NEUROENDOCRINE AND BEHAVIORAL ACTIONS OF CORTICOTROPIN R

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The overall goal of this project is to better understand how corticotropin-releasing hormone (CRH) and other CRH-like molecules allow mammals to respond successfully to stress. Mouse models will be studied to take advantage of gene knockout and replacement methods that we and others have created. 3 broad areas will be addressed: 1. The activation during stress of endocrine responses; 2. The activation during stress of behavioral responses; and 3. The suppression during stress of appetite and reproduction. Specifically: 1. Are glucocorticoids necessary for life? Adrenal insufficiency causes death, whereas CRH-deficient mice have a normal lifespan despite extremely low (but detectable) levels of glucocorticoid. We will determine it CRH deficiency prevents death in the face of complete glucocorticoid deficiency. If so, this will show that glucocorticoids are not essential for mammalian survival. What is the function of the circadian rhythm in ACTH? We will test the hypothesis that the daily rise in blood ACTH in normal mice functions to maintain basal adrenal integrity by preventing adrenocortical apoptosis. What are the relative roles of CRH and vasopressin (VP) in the stress-induced and circadian activation of the pituitary adrenal axis? We will study mice with deletions in the CRH, VP or both CRH and VP genes, which will be analyzed for their hypothalamic, pituitary and adrenal responses to acute and chronic stressors, as well as to circadian cues. 2. What is the identity of the CRH receptor 1 ligand that mediates fear responses in CRH knockout mice? Is it urocortin, or a new, mammalian CRH-like peptide? 3. What is the role of CRH and related molecules in the suppression of appetite and reproduction during the stress response?