Project Summary Repeated episodes of binge alcohol drinking dysregulate serotonin (5-hydroxytryptamine, 5-HT) systems throughout the brain, which may place an individual at greater risk of developing an alcohol use disorder (AUD). The orbitofrontal cortex (OFC) is one site of 5-HT innervation that has been shown to undergo plastic changes after heavy alcohol intake. Previous work has indicated that chronic alcohol exposure disrupts 5-HT signaling in the OFC, leading to a loss of its inhibitory control in this region. Preliminary findings from the parent R00 grant show that binge-like patterns of alcohol intake alter OFC activity across multiple species and produce profound impairments in 5-HT1A receptor signaling in this region. However, this work from our group and others has focused primarily on pyramidal neurons when evaluating alcohol’s impact on the OFC. Of note, the OFC has a complex microcircuitry that contains interspersed GABA interneurons (INs) that fine- tune the activity patterns of pyramidal cells and other IN populations. These cortical INs, which can be broadly classified based on their expression of parvalbumin (PV) or somatostatin (SST), appear to serve distinct roles in the coordination of OFC activity. Given the complex microcircuitry of the OFC and interplay between its mixed neuronal populations, it will be informative to examine the broader cellular network in which alcohol-induced adaptations may occur. At present, the impact of binge intake on OFC PV-INs and SST-INs remains unknown. The project proposed by the supplement candidate will address this knowledge gap through a series of experiments that evaluate plasticity induced by binge-like alcohol drinking in PV-INs and SST-INs and its effect on 5-HT signaling in these cell populations. In Aim 1, the candidate will perform whole-cell patch clamp electrophysiology recordings in the OFC of PV and SST reporter mice following repeated cycles of binge alcohol intake. Specifically, the candidate will examine changes in excitability, synaptic transmission, and 5-HT signaling in these genetically defined IN populations. In Aim 2, the applicant will use fluorescence in situ hybridization to measure the effect of binge alcohol on 5-HT receptor mRNA expression levels in OFC PV and SST INs. In addition to yielding novel information, this supplement award will add to the candidate’s existing scientific toolkit by allowing him to receive training in more advanced cellular and molecular techniques, including ex vivo electrophysiology, fluorescence in situ hybridization, and confocal microscopy. Beyond technical training, this diversity supplement will provide the candidate with professional development opportunities and an individualized mentoring plan that will support his graduate work and foster his career progression. Combined, the proposed project and supplemental training will enhance the candidate’s graduate research experience and facilitate his successful transition to the next ...