Forced Abstinence From Alcohol Induces Sex-Specific Depression-Like Behavioral and Neural Adaptations in Somatostatin Neurons in Cortical and Amygdalar Regions

Abstract

Forced abstinence (FA) from alcohol has been shown to produce a variety of anxietyand depression-like symptoms in animal models. Somatostatin (SST) neurons, a subtype of GABAergic neurons found throughout the brain, are a novel neural target with potential treatment implications in affective disorders, yet their role in alcohol use disorders (AUD) remains to be explored. Here, we examined the neuroadaptations of SST neurons during forced abstinence from voluntary alcohol consumption. Following 6 weeks of two-bottle choice alcohol consumption and protracted forced abstinence, male and female C57BL/6J mice exhibited a heightened, but sex-specific, depressivelike behavioral profile in the sucrose preference test (SPT) and forced swim test (FST), without changes in anxiety-like behaviors in the elevated plus maze (EPM) and open field test (OFT). FST-induced cFos expressions in the prefrontal cortex (PFC) and ventral bed nucleus of the stria terminalis (vBNST) were altered in FA-exposed female mice only, suggesting a sex-specific effect of forced abstinence on the neural response to acute stress. SST immunoreactivity in these regions was unaffected by forced abstinence, while differences were seen in SST/cFos co-expression in the vBNST. No differences in cFos or SST immunoreactivity were seen in the lateral central nucleus of the amygdala (CEA) and the basolateral amygdala (BLA). Additionally, SST neurons in female mice displayed opposing alterations in the PFC and vBNST, with heightened intrinsic excitability in the PFC and diminished intrinsic excitability in the vBNST. These findings provide an overall framework of forced abstinence-induced neuroadaptations in these key brain regions involved in emotional regulation and processing.

Bi-directional control of a prelimbic somatostatin microcircuit decreases binge alcohol consumption

“…We previously reported that PL SST neurons are hyperexcitable following prolonged withdrawal from alcohol drinking (> 4 weeks) in a 2-bottle choice model (34), which contrasts with the hypoexcitable state in acute withdrawal (24-h) from DID observed here. It should be noted that the excitability recording in the former report was done following an acute stressor (forced swim).…”

“…Whole cell voltage clamp and current clamp recordings were conducted in the PL similarly to those previously published (spontaneous excitatory and inhibitory postsynaptic currents, sEPSCs and sIPSCs respectivelu, and intrinsic excitability (20,21,34); confirmation of DREADD expression and function (30)). The PL was identified according to the Allen Mouse Brain Atlas.…”

Chronic Ethanol Exposures Leads to a Negative Affective State in Female Rats That Is Accompanied by a Paradoxical Decrease in Ventral Hippocampus Excitability

“…A caveat is that the majority of these preclinical studies have been conducted in male subjects. In studies that have looked at sex-dependent neuronal response differences in models of alcohol dependence and/or stress, examples of sex-divergent responses are numerous (Morales et al, 2018;Blume et al, 2019;Dao et al, 2020;Joffe et al, 2020;Kasten et al, 2020). The BLA is a brain region of particular interest in this context, given that it sends a strong excitatory projection to the vHC that, when activated, elicits anxiogenesis (Felix-Ortiz and Tye, 2014;Beyeler et al, 2018).…”

The Kappa Opioid Receptor is required for some intermittent alcohol drinking induced changes in stress and threat responding in male C57BL/6J mice

“…Taken together, these findings suggest repeated swim stress makes BNST Pdyn cells more excitable. Others have found that ventral BNST somatostatin cells have increased rheobase, reduced AP threshold, and reduced number of action potentials during protracted abstinence from EtOH, suggestive of GABAergic disinhibition (Dao et al 2020). Our lab recently has shown that withdrawal from chronic intermittent EtOH increases neuronal excitability of BNST CRF neurons, which overlap with Pdyn neurons in the dBNST (Pati et al 2020).…”