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.