Grants and Contracts Details
PROJECT SUMMARY/ABSTRACT Abstinence from alcohol use induces a negative affective state that can lead to maladaptive responses to stress and relapse. Preclinical studies have begun to identify neurocircuits and peptide targets that regulate negative affect during abstinence. As the field has begun to develop a deeper understanding of the circuitries participating in addiction and negative affect, the next step is to understand how communication within these circuits is modulated particularly at the neuropeptide and microcircuit level. The bed nucleus of the stria terminalis (BNST) is a fundamental component of abstinence-relevant neurocircuitry as it modulates stress and alcohol-related behavior in a neuropeptide-dependent manner. To investigate peptide-specific BNST circuitry modulating negative-affect during abstinence, we will focus on afferents from the parabrachial nucleus (PBN), a brainstem region that functions as a danger signal. PBN projections to the BNST release calcitonin gene- related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP), peptides that modulate pain and fear circuits, respectively. This proposal will investigate how CGRP and PACAP contribute to PBN-BNST circuit induced abstinence-induced behavior, in vivo and ex vivo activity. Accordingly, in the mentored K99 phase, I learned to use ex vivo multi-neuronal imaging to demonstrate PBN(CGRP) projections decrease BNST activity through recruitment of inhibitory and excitatory neuronal populations. Additionally, I demonstrated these PBN(CGRP) projections colocalize in part with PACAP expressing projections onto PKCδ -expressing BNST cells. Altogether supporting our hypothesis of a heterogenous PBN-BNST circuit. The independent R00 phase will build on this foundational evidence by using transgenic animal models, classic behavioral assays, trans-neuronal chemogenetic and viral strategies and in vivo and ex vivo physiology recordings to investigate the role of PACAP on BNST-PBN at the microcircuit level and on anxiety- and alcohol-relevant states. The proposed studies will help facilitate my transition to Assistant Professor role and serve as the foundation for my independent research program and future R01 submission, with the goal to further delineate the intricacies of peptide crosstalk while informing the use of peptidergic pharmacotherapies in alcohol use disorders.
|Effective start/end date||8/6/21 → 5/31/26|
- National Institute on Alcohol Abuse and Alcoholism: $406,729.00
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