses ultimately do?
stress ultimately signal via the hypothalamic parvocellular PVN to restore homeostasis
What are the two main parts of the forebrain in terms of stress?
• Hippocampus Contextual, episodic & spatial memory; down-regulation of stress response. Primarily activated by psychogenic stress: terminates HPAA response – regulates duration rather than magnitude [GR] decreases autonomic tone
• Amygdala Emotion, fear, anxiety, aggression, up-regulation of stress response. Central Amygdala activated by systemic > psychogenic stress; activates ANS > HPAA via projections to NTS
Prefrontal cortex decision making, working memory, controls impulsivity, down-regulation of stress response. It is primarily activated by psychogenic stress. Activation of prelimbic & dorsal regions terminates HPA response and reduces ANS response [GR]. Infralimbic regions initiate ANS & HPA responses via projections to NTS.
What does the pre frontal cortex do?
Prefrontal cortex decision making, working memory, controls impulsivity, down-regulation of stress response. It is primarily activated by psychogenic stress. Activation of prelimbic & dorsal regions terminates HPA response and reduces ANS response [GR]. Infralimbic regions initiate ANS & HPA responses via projections to NTS.
What neural inputs affect AVP and CRH release from the hypothalamus?
Neural - CRH and AVP neurones posses ionotropic glutamate and alpha – 1 adrenoceptors (n-ad), which are stimulatory, and GABAa receptors (inhibitory)
What simple experiment is there to assess corticosterone?
Rat. Measure corticosterone release after an injection of LPS versus a vehicle. Also induce hypo glycaemia, - Effects of hypoglycaemic stress on expression of CRH mRNA in the parvocellular PVN of the rat.
What evidence is there for chronic homotypic stress?
– Effect of repeated restraint stress for 1 h per day on expression of CRH and VP heteronuclear RNA levels in the medial parvocellular PVN of the rat. After repeated stress there is down-regulation of CRH mRNA. After repeated stress there is NO down-regulation of AVP mRNA
What is the experiment to look at chronic variable stress?
Experiment: Protocol:
– Random exposure to variety of mild stressors, e.g. novel environment, tilted cage, noise, wet bedding, strobe lighting
– Key features is the unpredictability of the nature and timing of the stress and the lack of ‘control’ the animal has of the situation.
– Compared to control, increased ACTH, Corticosterone, prolactin, increased adrenal gland weight and no change in thymus weight
Increase in number of cells expressing CRH mRNA. NB: these increases reflect increases in glutamatergic and noradrenergic inputs
Note that chronic variable stress does not increase the number of cells expressing AVP but does increase the amount of mRNA per cell
Where does the SNS response come from?
medullary preganglionic neurones of the intermediolateral cell column of the SC
Where does the PNS go through?
e.g. activation of NTS, then nucleus ambiguus & dorsal motor nucleus of the vagus nerve
What is the difference between the HPA and antonomic responses?
Slower onset (mins), more protracted than ANS response
What does the prefrontal cortex do?
Primarily activated by psychogenic stress
Activation of prelimbic & dorsal regions terminates HPAA response and reduces ANS response [GR]
infralimbic regions initiate ANS & HPA responses via projections to NTS
What does the amygdala do?
Central Amygdala activated by systemic > psychogenic stress; activates ANS > HPAA via projections to NTS
Medial & basolateral amygdala activated by psychogenic > systemic stress to up-regulate HPAA via interactions with PVN-projecting neurons
Think - involved in fear.
What does the hippocampus do?
Primarily activated by psychogenic stress
terminates HPAA response – regulates duration rather than magnitude [GR]
decreases autonomic tone
How do the brain stem and PVN communicate?
Through reciprocal connections. Brainstem NTS to PVN. and from dorsolateral parvocellular connection to brainstem.
Where do catecholaminergic inputs come from?
NTS
What is Hans Selye’s general adaptation syndrome
Initially there is adrenal NA and GC, homeostasis restored (dips then goes up again). Then defence and adaptation sustained and optimal (curve plateaus at peak). Then adaptive responses ceases - illness and death. He thought exhaustion is a failure to cope but this model is now outdated. Now thought to be excessive exposure to stress mediators.
What is allostasis?
Allostasis – ‘The process by which bodily functions change, in response to environmental challenges e.g. stressors:
‘The ability to achieve stability through change’