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 deficits. Im-OL were also identified in mice after RSDS, where oligodendrocyte-lineage cells expressed immune-related markers. Our findings demonstrate cellular and molecular changes in the oligodendroglial lineage in response to chronic stress and associate hypomyelination with Im-OL emergence during depression.
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Acknowledgements
We are grateful to Dr. Antonis E. Koromilas for providing reagents and insightful discussion on the manuscript. We also thank Drs. Ramin Parsey, Christine DeLorenzo, Joel Levine and Holly Colognato for their valuable insight and discussions. This work was supported by the National Institute of Mental Health, Grant/Award Numbers: R01MH123093-01, R01MH123093-01S1 (MMM), the American Heart Association (19PRE34370044; AGK) and Scholars in BioMedical Sciences Program (T32GM127253).
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AGK and SET conceptualized the project. AGK designed, performed, and analyzed experiments. MMM wrote the code and performed bioinformatic analyses, image quantification and data analyses. MRM performed image quantification, Neurolucida tracing and data analyses. AGK, MMM, and SET drafted and edited the manuscript. SET provided technical expertise, funding, and supervised the project.
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Kokkosis, A.G., Madeira, M.M., Mullahy, M.R. et al. Chronic stress disrupts the homeostasis and progeny progression of oligodendroglial lineage cells, associating immune oligodendrocytes with prefrontal cortex hypomyelination. Mol Psychiatry 27, 2833–2848 (2022). https://doi.org/10.1038/s41380-022-01512-y
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