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Somatostatin (SST) neurons have been implicated in a variety of neuropsychiatric disorders such as depression and anxiety, but their role in substance use disorders, including alcohol use disorder (AUD), is not fully characterized. Here, we found that repeated cycles of alcohol binge drinking via the Drinking-in-the-Dark (DID) model led to hypoactivity of SST neurons in the prelimbic (PL) cortex by diminishing their action potential firing capacity and excitatory/inhibitory transmission dynamic. We examined their role in regulating alcohol consumption via bidirectional chemogenetic manipulation. Both hM3Dq-induced excitation and KORD-induced silencing of PL SST neurons reduced alcohol binge drinking in males and females, with no effect on sucrose consumption. Alcohol binge drinking disinhibited pyramidal neurons by augmenting SST neurons-mediated GABA release and synaptic strength onto other GABAergic populations and reducing spontaneous inhibitory transmission onto pyramidal neurons. Pyramidal neurons additionally displayed increased intrinsic excitability. Direct inhibition of PL pyramidal neurons via hM4Di was sufficient to reduce alcohol binge drinking. Together these data revealed an SST-mediated microcircuit in the PL that modulates the inhibitory dynamics of pyramidal neurons, a major source of output to subcortical targets to drive reward-seeking behaviors and emotional response.

Somatostatin neurons have been implicated in a variety of neuropsychiatric disorders such as depression and anxiety, but their role in substance abuse disorders, including alcohol use disorder (AUD), is not fully characterized. Here we found that repeat cycles of alcohol binge drinking in the Drinking-in-the-Dark (DID) model led to hypoactivity of somatostatin (SST) neuronal in the prelimbic (PL) cortex by diminishing their action potential firing capacity and excitatory/inhibitory transmission dynamic. We examined their role in regulating alcohol consumption via bidirectional chemogenetic manipulation. Both hM3Dq-induced excitation and KORD-induced silencing of PL SST neurons paradoxically reduced alcohol binge drinking in males and females, with no effect on sucrose consumption. This effect is mediated directly via monosynaptic connection from SST neurons onto pyramidal neurons and indirectly via an intermediate GABAergic source. Optogenetic-assisted circuit mapping revealed that PL SST neurons preferentially synapse onto pyramidal neurons over other GABAergic populations in males, whereas SST neuron-mediated inhibition is balanced across cell types in females. Alcohol binge drinking disinhibits pyramidal neurons by augmenting SST neurons-mediated GABA release and synaptic strength onto other GABAergic populations. Together these data suggest substantial interaction between alcohol binge drinking and SST neurons inhibitory circuit in the PL, as well as provide evidence for these neurons as a potential therapeutic candidate for the treatment of alcohol use disorders, including binge drinking.