Saturday, December 21, 2024
12/21/2024
PROJECT SUMMARY/ABSTRACT Post-traumatic stress and alcohol use disorder (PTSD/AUD) are frequently comorbid and are a major US health burden. Individuals with comorbid PTSD/AUD manifest complex symptoms including greater risk for alcohol drinking and relapse, sleep disturbances, hyperarousal, drinking-related aggression, and increased suicidal ideations. Identification of the molecular mechanisms underlying PTSD/AUD disorder will aid the development of novel therapeutic strategies. In this proposal, my focus will be on two key components of the extended amygdala (EA), the central amygdala (CeA) and the bed nucleus stria terminalis (BNST). The CeA and BNST are regions essential for the regulation of alcohol consumption, stress, and anxiety. In the EA, overactive brain stress systems are hallmark feature of comorbid PTSD/AUD, primarily driven by the pro-stress neuropeptide, corticotrophin releasing factor (CRF), resulting in long-lasting negative emotional states. New research has highlighted that the neuropeptide somatostatin (SST) displays anxiolytic (anti-stress) and alcohol-reducing properties and may act to oppose the effects of CRF in the brain. Both CeA and BNST are abundant in SST/CRF, and blockade of CRF or activation of SST system reduces consumption of alcohol and anxiety-like behavior in various rodent models and species. In this proposal, I will apply a multidisciplinary approach (e.g., in situ hybridization, ex vivo electrophysiology, chemogenetics, viral gene transfer of SST, and site-specific behavioral pharmacology) to understand the role of SST system in the EA in PTSD/AUD comorbidity. My overarching hypothesis is that SST signaling may exert reductions of PTSD/AUD phenotypes counteracting an “overactive” CRF in the EA. During my K99 mentoring phase, I will receive critical training in in situ hybridization, and ex vivo electrophysiology to understand neuronal expression and synaptic function of SST/CRF systems in PTSD/AUD. During my independent R00 phase, I will continue to perform electrophysiology, and apply site-specific behavioral pharmacology combined with chemogenetics and viral expression of SST to examine the behavioral modulation of PTSD/AUD by SST/CRF systems. The goal of this MOSAIC K99/R00 is to enhance my training in in situ hybridization and electrophysiological methods to complement my prior training in addiction neuroscience. This award will also provide critical professional career development to guide me in building an independent research program centered around stress disorders and AUD. Collectively, the proposed work will provide novel insight into the mechanistic role of SST and its potential therapeutic use for PTSD/AUD.
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