Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure

Abstract

Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-like motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, activation of SST neurons in the PLC of male and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos+and FosB+neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. Our studies provide a mechanistic rationale for antidepressant efficacy of dendrite-targeting, low-potency GABAAreceptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.

Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure

“…By contrast, the CVSinduced DEGs of female stress-vulnerable and stress-resilient mice were similar in numbers (Figure 2F), and the directional changes in expression of DEGs remained correlated (r = 0.44 and 0.49, respectively, not shown). In a separate study that is currently under review we have used a stereotaxically-targeted chemogenetic approach to map SST neuron mediated stress resilience to specific brain regions 21 . Selective activation of SST neurons in the mPFC resulted in resilience of male but not female mice while activation of SST neurons in the ventral hippocampus led to resilience in female but not male mice.…”

“…The genetically induced SSTCre:γ2 f/f model used here differs in that it focuses a priori on GABAergic microcircuits that promote stress resilience via cortical brain regions 8,16,21 . This model comes with the key advantage that it allows for the molecular comparison of nonstressed (NS) stress-resilient mice with stressed or NS stress-susceptible mice as well as stressed stress-resilient mice -a feature that is not possible with the CSDS model.…”