PATHWAYS INTEGRATING STRESS AND CARDIOVASCULAR RESPONSES

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DESCRIPTION (applicant's abstract): Cardiovascular sensory information is received and processed by the nucleus of the solitary tract (NTS) and then forwarded to relays in the ventrolateral medulla (VLM) that launch adaptive responses by way of highly differentiated projections to autonomic effectors in the brainstem and spinal cord, and to neurosecretory neuron populations in the paraventricular hypothalamic nucleus (PVH). While basic stimulus-effect relationships in this network are reasonably well understood, there remain major gaps in knowledge of the intervening pathways that provide for integrated responses. Guided by immediate-early gene (IEG) markers of neuronal activation, changes in the expression of genes encoding key effector or transmitter-related molecules will be followed, in situ, in response to cardiovascular challenges, central ablations, and pharmacologic manipulations, and complemented with neuroanatomical tract tracing experiments at the light and electron microscopic levels, to clarify the functional organization of pathways that mediate neuroendocrine and autonomic responses to perturbations in the circulatory milieu. An initial study will exploit the ability of IEGs to demarcate NTS populations presumed to receive primary arterial baroreceptor afferent input to determine how this may be distributed to populations that project to sympathetic premotor neurons, vagal cardiomotor neurons, and cells that innervate distinct neurosecretory neuron populations in the PVH. Next, the organization of barosensitive projections to the locus coeruleus and of local GABAergic interneurons to the PVH will be determined, and their responses to challenges that differentially affect blood pressure and/or volume will be characterized. Third, neurotoxin lesioning methods will be used to evaluate the roles of aminergic pathways arising from the caudal medulla and from the locus coeruleus mediating hemorrhage-induced activational and biosynthetic responses in magno- and parvo-cellular neurosecretory neurons; local microinjection experiments will assess the ability of adrenoceptor antagonists to interfere with hemorrhage-induced responses. Finally, a discrete aspect of the septal region has been implicated in the baroreceptor-mediated inhibition of magnocellular neurosecretory neurons. Excitotoxin lesioning methods will be used to evaluate the contribution of this cell group in mediating the effects of hyper- and hypotensive challenges on PVH effector populations. The neural and neuroendocrine systems under scrutiny mediate essential physiologic processes, dysregulations of which have, in isolation or interactively, been implicated in the genesis of multiple forms of hypertension. Aspects of this circuitry are targeted by a promising new class of antihypertensive pharmaceuticals. The results are expected to contribute to clearer understanding of its functional organization.