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

Molecular Psychiatry volume 27, pages 2833–2848 (2022)Cite this article

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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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Fig. 1: Chronic psychosocial stress induces depressive-like behavior leading to OPC reductions and impaired proliferation in the mPFC.
Fig. 2: Chronic psychosocial stress induces the maturation of label-retaining OPCs into OLs post-RSDS in the mPFC.
Fig. 3: Myelin deficits and oligodendroglial apoptosis are induced in response to chronic psychosocial stress.
Fig. 4: Single-nucleus transcriptomic characterization of oligodendroglial-lineage populations in the dlPFC of MDD and Control patients.
Fig. 5: Oligodendroglial expression of MHCII and complement C3 in mPFC post RSDS.

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References

  1. Birey F, Kokkosis AG, Aguirre A. Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders. Curr Opin Neurobiol. 2017;47:93–103. https://doi.org/10.1016/j.conb.2017.09.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hughes EG, Kang SH, Fukaya M, Bergles DE. Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat Neurosci. 2013;16:668–76. https://doi.org/10.1038/nn.3390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Birey F, Aguirre A. Age-dependent Netrin-1 signaling regulates NG2+ glial cell spatial homeostasis in normal adult gray matter. J Neurosci. 2015;35:6946–51. https://doi.org/10.1523/jneurosci.0356-15.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bergles DE, Roberts JD, Somogyi P, Jahr CE. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature. 2000;405:187–91. https://doi.org/10.1038/35012083.

    Article  CAS  PubMed  Google Scholar 

  5. Doyle S, Hansen DB, Vella J, Bond P, Harper G, Zammit C, et al. Vesicular glutamate release from central axons contributes to myelin damage. Nat Commun. 2018;9:1032. https://doi.org/10.1038/s41467-018-03427-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ge WP, Yang XJ, Zhang Z, Wang HK, Shen W, Deng QD, et al. Long-term potentiation of neuron-glia synapses mediated by Ca2+-permeable AMPA receptors. Science. 2006;312:1533–7. https://doi.org/10.1126/science.1124669.

    Article  CAS  PubMed  Google Scholar 

  7. Sakry D, Yigit H, Dimou L, Trotter J. Oligodendrocyte precursor cells synthesize neuromodulatory factors. PLoS ONE. 2015;10:e0127222. https://doi.org/10.1371/journal.pone.0127222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Birey F, Kloc M, Chavali M, Hussein I, Wilson M, Christoffel DJ, et al. Genetic and stress-induced loss of NG2 glia triggers emergence of depressive-like behaviors through reduced secretion of FGF2. Neuron. 2015;88:941–56. https://doi.org/10.1016/j.neuron.2015.10.046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nagy C, Maitra M, Tanti A, Suderman M, Théroux JF, Davoli MA, et al. Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons. Nat Neurosci. 2020;23:771–81. https://doi.org/10.1038/s41593-020-0621-y.

    Article  CAS  PubMed  Google Scholar 

  10. Liu J, Dietz K, DeLoyht JM, Pedre X, Kelkar D, Kaur J, et al. Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nat Neurosci. 2012;15:1621–3. https://doi.org/10.1038/nn.3263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Makinodan M, Ikawa D, Yamamuro K, Yamashita Y, Toritsuka M, Kimoto S, et al. Effects of the mode of re-socialization after juvenile social isolation on medial prefrontal cortex myelination and function. Sci Rep. 2017;7:5481. https://doi.org/10.1038/s41598-017-05632-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang H, Yan G, Xu H, Fang Z, Zhang J, Zhang J, et al. The recovery trajectory of adolescent social defeat stress-induced behavioral, (1)H-MRS metabolites and myelin changes in Balb/c mice. Sci Rep. 2016;6:27906. https://doi.org/10.1038/srep27906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang Y, Zhang Y, Luo F, Li B. Chronic stress regulates NG2+ cell maturation and myelination in the prefrontal cortex through induction of death receptor 6. Exp Neurol. 2016;277:202–14. https://doi.org/10.1016/j.expneurol.2016.01.003.

