Chronic Stress Induces Coordinated Cortical Microcircuit Cell-Type Transcriptomic Changes Consistent With Altered Information Processing

ABSTRACT: Major depressive disorder (MDD) is a severe psychiatric disorder, characterized by deficits in GABAergic and glutamatergic signaling in cortical brain regions. Unpredictable chronic mild stress (UCMS), a murine stress model, induces behavioural and neurobiological changes reminiscent of MDD. Despite increasing knowledge of the cellular complexity of the cortical microcircuitry, our understanding of how distinct cell-types are impacted by UCMS is extremely limited. We thus endeavoured to determine the effect of UCMS on Pyramidal (PYR) cells and three classes of interneurons: Somatostatin (SST), Parvalbumin (PV), and Vasoactive intestinal peptide-expressing (VIP) cells in the medial prefrontal cortex. C57Bl/6 mice, exposed to UCMS or control housing for five weeks, were assessed with a battery of anxiety- and depressive-like behavioural tests. Laser-capture microdissection was used to isolate samples of microcircuit cell-types, which underwent RNA-sequencing. UCMS-exposed mice showed significantly elevated emotionality, and isolate cell-types showed robust specificity. Cell-types exhibited unique transcriptomic profiles after UCMS. Briefly, PYR-cells showed decreased signaling and post-synaptic receptor expression, SST-cells showed increased activation of the unfolded protein response, PV-cells showed increased axonal microtubule expression, and VIP-cells showed increased apoptotic signaling and altered cytoskeletal gene expression. Co-expression analyses revealed that these changes were largely correlated across cell-types and that UCMS increased transcriptome-wide co-expression between PYR and both PV and SST cells. Overall, these findings suggest decreased PYR, SST, and VIP-cell function, elevated PV-cell function, and identify the dysregulation of PYR-cells as a central locus of UCMS-induced transcriptomic change. Further studies interrogating potential antidepressant-like activity of compounds reversing these cell-specific changes are warranted.

ORGANISM(S): Mus musculus

PROVIDER: GSE145521 | GEO | 2022/02/18

REPOSITORIES: GEO