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A Further Analysis and Commentary on: Profiling Changes in Cortical Astroglial Cells Following Chronic Stress.

ABSTRACT: The neuroplasticity hypothesis of depression proposes that major depressive disorders are related to decreased hippocampal and cortical neural plasticity, which is reversed by antidepressant treatment. Astroglial cells have emerged as key mediators of neural plasticity and are involved in the cause and treatment of depression and anxiety-like behaviors. One of the ways that astroglia modulate neuroplasticity is through the formation and maintenance of perineuronal nets (PNNs). Perineuronal nets are important extracellular matrix components that respond to stress and are implicated in anxiety-like behaviors. Normally, astroglial cells continuously turnover PNNs by degrading and donating PNN proteins; however, chronic stress slows PNN protein degradation and increases cortical PNN expression overall. In this report, we used weighted gene co-expression network analysis and eigengene analysis to further delineate the pathways and key regulators involved in the astroglial-PNN relationship following chronic stress. Our analyses indicate that chronic variable stress induces the expression of PNNs through inhibition of trophic pathways and key transcription factors in astroglial cells. These data further support the integral role of astroglial cells in the neuroplasticity hypothesis of depression through their modulation of anxiety-like behaviors and PNNs.

SUBMITTER: Coppola G

PROVIDER: S-EPMC6698990 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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A Further Analysis and Commentary on: Profiling Changes in Cortical Astroglial Cells Following Chronic Stress.

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