Somatostatin neurons control an alcohol binge drinking prelimbic microcircuit in mice

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.

Somatostatin Neurons in the Bed Nucleus of the Stria Terminalis Play a Sex-Dependent Role in Binge Drinking

“…Using a multiplexed chemogenetic approach, we found that activation of this population of neurons reduced binge drinking in female, but not male, mice using the DID protocol. These effects were seen following multiple weeks of baseline drinking (allowing for control injections for DREADD manipulations), however intake levels were relatively stable across weeks (consistent with our previous publications such as Dao et al 2021 and those published by others (Rinker et al, 2017). Future work should investigate whether chemogenetic manipulation of BNST SST neurons has an effect on alcohol drinking concurrent with the first exposure to alcohol.…”

“…Vehicle: p < 0.001), but there was also a small but significant reduction in alcohol consumption levels following SalB administration (SalB vs. Vehicle: p = 0.020), reminiscent of the effects we previously reported in prelimbic SST neurons (Dao et al, 2021). In contrast, neither CNO nor SalB was able to reduce alcohol consumption in males ( p > 0.1).…”

“…Upregulation of SST neurons throughout the brain has been shown to ameliorate anxiety-like and depressive-like behavior (Fuchs et al, 2017). Indeed, SST neurons have been reasonably well characterized in cortical circuits (Urban-Ciecko & Barth, 2016; Cummings and Clem, 2020; Dao et al, 2021)_where they are found to have unique electrophysiological properties and can modulate a variety of behaviors. SST neurons have been less thoroughly investigated in subcortical regions, however.…”

“…The BNST, and the amygdala more broadly, are implicated in the withdrawal and negative affect stage of drug addiction (Koob & Volkow, 2010; Kash et al, 2015; Pleil et al, 2015). Our lab and others have shown alcohol influences SST neurons in regions of the mPFC (Joffe, Winder, & Conn, 2020; Dao et al, 2021; Li et al, 2021) - though little has been done to characterize BNST SST neurons and alcohol. Previous work by our lab showed that BNST SST neurons display decreased intrinsic excitability following a forced abstinence model (Dao et al 2020).…”

Adolescent Alcohol and Stress Exposure Rewires Key Cortical Neurocircuitry

“…Other populations of GABAergic neurons, including somatostatin (SST)-expressing and vasoactive intestinal peptide (VIP)-expressing interneurons were not found to change in number during the adolescent period ( Ueda et al, 2015 ). However, other studies show an increase followed by pruning of SST-expressing GABAergic cells in females ( Du et al, 2018 ) and their broad role in the PFC functioning ( Dao et al, 2020 , 2021 ) warrant further developmental investigation. There are also developmental changes in the interaction between other neurotransmitter systems and PFC GABA neurons.…”