Hypertension is often characterized chronic changes in autonomic regulation including exaggerated sympathetic drive and baroreflex dysfunction. Two important brain nuclei which may provide a link to understanding the pathophysiology of hypertension are the midbrain periaqueductal gray (PAG) and parabrachial nucleus (PBN). Both the dlPAG and PBN have been previously linked to the development or maintenance of hypertension in animal models and activation of either nuclei evokes a rapid rise in sympathetic activity which is coupled with central attenuation of baroreflex function. Although the cardiovascular responses to stimulation of these regions are well documented, the central pathways mediating these changes remain to be fully identified. Recently, however, it was demonstrated that lesion of PBN essentially eliminated the hypertension and baroreflex inhibition evoked by dlPAG stimulation. This data suggested for the first time an important interconnection between the dlPAG and PBN which was critical for centrally evoked sympathoexcitation. Therefore, the primary aim of the present proposal is to investigate the interconnections between the dlPAG and PBN, defining more specifically the descending pathways through which dlPAG activation mediates sympathoexcitation and baroreflex modulation. The hypothesis to be tested is that activation of dlPAG mediates sympathoexcitation and baroreflex inhibition via selective excitation of neurons in the external lateral regions of the PBN. Activation of these PBN neurons, in turn, modulates baroreflex control of heart rate via descending inhibitory projections to cardiac parasympathetic preganglionic neurons and produces rapid increases sympathetic outflow via interconnections with the ventrolateral pons (A5 region). Pharmacological (microinjection) and electrophysiologial techniques (whole sympathetic nerve and single neuronal recordings) will be used to address five specific aims evaluating interconnections between the dlPAG, A5 and PBN regions. The results of these studies will investigate for the first time the role of descending inputs from the PAG on cardiovascular afferent processing by PBN and A5 neurons. These studies will also identify for the first time the neurotransmitters involved in these descending connections. In the long term it is hoped that the results of these studies will stimulate new investigations into the role of the dlPAG, A5 and the PBN in normal and pathophysiological cardiovascular regulation.