Luis E Rosas-Vidal - US grants

DESCRIPTION (provided by applicant): Deficient BDNF signaling has been associated with extinction failure and with a poor response to extinction- based therapies for PTSD. Deficient hippocampal-prefrontal connectivity has been correlated with PTSD severity. Our recent work in rats suggests that BDNF signaling from the ventral hippocampus (vHPC) to the infralimbic prefrontal cortex (IL) modulates fear extinction. Much of what we understand about the emotional regulation related to PTSD comes from experimental fear conditioning and extinction, which model the hyperarousal and re-experiencing of symptoms of PTSD. Much less is known, however, about excessive avoidance seen in PTSD. In Aim 1, we will investigate the role of BDNF signaling in extinction of avoidance. In Aim 2, we will improve BDNF signaling to facilitate extinction in rats unable to extinguish avoidance responses.

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.