Sex differences in fast-spiking interneurons promote AUD-related PFC dysfunction: remediation by modulating mGlu1 and mGlu5 - Supplement Rev

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Project Summary We are requesting administrative supplement PA-20-272; NOT-OD-20-055: “Notice of Special Interest (NOSI): Administrative Supplement for Continuity of Biomedical and Behavioral Research Among First-Time Recipients of NIH Research Project Grant Awards.” The supplement is requested due to a critical life event for the PI, the birth of his second child. Additional funds are needed to support a part-time postdoctoral associate who will perform the whole-cell patch-clamp electrophysiology experiments, analyze data, and disseminate study findings via manuscripts and conferences presentations. This associate will be essential in returning our lab to our expected levels of productivity following the PI’s critical life event. No Change to Original Aims: Aim 1 (K99): To test the hypothesis that mGlu1 and mGlu5 modulation can ameliorate sex-specific alcohol- induced pathophysiology through actions on PFC PV-INs. PV-IN synaptic physiology and plasticity will be interrogated in an ex vivo slice preparation. In addition, PV-IN function will be examined in vivo with fiber photometry while female and male mice seek alcohol and perform other PFC-dependent behaviors. Aim 2 (R00): To test the hypothesis that sex-specific alcohol-induced dysregulation of distinct PFC outputs can be remediated through mGlu1 and mGlu5 modulation of inhibitory transmission. A viral approach will be used to label PFC pyramidal cells based on projection target in female and male transgenic optogenetic mice (PV- ChR2). We will assess how PV-INs control specific PFC output pathways following intermittent alcohol exposure, and how these phenomena are regulated by sex and mGlu1/mGlu5.