The inhibitory neurotransmitter gamma-amino-butyric acid (GABA) has been shown to have a profound effect on the integration of baroreceptor inputs by neurons within the nucleus of the solitary tract (NTS), the initial site of termination of baroreceptor afferent fibers. However, detailed information on the receptor subtypes, types of modulation and other factors, at the level of the single cell are presently lacking. The proposed experiments will test the hypothesis that GABAergic mechanisms determine the pressure threshold and supra-threshold sensitivity of neurons in the nucleus of the solitary tract (NTS) in response to baroreceptor stimuli. It is further hypothesized that GABAergic interneurons within the NTS mediate these effects and can thereby set the operating point and range of the arterial baroreflex. These GABAergic interneurons are hypothesized to receive inputs from peripheral afferents (baroreceptors) and central (parabrachial nucleus) sources. The final hypothesis to be tested is that in hypertensive rats, descending inputs from the parabrachial nucleus mediate enhanced GABA-B receptor mediated inhibition of NTS neurons. This effectively shifts the baroreflex curve to higher pressures and contributes to the maintenance of the hypertension. To test these hypotheses, a variety of experimental approaches will be used. Acute experiments in anesthetized rats will use: Extracellular recordings combined with iontophoretic techniques to examine if activation or antagonism of GABA receptor subtypes on NTS neurons alters neuronal responses to changes in arterial pressure; Intracellular recording techniques to characterize the membrane basis of inhibitory responses and how stimulus frequency might attenuate or enhance synaptic inhibition; Intracellular recording techniques combined with immunocytochemistry to identify GABAergic interneurons within NTS and characterize their responses to changes in arterial pressure and activation of other central nuclei; Microinjection and electrophysiological techniques will be used to determine the role of GABAergic mechanisms within the NTS in 2 models of hypertension (one kidney renal wrap and angiotensin II dependent). These results will provide important insights into the integration of baroreceptor inputs within the NTS and mechanisms whereby these integrative processes can be modified by GABAergic inhibition. They will also provide insights into the organization of the NTS by characterizing a specific class of interneuron, identified by content of GABA, and other NTS neurons identified by their projection sites. This will indicate whether NTS neurons are a homogeneous population or if neurons with differing output projections exhibit different characteristics. Finally, these results will also provide insights into baroreflex regulation of arterial pressure in hypertensive states.
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