1. Brain-Endocrine-Stress Review The HPA axis

2. HPA axis PVN -ve CRF Cortisol Anterior Pituitary -ve ACTH Adrenal Gland

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.