    Article  CAS  PubMed  Google Scholar 

  14. Lehmann ML, Weigel TK, Elkahloun AG, Herkenham M. Chronic social defeat reduces myelination in the mouse medial prefrontal cortex. Sci Rep. 2017;7:46548. https://doi.org/10.1038/srep46548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bonnefil V, Dietz K, Amatruda M, Wentling M, Aubry AV, Dupree JL, et al. Region-specific myelin differences define behavioral consequences of chronic social defeat stress in mice. Elife. 2019;8:e40855. https://doi.org/10.7554/eLife.40855.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bae JN, MacFall JR, Krishnan KR, Payne ME, Steffens DC, Taylor WD. Dorsolateral prefrontal cortex and anterior cingulate cortex white matter alterations in late-life depression. Biol Psychiatry. 2006;60:1356–63. https://doi.org/10.1016/j.biopsych.2006.03.052.

    Article  PubMed  Google Scholar 

  17. Aston C, Jiang L, Sokolov BP. Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. Mol Psychiatry. 2005;10:309–22. https://doi.org/10.1038/sj.mp.4001565.

    Article  CAS  PubMed  Google Scholar 

  18. van Velzen LS, Kelly S, Isaev D, Aleman A, Aftanas LI, Bauer J, et al. White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group. Mol Psychiatry. 2020;25:1511–25. https://doi.org/10.1038/s41380-019-0477-2.

    Article  PubMed  Google Scholar 

  19. Euston DR, Gruber AJ, McNaughton BL. The role of medial prefrontal cortex in memory and decision making. Neuron. 2012;76:1057–70. https://doi.org/10.1016/j.neuron.2012.12.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25. https://doi.org/10.1038/nrn3381.

    Article  CAS  PubMed  Google Scholar 

  21. Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–5. https://doi.org/10.1126/science.1171203.

    Article  CAS  PubMed  Google Scholar 

  22. Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10:410–22. https://doi.org/10.1038/nrn2648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Elsayed M, Magistretti PJ. A new outlook on mental illnesses: glial involvement beyond the glue. Front Cell Neurosci. 2015;9:468. https://doi.org/10.3389/fncel.2015.00468.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Golden SA, Covington HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91. https://doi.org/10.1038/nprot.2011.361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2010;13:133–40. https://doi.org/10.1038/nn.2467.

    Article  CAS  PubMed  Google Scholar 

  26. Riva-Posse P, Choi KS, Holtzheimer PE, McIntyre CC, Gross RE, Chaturvedi A, et al. Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2014;76:963–9. https://doi.org/10.1016/j.biopsych.2014.03.029.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Versace A, Thompson WK, Zhou D, Almeida JR, Hassel S, Klein CR, et al. Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces: state versus trait vulnerability markers of depression in bipolar disorder. Biol Psychiatry. 2010;67:422–31.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Keirstead HS, Levine JM, Blakemore WF. Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord. Glia. 1998;22:161–70.

    Article  CAS  PubMed  Google Scholar 

  29. Wang J, Tsirka SE. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain. 2005;128:1622–33. https://doi.org/10.1093/brain/awh489.

    Article  PubMed  Google Scholar 

  30. Lehmann ML, Weigel TK, Poffenberger CN, Herkenham M. The behavioral sequelae of social defeat require microglia and are driven by oxidative stress in mice. J Neurosci. 2019;39:5594–605. https://doi.org/10.1523/jneurosci.0184-19.2019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Butts BD, Houde C, Mehmet H. Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease. Cell Death Differ. 2008;15:1178–86. https://doi.org/10.1038/cdd.2008.70.

    Article  CAS  PubMed  Google Scholar 

  32. Spaas J, van Veggel L, Schepers M, Tiane A, van Horssen J, Wilson DM, et al. Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders. Cell Mol Life Sci. 2021;78:4615–37. https://doi.org/10.1007/s00018-021-03802-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Way SW, Podojil JR, Clayton BL, Zaremba A, Collins TL, Kunjamma RB, et al. Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic. Nat Commun. 2015;6:6532. https://doi.org/10.1038/ncomms7532.

    Article  CAS  PubMed  Google Scholar 

  34. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol cell Biol. 2007;8:519–29.

    Article  CAS  PubMed  Google Scholar 

  35. Schmaal L, Pozzi E, T CH, van Velzen LS, Veer IM, Opel N, et al. ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing. Transl Psychiatry. 2020;10:172. https://doi.org/10.1038/s41398-020-0842-6.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Jäkel S, Agirre E, Mendanha Falcão A, van Bruggen D, Lee KW, Knuesel I, et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature. 2019;566:543–7. https://doi.org/10.1038/s41586-019-0903-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Trapnell C, Cacchiarelli D, Grimsby J, Pokharel P, Li S, Morse M, et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol. 2014;32:381–6. https://doi.org/10.1038/nbt.2859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li Q, Barres BA. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol. 2018;18:225.

