CNS GABA PHARMACOLOGY AND CONTROL OF AUTONOMIC FUNCTION

Indiana Univ-Purdue Univ At Indianapolis, Indianapolis IN

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Abstract

DESCRIPTION: Emotional stress in mammals triggers a diverse but highly stereotyped pattern of physiological changes, and these are thought to contribute to a wide variety of human disorders and disease states. While the central mechanisms and pathways mediating these changes are largely unknown, the hypothalamus has long been conceded to embody the neural "command center" for the stress response. For nearly two decades the primary role for the hypothalamic integration of the autonomic and neuroendocrine response to stress has been attributed - virtually unchallenged - to the paraventricular nucleus of the hypothalamus (PVN). However, previous findings from the applicants indicate that neurons responsible for generating the autonomic - particularly the cardiovascular - changes associated with stress are found in the region of the dorsomedial hypothalamic nucleus (DMH) and not the PVN. The studies planned will extend these published findings and expand upon more recent preliminary data to 1) test the hypothesis that neurons in the region of the DMH - and not the PVN - are responsible for the integrated autonomic and neuroendocrine response to stress, and 2) identify the local neurons and the central neural pathways that may mediate these effects. The specific aims are to 1) characterize the effect of chemical stimulation of the DMH on plasma ACTH in conscious rats, and examine the effect of inhibition and lesion of neurons in the DMH and the PVN on the increase in plasma ACTH, heart rate and blood pressure seen in air stress, 2) compare the effect of air stress and of chemical stimulation of the DMH on the pattern of stress-induced Fos expression in the brain in conscious rats, and assess the effect of inhibition and lesion of neurons in the DMH on this pattern, with particular attention to the nearby PVN, and to vagal and sympathetic preganglionic neurons in the brainstem and spinal cord, and 3) identify the specific neurons in the region of the DMH and their efferent projections that are likely to be responsible for these changes by a combination of high-resolution functional mapping of the region, localization of stress-induced Fos expression, and anterograde and retrograde tracer studies. The experiments proposed will enhance our understanding of the DMH and its place in hypothalamic circuitry and function, and in so doing should provide the basis for revolutionizing current thinking regarding the location of hypothalamic neurons integrating the multi-system physiologic response to stress.