Thursday, May 15, 2025
5/15/2025
Targeting parvalbumin interneurons to mediate genetic risk for excessive drinking - Project Summary/Abstract Impulsivity has been identified as both a risk factor for and consequence of an Alcohol Use Disorder. To identify novel interventions to reduce alcohol use disorder development in at-risk populations, it is critical to clearly define how neural circuits that underlie impulsivity are altered by familial risk. Thus, the overarching goal of this work is to identify the neural circuit mechanisms underlying impulsivity, and how they are altered by genetic risk for excessive drinking. The dorsomedial prefrontal cortex (dmPFC) is a brain region that controls impulsive decision-making. Our lab has observed that dmPFC ensembles are required for strategy updates during delay discounting (DD), a task which models impulsive choice, but the distinct roles of specific cell types within dmPFC remain undetermined. This proposal will dive deeper into the contributions of specific cell-types and provide conceptual training in translational behavioral models, PFC microcircuitry, computational techniques, and technical training in high-density electrophysiology. Parvalbumin inhibitory interneurons (PV) are one of the most abundant interneuron subtypes in dmPFC and are capable of precisely regulating dmPFC activity. In particular, dmPFCPV-mediated gamma (ɣ) oscillations are known to be important for strategy updating and flexible behavior. Alcohol-preferring (P) rats are a well-validated preclinical model of behavioral genetic risk for excessive alcohol drinking. P rats drink much more alcohol than non-genetic risk progenitor strain controls (Wistars) and exhibit similar behavioral phenotypes due to familial risk that match clinical findings (i.e., increased impulsive choice). Preliminary data from our lab indicates that markers of PV function (PV protein and perineuronal net expression) are innately altered in P rats as compared to Wistars in dmPFC. This proposal will test the hypothesis that genetic risk for excessive drinking is associated with reduced dmPFCPV interneuron ɣ oscillatory activity, which results in deficits in strategy updating and increased impulsive choice. Aim 1 of this proposal will combine high-density in vivo electrophysiology and optotagging techniques to characterize 1) whether dmPFCPV interneuron-mediated ɣ oscillations facilitate strategy updating during DD and 2) whether dmPFCPV activity is disrupted in P rats. Aim 2 of this proposal will determine whether restoring dmPFC inhibitory tone via optogenetically inducing dmPFCPV ɣ oscillations is sufficient to reduce impulsive choice in P rats. Performing these experiments in conjunction with my professional development activities will enhance my conceptual training in the alcohol field and will provide the computational neuroscience skills critical for my research and necessary to transition to independence. Further, these results are expected to increase our understanding of the neurobiological and behavioral changes that underlie genetic risk for alcohol misuse and assist in the development of novel approaches to treat alcohol use disorder.
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