    Article  CAS  PubMed  Google Scholar 

  39. van der Poel M, Ulas T, Mizee MR, Hsiao C-C, Miedema SSM, Adelia, et al. Transcriptional profiling of human microglia reveals grey–white matter heterogeneity and multiple sclerosis-associated changes. Nat Commun. 2019;10:1139. https://doi.org/10.1038/s41467-019-08976-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schetters STT, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y. Neuroinflammation: microglia and T cells get ready to tango. Front Immunol. 2018;8. https://doi.org/10.3389/fimmu.2017.01905.

  41. Harrington EP, Bergles DE, Calabresi PA. Immune cell modulation of oligodendrocyte lineage cells. Neurosci Lett. 2020;715:134601. https://doi.org/10.1016/j.neulet.2019.134601.

    Article  CAS  PubMed  Google Scholar 

  42. Ridler C. Oligodendrocytes—active accomplices in MS pathogenesis? Nat Rev Neurol. 2019;15:3–3. https://doi.org/10.1038/s41582-018-0111-y.

    Article  PubMed  Google Scholar 

  43. Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci. 2011;7:121–47. https://doi.org/10.1007/7854_2010_108.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Banasr M, Valentine GW, Li XY, Gourley SL, Taylor JR, Duman RS. Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat. Biol Psychiatry. 2007;62:496–504. https://doi.org/10.1016/j.biopsych.2007.02.006.

    Article  CAS  PubMed  Google Scholar 

  45. Hill RA, Nishiyama A. NG2 cells (polydendrocytes): listeners to the neural network with diverse properties. Glia. 2014;62:1195–210. https://doi.org/10.1002/glia.22664.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Nishiyama A, Komitova M, Suzuki R, Zhu X. Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci. 2009;10:9–22. https://doi.org/10.1038/nrn2495.

    Article  CAS  PubMed  Google Scholar 

  47. Nie X, Kitaoka S, Tanaka K, Segi-Nishida E, Imoto Y, Ogawa A, et al. The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation. Neuron. 2018;99:464–79.e467. https://doi.org/10.1016/j.neuron.2018.06.035.

    Article  CAS  PubMed  Google Scholar 

  48. Kokkosis AG, Tsirka SE. Neuroimmune mechanisms and sex/gender-dependent effects in the pathophysiology of mental disorders. J Pharmacol Exp Therapeutics. 2020;375:175–92.

    Article  Google Scholar 

  49. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22–34. https://doi.org/10.1038/nri.2015.5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mecha M, Torrao AS, Mestre L, Carrillo-Salinas FJ, Mechoulam R, Guaza C. Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress. Cell Death Dis. 2012;3:e331. https://doi.org/10.1038/cddis.2012.71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619–33. https://doi.org/10.1016/S1097-2765(03)00105-9.

    Article  CAS  PubMed  Google Scholar 

  52. Way SW, Popko B. Harnessing the integrated stress response for the treatment of multiple sclerosis. Lancet Neurol. 2016;15:434–43. https://doi.org/10.1016/S1474-4422(15)00381-6.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science. 2020:368. https://doi.org/10.1126/science.aat5314.

  54. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013;15:481–90. https://doi.org/10.1038/ncb2738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Falcao AM, van Bruggen D, Marques S, Meijer M, Jakel S, Agirre E, et al. Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nat Med. 2018;24:1837–44. https://doi.org/10.1038/s41591-018-0236-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Taylor S, Mehina E, White E, Reeson P, Yongblah K, Doyle KP, et al. Suppressing interferon-gamma stimulates microglial responses and repair of microbleeds in the diabetic brain. J Neurosci. 2018;38:8707–22. https://doi.org/10.1523/JNEUROSCI.0734-18.2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kirby L, Jin J, Cardona JG, Smith MD, Martin KA, Wang J, et al. Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination. Nat Commun. 2019;10:3887. https://doi.org/10.1038/s41467-019-11638-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci. 2008;11:1392–401. https://doi.org/10.1038/nn.2220.

    Article  CAS  PubMed  Google Scholar 

  59. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404. https://doi.org/10.1016/j.cell.2007.09.018.

    Article  CAS  PubMed  Google Scholar 

  60. Ferlemi AV, Avgoustatos D, Kokkosis AG, Protonotarios V, Constantinou C, Margarity M. Lead-induced effects on learning/memory and fear/anxiety are correlated with disturbances in specific cholinesterase isoform activity and redox imbalance in adult brain. Physiol Behav. 2014;131:115–22. https://doi.org/10.1016/j.physbeh.2014.04.033.

