The proposal represents a continuation of a Program in Experimental Neurogenic Hypertension. It delineates a series of fundamental multidisciplinary studies into the neurobiology of the central control of portions of the autonomic nervous system regulating arterial pressure. The broad objectives of this study are: (a) to map by neuroanatomical techniques using transport of tracers, functional mapping with 2-deoxyglucose and immunocytochemical methods both by light and electron microscopy the pathways, neurotransmitters and synaptic interactions of pathways in the brain subserving cardiovascular control, including those of the nucleus tractus solitarii (NTS), rostral regions of the medulla including those containing C1 adrenergic neurons, and portions of the anterior hypothalamus; (b) to examine the manner by which the brain regulates cerebral blood flow and metabolism and, in particular, the adrenal and adrenal-independent mechanisms eliciting global metabolic changes elicited from the medullary reticular formation; (c) to determine by light and electron miscroscopy, by electrophysiology, including iontophoretic techniques, the synaptic interactions and transmitter characteristics of pathways between the NTS, the C1 area of the rostral ventrolateral medulla and the sympathetic preganglionic neurons of the spinal cord, regions critically involved in the tonic and reflex control of blood pressure; (d) to characterize by neurochemical and autoradiographic procedures the neurotransmitters and their receptors residing in the critical medullary cardiovascular sites, the NTS and C1 area, with identification, if possible, of new transmitter agents; (e) to characterize the role of cholinergic mechanisms in brainstem cardiovascular control; (f) to identify the pathways in the brain which subserve the expression of the elevations of arterial pressure associated with emotional conditioning (the conditioned emotional response), and to trace the pathways through which the conditioned auditory signals acquire their emotional coloration; (g) to isolate the genes responsible for the biosynthesis of catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH), dopamine-B-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT); (h) to characterize the steps in transcriptional and translational control of the expression of adrenal medullary catecholamine biosynthetic enzymes; (i) to determine the timing and regulation of the differentiation of cholinergic elements of the autonomic nervous system by use of biochemical, immunocytochemical and genetic analysis in vivo and in vitro in relationship to the expression or suppression of catecholamine phenotypes.
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