Project Summary Despite therapeutic advances, ~20% of patients with hypertension have uncontrolled high blood pressure, a condition that is associated with dysfunction in brain cardiovascular control centers. Therefore, there is a critical need to understand the neural pathways involved in cardiovascular regulation and how their dysfunction contributes to high blood pressure. This is particularly important for hypertension that is induced by chronic social stress, a major problem in today’s world, which involves activation of neuroendocrine and autonomic mechanisms. Our previous studies using novel genetic mouse models, viral-mediated gene transfer and optogenetics have revealed angiotensin type-2 receptor (AT2R)-containing neural pathways within the nucleus of the solitary tract (NTS) as important anti-hypertensive targets. Activation of AT2R-containing NTS neurons [referred to as NTSAT2R neurons] elicits profound increases in blood pressure; in contrast the AT2R(s) themselves serve a negative regulatory function, as their activation decreases blood pressure under both normal and hypertensive conditions. Based on our findings, we have developed the hypothesis that NTSAT2R neurons are a critical component of the neural pathways that mediate hypertension induced by chronic social stress. Specifically, we predict that during chronic social stress their activity is driven by excitatory (glutamatergic) inputs from the paraventricular nucleus of the hypothalamus (PVN), and that they in turn raise blood pressure via two mechanisms: Activation of GABAergic NTSAT2R neurons, which are the largest population of AT2R containing cells in the NTS, elicits baroreflex inhibition; Activation of Glutamatergic NTSAT2R neurons, which project to higher order brain regions such as the PVN, increases sympathetic outflow and neuroendocrine secretion. We further predict that selective activation of AT2R(s) present on NTS neurons will offset social stress-induced hypertension by restoring baroreflex function and normalizing sympathetic outflow and neuroendocrine secretions. Our overall hypothesis will be tested in three Aims that utilize a novel model of hypertension in mice (Chronic Social Defeat Stress [CSDS]) along with genetic (e.g., optogenetic and chemogenetic) and pharmacological approaches. Aim 1: Dissecting a specific neural circuit that impinges on and regulates NTSAT2R neurons, will test the specific hypothesis that PVN inputs to NTSAT2R neurons are necessary and sufficient to promote CSDS hypertension. Aim 2: Investigating distinct mechanistic roles for GABAergic vs. glutamatergic NTSAT2R neurons in regulation of blood pressure during hypertension, will test the specific hypothesis that GABAergic NTSAT2R neurons inhibit the baroreflex, while glutamatergic PVN-projecting NTSAT2R neurons stimulate vasopressin neurons and sympathetic outflow. Aim 3: Targeting NTSAT2R neurons to alleviate CSDS hypertension, will test the specific hypotheses that NTSAT2R neurons a...