    Article  CAS  PubMed  Google Scholar 

  61. Kokkosis A, Valais K, Mullahy M, Tsirka SE. Depression mediated by inflammatory responses to chronic stress. FASEB J. 2020;34:1.

    Article  Google Scholar 

  62. Castagne V, Moser P, Roux S, Porsolt RD. Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Pharmacol. 2010. https://doi.org/10.1002/0471141755.ph0508s49.

  63. Castagne V, Moser P, Roux S, Porsolt RD. Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci. 2011. https://doi.org/10.1002/0471142301.ns0810as55.

  64. Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry. 2008;13:717–28. https://doi.org/10.1038/sj.mp.4002055.

    Article  CAS  PubMed  Google Scholar 

  65. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. https://doi.org/10.1038/nature17998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Camargo A, Pazini FL, Rosa JM, Wolin IA, Moretti M, Rosa PB, et al. Augmentation effect of ketamine by guanosine in the novelty-suppressed feeding test is dependent on mTOR signaling pathway. J Psychiatr Res. 2019;115:103–12.

    Article  PubMed  Google Scholar 

  67. Zeng C, Pan F, Jones LA, Lim MM, Griffin EA, Sheline YI, et al. Evaluation of 5-ethynyl-2’-deoxyuridine staining as a sensitive and reliable method for studying cell proliferation in the adult nervous system. Brain Res. 2010;1319:21–32. https://doi.org/10.1016/j.brainres.2009.12.092.

    Article  CAS  PubMed  Google Scholar 

  68. Bindokas VP, Jordán J, Lee CC, Miller RJ. Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci. 1996;16:1324–36. https://doi.org/10.1523/jneurosci.16-04-01324.1996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nazarewicz RR, Bikineyeva A, Dikalov SI. Rapid and specific measurements of superoxide using fluorescence spectroscopy. J Biomol Screen. 2013;18:498–503. https://doi.org/10.1177/1087057112468765.

    Article  CAS  PubMed  Google Scholar 

  70. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82. https://doi.org/10.1038/nmeth.2019.

    Article  CAS  PubMed  Google Scholar 

  71. Chavali M, Klingener M, Kokkosis AG, Garkun Y, Felong S, Maffei A, et al. Non-canonical Wnt signaling regulates neural stem cell quiescence during homeostasis and after demyelination. Nat Commun. 2018;9:36. https://doi.org/10.1038/s41467-017-02440-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Eyermann C, Czaplinski K, Colognato H. Dystroglycan promotes filopodial formation and process branching in differentiating oligodendroglia. J Neurochem. 2012;120:928–47. https://doi.org/10.1111/j.1471-4159.2011.07600.x.

    Article  CAS  PubMed  Google Scholar 

  73. Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36:411–20. https://doi.org/10.1038/nbt.4096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM 3rd, et al. Comprehensive integration of single-cell data. Cell. 2019;177:1888–902 e1821. https://doi.org/10.1016/j.cell.2019.05.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kolde R. Pheatmap: pretty heatmaps. R Package version 1.0.12. 2019. https://CRAN.R-project.org/package=pheatmap.

  76. Qiu X, Hill A, Packer J, Lin D, Ma YA, Trapnell C. Single-cell mRNA quantification and differential analysis with Census. Nat Methods. 2017;14:309–15. https://doi.org/10.1038/nmeth.4150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu G, Wang L-G, Han Y, He Q-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics A J Integr Biol. 2012;16:284–7.

    Article  CAS  Google Scholar 

  78. Shapiro SS, Wilk MB. An analysis of variance test for normality (complete samples). Biometrika. 1965;52:591–611.

    Article  Google Scholar 

  79. The SAGE Dictionary of Statistics. The SAGE Dictionary of Statistics. SAGE Publications, Ltd., Thousand Oaks, CA, 2004.

  80. Doane DP, Seward LE. Measuring skewness: a forgotten statistic? J Stat Edu. 2011;19:1–18.

    Google Scholar 

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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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  1. Alexandros G. Kokkosis

    Present address: Regeneron Genetic Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA

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  1. Department of Pharmacological Sciences, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 11794-8651, USA

    Alexandros G. Kokkosis, Miguel M. Madeira, Matthew R. Mullahy & Stella E. Tsirka

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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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Correspondence to Stella E. Tsirka.

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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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