Opioid-BNST interactions in the regulation of trauma-induced anxiety states

Project Summary
The Department of Psychiatry is deeply committed to the career development of the candidate. As such, he is
being recruited as Assistant Professor of Psychiatry and Behavioral Sciences, on the Clinician Educator track,
in the Division of General Psychiatry with plans to transition to tenure track in the near future. He will be provided
with over 75% protected research time. The career development plan is designed to ensure a transition towards
independence. A career development committee will guide this transition with Dr. Sachin Patel being the primary
mentor. Dr. Danny Winder and Dr. Jennifer Blackford will serve as internal members and Dr. Thomas Kash from
University of North Carolina at Chapel Hill as external member. The candidate plans to obtain technical training
in state-of-the-art slice electrophysiology, intersectional viral approaches, and sophisticated data analysis
methods for in vivo single cell calcium imaging and expand his knowledge in optogenetics, microinfusions, and
mouse behavioral models. This will be done while leveraging on the many available resources at Vanderbilt and
its collegial environment.
It is estimated that up to half of patients seeking treatment for substance use disorders have PTSD, and these
individuals have worse treatment outcomes for both conditions. Opioid use disorder (OUD) is a common sequela
following trauma and is highly comorbid with PTSD. This project entitled “Opioid-BNST interactions in the
regulation of trauma-induced anxiety states- Towards common substrates in trauma-related disorders and opioid
use disorder comorbidity.” will focus on elucidating the neurobiology of co-morbidity between post-traumatic
stress disorder and opioid use disorder, a highly devastating combination. This proposal aims to test the novel
hypothesis that following a traumatic event, the endogenous opioid system becomes dysregulated in the bed
nucleus of the stria terminalis (BNST) which in turn lead to dysregulated anxiety and could explain vulnerability
to opioid use. Aim 1 will elucidate a putatively anxiolytic circuit, the basomedial amygdala (BMA) to BNST to
lateral hypothalamus (LH). Aim 2 will assess how the BMA-BNST-LH circuit is modulated by mu opioid receptors
to reduce fear and anxiety behaviors and how this system is disrupted following a traumatic stress. Aim 3 will
focus on characterizing in vivo neural activity of BNST-LH neurons in freely behaving mice during fear and
anxiety assays, how this signaling becomes disrupted following a traumatic event, and how the disrupted circuit
normalizes with exogenous opioids.
This project takes advantage of opportunities for independent scientific thinking, technical and professional
training from Dr. Patel and the mentoring committee, and the resources at Vanderbilt while simultaneously
allowing differentiation from his mentors towards an important novel scientific direction. Receiving the K08 will
maximize candidate’s training by increasing important protected time and resources to ensure a timely
development of a successful physician-scientist career.