Grants and Contracts Details
Description
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.
Status | Active |
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Effective start/end date | 8/6/21 → 5/31/26 |
Funding
- National Institute on Alcohol Abuse and Alcoholism: $652,716.00
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