Arterial pressure (AP) and regional blood flows are finely tuned by the central nervous system CNS) via the sympathetic system. This neural control is essential to match circulation with respiration and behavior. It is also critical to the maintenance of a stable level of AP. Most of the work will be focused on a region of the brain (rostral ventrolateral medulla, RVLM) that plays a critical role in regulating sympathetic tone and AP. RVLM also deserves intensive study because it is the main site of action of numerous drugs that have actions either beneficial or detrimental to circulation. RVLM controls sympathetic tone via a small group of neurons (BS neurons) that project to the spinal cord. A key to understanding how RVLM controls AP is to find how BS neurons are in turn regulated and what type of transmitters they release. A third of the work proposed is to analyze with state of the art patch-clamp recording methods the local neuronal circuitry that regulates the activity of BS neurons. We will first identify the major synaptic inputs of these neurons. We will then examine in detail how catecholamines regulate their excitatory inputs since our preliminary data suggests that the antihypertensive clonidine and its new imidazoline congeners may work by mimicking the effect of noradrenaline at this level. Next we will study the presynaptic regulation of the synaptic inputs of BS neurons by other substances of pharmacological or toxicological interest like neuropeptides, nicotine and opiates. We will then determine whether RVLM contains interneurons that regulate the discharges of the BS neurons and we will identify the transmitters used by these interneurons. A second major aspect of the work will be to analyze the structure of various subclasses of BS neurons and to identify the type of transmitters that they release. This will be done with a new method that permits to localize an enzyme or an mRNA within a single neuron physiologically characterized """"""""in vivo"""""""". In the last part of the work we will examine the possibility that sympathetic tone could also be regulated by GABAergic inhibitory inputs that originate from the brainstem and, in particular, from the nucleus of the solitary tract. The research will contribute to the basic physiological knowledge needed to understand how sympathetic tone is regulated in health and in diseases such as arrhythmias, hypertension and dysautonomias.
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