# Neurovascular signaling and associated forebrain circuits in PTSD

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2022 · —

## Abstract

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...

## Key facts

- **NIH application ID:** 10293565
- **Project number:** 5I01BX001075-09
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** RENU SAH
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-04-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293565

## Citation

> US National Institutes of Health, RePORTER application 10293565, Neurovascular signaling and associated forebrain circuits in PTSD (5I01BX001075-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10293565. Licensed CC0.

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