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

Abstract

251 words Main Text: 6367 words Figures: 6 Dao et al. Forced Abstinence in Cortico-Amygdalar Regions 2 ABSTRACT Forced abstinence (FA) from alcohol has been shown to produce a variety of anxiety-and 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 six weeks of two-bottle choice alcohol consumption and protracted forced abstinence, male and female C57BL/6J mice exhibited a heightened, but sexspecific, depressive-like 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). FSTinduced 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 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.…”

Fluoxetine and Ketamine Reverse the Depressive but Not Anxiety Behavior Induced by Lesion of Cholinergic Neurons in the Horizontal Limb of the Diagonal Band of Broca in Male Rat

“…In order to assess whether a lesion of the cholinergic neurons in the HDB produces depressive-like behavior and FLX or ketamine inhibits such depressive-like behavior, three sets of experiments were conducted according to the following experimental design. The sequence of the behavioral tests was described in previous studies with minor modifications ( Cutuli et al, 2013 ; Ke et al, 2019 ; Dao et al, 2020 ). Experiment 1 ( Figure 3A ): Rats were randomly divided into three groups ( n = 10 rats per group): non-operated (Control), sham operated (Sham) and 192 IgG-saporin injection (Ig-saporin).…”