Posttraumatic Stress Disorder (PTSD) is a disabling psychiatric condition that is highly prevalent in combat veterans. Only a fraction of trauma-exposed individuals develop PTSD, suggesting that pre-existing neurobiological factors contribute to susceptibility/ risk. Currently, specific molecular/ circuit-level mechanisms that contribute to PTSD risk are not well-defined. Substantial information supports that pre-existing dysfunction in fear circuits may promote vulnerability to PTSD, however mechanisms contributing to pre-trauma individual differences in fear regulation are unclear. To date, most of our current understanding of fear is based on defensive reactions to external threats. While the importance of “body-to-brain” signaling in emotional regulation has long been recognized, the role of homeostatic threats in shaping individual differences in fear and PTSD risk has not been investigated. Previous studies reported increased sensitivity in veterans with PTSD to carbon dioxide (CO2), a homeostatic threat producing intense fear. Importantly, pre-deployment CO2 sensitivity associates with later development of PTSD symptoms, suggesting that CO2 sensitivity and associated mechanisms can provide valuable information on PTSD risk. Previous work from the PI’s lab reported a unique role of interleukin 1 receptor (IL-1R1) signaling within blood-brain-barrier (BBB) compromised sensory circumventricular area, subfornical organ (SFO) in CO2-evoked fear responses. In a mouse model of CO2 sensitivity-PTSD, we observed delayed fear extinction deficits and enhanced startle in CO2-sensitive mice, a response attenuated by IL-1R1 antagonism in SFO. Our molecular studies reveal IL-1R1 localization on SFO endothelial cells and interaction with renin angiotensin system (RAS) targets, and forebrain regions infralimbic cortex and bed nucleus of stria terminalis (BNST), also implicated in PTSD. Collectively, our data support a unique neurovascular signaling mechanism in an interoceptive brain region (SFO) that may regulate forebrain fear circuits contributing to increased PTSD risk. Proposed studies will investigate how neurovascular mechanisms within the SFO regulate fear circuits and contribute to PTSD- relevant behaviors. We will use cell-circuit based transgenic, electrophysiological and chemogenetic approaches in male and female mice. Our hypothesis that, SFO neurovascular IL-1R1-RAS interactions with forebrain circuits promote CO2-sensitivity and PTSD relevant behaviors will be tested under three aims. Aim 1 will test the hypothesis that CO2-associated PTSD relevant behaviors are dependent on SFO endothelial IL-1R1 and RAS Delayed fear conditioning, extinction, and startle (PTSD-relevant behaviors) will be measured in air/CO2 exposed wild type or endothelial-specific deletion of IL-1R1 (Tie-2Cre:IL1R1fl/fl) mice treated with SFO-targeted RAS modulators. Aim 2 will test the hypothesis that CO2-evoked activation of SFO projection neurons is dependent on endoth...