Brain-Endocrine-Stress Review The HPA axis

1. Brain-Endocrine-Stress Review The HPA axis

3. CRF Regulates basal and stress-induced release of pituitary ACTH Detected in cerebral cortex, hypothalamus, anterior pituitary, adrenal glands, testis, ovary, gut, heart, and lungs Three homologus neuropeptides � Urcortin I, Urcortin II, and Urcortin III CRF gene expression can be altered (catecholamines, serotonin, cytokines, glucocorticoids)

4. CRF-continued CRF R1 Corticotrophs of the anterior pituitary Mediates actions of the HPA axis and anxiety-related behavior CRF R2 Brain and periphery Regulation of feeding behavior and cardiovascular function

5. POMC Proopiomelanocortin (POMC) Binding of CRF with CRF R1 on corticotrophs Simulation of POMC mRNA synthesis ACTH release

6. Actions of glucocorticoids Two receptors Mineralocorticoid receptors Hippocampus and sensory and motor nuclei outside the hypothalamus Regulation of basal expression of ACTH, CRF and AVP Glucocorticoid receptors Hypothamic PVN, brainstem catecholaminergic cell groups, amygdala, hippocampus, pituitary Termination of the HPA axis response to stress

7. Actions of glucocorticoids Fetal organ maturation (esp. lungs) Metabolism (stimulates gluconeogenesis) Immune system (anti-inflammatory, immunosuppression) Maintain vascular tone

8. Regulators of the HPA axis Cytokines (leukemia-inhibitory factor (LIF), interleukin-6 (IL-6) Stimulatory on POMC gene expression and ACTH expression Vasopressin (AVP) Potentates the effects of CRF on ACTH release Chronic stress Noradrenaline

9. Negative feed-back Mediated by glucocorticoids at the level of the pituitary and hypothalamus Two phases Rapid feedback (inhibition of CRF and ACTH release) Delayed (down regulation of CRF and POMC gene expression)

10. Circadian rhythmicity Supraoptic nucleus (SCN) Peak glucocorticoids just before active period CRF required

11. HPA axis and stress response Acute stress Systemic and neurogenic Short term, enhanced secretion of ACTH and glucocorticoids Immunological stress Stimulation by inflammatory cytokines (IL-1, IL-6, TNF-? Repeated stress Chronic stress

12. HPA axis and stress response Repeated stress Habituation Chronic stress

13. QuestionsFulford and Harbuz, 2005 What are the two systems that cause an endocrine response to stress? What peptides are synthesized in the parvocellular cells? What are the differences between rapid and delayed feedback? What are the 2 corticosteroid receptors and how do their functions differ? Give examples of afferent regulation of the HPA axis. What are the two main categories of acute stress? Give examples. What effect does injecting animals with Lipopolysaccaride have on cytokine production and on the HPA axis? Name some measures that can be used to evaluate an acute or chronic stress response. How are endogenous opioids involved in the regulation of the HPA axis? What other factors are involved in the stress response?

14. QuestionsAbel and Majzoub, 2005 Describe the HPA axis. What is POMC? In what regions of the body has CRF mRNA being detected? What are the 2 CRF receptors and where are they distributed? What peptide is required for normal diurnal pattern of glucocorticoids? What is the importance of maternally derived glucocorticoids? Describe an experimental design using knock-out mice to study the effects of CRF on anxiety behavior.