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Here we show that isolation escalates alcohol drinking in male mice but suppresses it in females. Whole-cell recordings revealed that neurons in the basolateral amygdala projecting to the medial prefrontal cortex (BLA-mPFC) track alcohol intake in both sexes. Isolation increased BLA-mPFC excitability in males but decreased it in females, mirroring their opposite behavioral adaptations. Given this divergence, we focused subsequent mechanistic studies on males to isolate neural pathway-level drivers of escalated alcohol intake. Cellular-resolution calcium imaging showed that activity in BLA-mPFC neurons encodes and predicts alcohol drinking, and optogenetic activation of this pathway increased alcohol intake. Simultaneous optogenetics and calcium imaging revealed that BLA-mPFC stimulation enhanced mPFC neuronal responses to alcohol, mimicking isolation-induced activity patterns, while photoinhibition reduced drinking in isolated mice. Together, these findings identify a BLA-mPFC pathway mechanism through which social isolation reconfigures prefrontal processing to promote alcohol intake.<\/jats:p>","DOI":"10.1101\/2023.11.09.566421","type":"posted-content","created":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T13:55:22Z","timestamp":1699624522000},"source":"Crossref","is-referenced-by-count":1,"title":["Social isolation recruits amygdala-medial prefrontal cortex projections to escalate alcohol drinking in male mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3913-6311","authenticated-orcid":false,"given":"Reesha R.","family":"Patel","sequence":"first","affiliation":[{"name":"Salk Institute for Biological Studies, La Jolla, CA, USA"},{"name":"Stephen M. 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