BETA2* NICOTINIC RECEPTORS TUNE PREFRONTAL BEHAVIOR THROUGH DISTINCT NEURONAL POPULATIONS

Nicotinic acetylcholine receptors containing beta2 subunit (beta2* nAChRs) are widely expressed in the mouse prefrontal cortex (PFC), where they regulate behavioral and cognitive domains associated with this region and represent potential therapeutic targets for neuropsychiatric symptoms. However, current pharmacological tools cannot distinguish among receptors expressed by different neuronal populations, and the functional roles of beta2* nAChRs in specific neuronal types remain poorly understood. In this study, we examined the expression and behavioral significance of beta2* nAChRs in distinct neuronal populations of the mouse PFC. We first used fluorescence in situ hybridization (FISH) to analyze the expression of the beta2 nicotinic subunit in major neuronal types and cortical layers. We then used CRISPR to knock down (KD) the beta2 subunit in two PFC populations and, for comparison, in a striatal population. KD of the beta2 subunit in deep-layer PFC neurons defined by neuropeptide Y (NPY) expression specifically altered working memory and exploratory behavior and affected social and anxiety-like behavior. In contrast, KD in PFC interneurons expressing serotonin receptor 5HT3a led to a hypersocial phenotype. KD of beta2* nAChRs in a rare NPY-expressing striatal population resulted in subtler and largely opposing changes in similar behavioral domains. These findings show that beta2* nAChRs expressed by distinct neuronal populations contribute differentially, and sometimes oppositely, to behavioral regulation. Our data suggest that cell-type- and region-specific expression of beta2* nAChRs is required for the modulation and fine-tuning of behavioral domains relevant to neuropsychiatric disorders.