PPP1R1B differentially modulates alcohol intake and emotional comorbidity through distinct prefrontal circuits.

Activation of medial prefrontal prelimbic-to-nucleus accumbens core glutamatergic projections in mice reduces short-term alcohol intake and anxiety- and depression-like behaviors.

• Why it matters: Alcohol use disorder often co-occurs with anxiety and depression, but the projection-specific neural circuits and molecular drivers coordinating these comorbid symptoms are not well defined.
• What they did: In a 4-wk intermittent access to alcohol paradigm, mice received chemogenetic activation of PL or IL projections to Nac core, Nac shell, or BLA, alongside retrograde tracing, electrophysiology, spatial proteomics, and circuit-specific PPP1R1B gene editing.
• The result: PPP1R1B was downregulated in PL-Nac core neurons after IAA, and circuit-specific knockout recapitulated alcohol- and affective phenotypes while overexpression reversed them; IL-BLA PPP1R1B manipulation affected alcohol intake and anxiety but not depression.

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