Chronic stress disrupts the homeostasis and progeny progression of oligodendroglial lineage cells, associating immune oligodendrocytes with prefrontal cortex hypomyelination

Abstract

Major Depressive Disorder (MDD) is a chronic debilitating illness affecting yearly 300 million people worldwide. Oligodendrocyte-lineage cells have emerged as important neuromodulators in synaptic plasticity and crucial components of MDD pathophysiology. Using the repeated social defeat (RSDS) mouse model, we demonstrate that chronic psychosocial stress induces long-lasting losses and transient proliferation of oligodendrocyte-precursor cells (OPCs), aberrant differentiation into oligodendrocytes, and severe hypomyelination in the prefrontal cortex. Exposure to chronic stress results in OPC morphological impairments, excessive oxidative stress, and oligodendroglial apoptosis, implicating integrative-stress responses in depression. Analysis of single-nucleus transcriptomic data from MDD patients revealed oligodendroglial-lineage dysregulation and the presence of immune-oligodendrocytes (Im-OL), a novel population of cells with immune properties and myelination de cits. Im-OL were also identi ed in mice after RSDS, where oligodendrocyte-lineage cells expressed immune-related markers. Our ndings demonstrate cellular and molecular changes in the oligodendroglial lineage in response to chronic stress and associate hypomyelination with Im-OL emergence during depression.

Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes

“…A subset of microglia clustered next to oligodendrocytes in the UMAP, which could reflect misclassified cells, doublets, or even immune oligodendroglia 29,30 or white matter microglia 31 . To determine the robustness of our microglial results to the presence of this subset of cells, we sub-clustered the microglial cluster.…”

Involvement of inflammatory responses in the brain to the onset of major depressive disorder due to stress exposure

“…Furthermore, in brain imaging and postmortem evaluations of the human brain, patients with MDD have been found to show abnormalities in the white matter and/or oligodendrocytes (Czéh and Nagy, 2018;Vostrikov and Uranova, 2020). Interestingly, stress exposure in animal models can decrease the number of oligodendrocytes in the cortex and amygdala, indicating potential links between disturbed myelination and MDD (Liu et al, 2018a;Kokkosis et al, 2022;Madeira et al, 2022). In contrast, it has been reported that astrocytes are related to neuroinflammation, and astrocyte density in the frontal region is reduced in chronic stress conditions (Banasr et al, 2010;Hattori et al, 2017;Takarada-Iemata et al, 2018;Roboon et al, 2021).…”

NG2-glia: rising stars in stress-related mental disorders?

“…In the adult mPFC, social defeat stress led to increased [14] and decreased [6] OPCs density in susceptible mice, while no changes in OPCs density were observed upon chronic social stress [3]. Reduction of NG2-glia proliferation was also observed in the mPFC of adult mice exposed to chronic stress [3,7]. Interestingly, social defeat led to increased calcium signalling in hippocampal NG2-glia and the photoactivation of these cells elicited an anxiety-like phenotype in the mice in the absence of stress [15].…”

“…Amongst the glia cells, oligodendrocyte progenitor cells (OPCs)also identified as NG2-glia-play a fundamental role in brain function and plasticity, via interaction with glial and neuronal cells, and modulation of neurotransmission [1]. Although in their initial stages, preclinical and clinical studies are identifying the involvement of OPC alterations in stress responding and stress-related psychiatric illnesses [2][3][4][5][6][7].…”

“…Immunostaining-based structural analysis could also reveal potential morphological changes in OPCs induced by exposure to early adversity. Indeed, reduced morphological complexity of OPCs was observed in the medial prefrontal cortex (mPFC) of adult mice exposed to chronic social defeat stress [7]. Here, whilst staining of NG2-glia in post-mortem tissues would be informative of OPC morphology and connections, technical difficulties in NG2staining of human post-mortem tissues must be taken into consideration.…”