Abstract
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.
Highlights
Alcohol use disorder (AUD) is a chronically relapsing disorder, and is characterized by the presence of a minimum of 2 symptoms related to both alcohol consumption behavior and the ramifications of that behavior [1, 2]
Alcohol binge-like drinking alters excitatory transmission onto, and neuronal intrinsic excitability of, PL SST neurons To examine Drinking in the Dark (DID)-induced plasticity in PL SST neurons, SST-IRES-CRE:: Ai9 male and female mice underwent DID for four cycles (Fig. 1A for representative expression and experimental timeline)
Both DID-exposed male and female DID exposed SST neurons showed an attenuation of sEPSC frequency as compared to their control counterparts (control male: n = 11 cells/5 mice, DID male: n = 11 cells/6 mice, control female: n = cells/5 mice, DID female: n = cells/ 5 mice, Fsex(1,39) = 2.1, p = 0.155; Somatostatin neurons control an alcohol binge drinking prelimbic
Summary
Alcohol use disorder (AUD) is a chronically relapsing disorder (with three sub-classifications: mild, moderate, severe), and is characterized by the presence of a minimum of 2 symptoms related to both alcohol consumption behavior and the ramifications of that behavior [1, 2]. The prelimbic (PL) cortex is a key brain region in addiction and substance use [6, 7], with projections to many limbic areas [7] including the bed nucleus of the stria terminalis (BNST) [8, 9] and the nucleus accumbens [10]. These PL glutamatergic outputs are thought to provide top-down regulation of affective and motivational behaviors. Recent work has demonstrated that repeated cycles of binge drinking diminishes NPY expression in the PL, and that activation of NPY signaling within the PL otherwise can reduce binge drinking [17], highlighting the engagement of these peptide-expressing GABA neurons in AUD and their therapeutic potentials
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