Extended amygdala somatostatin role in post-traumatic stress and alcohol use disorder - 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.
