BNST PKCdelta Roles in Affective Behavior

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Chronic stress exposure is implicated in several psychological disorders such as PTSD, anxiety, depression, and addiction, and stressful experiences are one of the most common causes of drug relapse. The Bed Nucleus of the Stria Terminals (BNST) is known to mediate many stress responses and anxiety-like behaviors that contribute to the cycle of relapse characteristic of substance use disorders. In the BNST, cells expressing corticotropin-releasing factor (BNSTCRF) play a role in increasing anxiety-like behaviors, and inhibition of CRF signaling in the BNST can prevent stress-induced reinstatement of drug seeking in rodent models. However, clinical efforts to target the CRF system as a treatment for substance use disorders have proved largely unsuccessful, highlighting the need for innovative therapeutic targets. BNST cells expressing Protein Kinase C- delta (BNSTPKCd) are an equally abundant but largely distinct population from the BNSTCRF cells. We have found that expression of this kinase is also dynamically regulated by stress, but the role of PKCd and BNSTPKCd cells in stress responses and anxiety-like behaviors remains understudied. Specific Aim 1 details the progress the applicant, Kellie Williford, has made toward characterizing the function of BNSTPKCd cells in stress- and anxiety-like behavior using a combination of in vivo optogenetics and fiber photometry approaches. The F99 phase of this proposal (Specific Aim 2) will expand upon these findings by investigating the function of BNSTPKCd cells through circuit-based connectivity. Here, rabies-mediated tracing will be used to determine the brain-wide afferents of the BNSTPKCd population. Additionally, shRNA-mediated knockdown will be used to investigate the functional significance of PKCd expression within cells in the BNST in mediating anxiety-like behavior. The K00 phase of this proposal (Specific Aim 3) will help prepare the applicant for a successful academic research career investigating the contributions of stress to drug relapse in substance use disorders. This postdoctoral phase will provide Ms Williford with experience in addiction-based experimental techniques and sharpen critical managerial and mentoring skills to thrive as an independent investigator. In doing so, this proposal will help provide insight into potential new therapeutic targets that can be manipulated to prevent maladaptive stress responses. In the long term, it will also equip the candidate to extend this work to stress- induced relapse of drug seeking and improve treatment outcomes for those struggling with substance use disorders.