This is a rerevised, competitive renewal application (HL66023) that continues our examination of the physiologic relevance of recently described neuropeptides which we have demonstrated to act at least pharmacologically to stimulate stress hormone secretion (prolactin, PRL, and adrenocorticotropin, ACTH) by a brain site of action. Additionally, these peptides stimulate stress-related behavioral responses (activity) and at least one acts in brain to stimulate sympathetic activity resulting in increased blood pressure. These peptides (prolactin releasing peptide, PrRP;neuropeptide W, NPW;and neuropeptide B, NPB) are produced in separate populations of neurons in brain, many of which innervate the hypothalamic paraventricular nucleus (PVN), arcuate nucleus (ARC) and ventromedial and dorsomedial hypothalamic nuclei (VMH/DMH). All three peptides are contained in neurons that innervate autonomic centers in hypothalamus and brain stem. It is our goal to understand the roles these peptides play in the hypothalamic and extrahypothalamic responses to stress. We address multiple specific aims all related to the founding hypothesis that one or more of these peptides is essential for the endocrine and/or cardiovascular response to stress, under certain paradigms of stress. Our approach will be to demonstrate direct effects of these peptides on identified fore- and hindbrain neurons [e.g. in PVN, ARC, VMH/DMH, nucleus tractus solitarius (NTS), rostral lateral medulla (RVLM), and dorsal motor nucleus of the Vagus] using electrophysiologic, pharmacologic and single cell RT- PCR approaches. We will then attempt compromise of peptide production and examine hormone secretion in response to physical stress and the cardiovascular response to hypertensive and hypotensive challenge (i.e. baroreflex sensitivity). Understanding the normal mechanisms controlling the response to stress will reveal potential strategies for the management of stress in the human population and the cardiovascular and metabolic consequences of that stress. These studies may also provide insight into the central mechanisms contributing to development of the metabolic syndrome (Syndrome X), which is characterized by obesity, poor glycemic control, altered metabolic and autonomic function and a propensity for adverse cardiovascular outcomes. Additionally, these studies will provide further insight into the coordinated hormonal and autonomic responses to stress.
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