Abstract
Child abuse (CA) is a major risk factor for depression, and strongly associates with suicidal behavior during adulthood. Neuroimaging studies have reported widespread changes in white matter integrity and brain connectivity in subjects with a history of CA. Although such observations could reflect changes in myelin and oligodendrocyte function, their cellular underpinnings have never been addressed. Using postmortem brain samples from depressed suicides with or without history of CA and matched controls (18 per group), we aimed to characterize the effects of CA on oligodendrocyte-lineage (OL) cells in the ventromedial prefrontal white matter. Using immunoblotting, double-labeling immunofluorescence and stereological estimates of stage-specific markers, we found that CA is associated with increased numbers of mature myelinating oligodendrocytes, accompanied by decreased numbers of more immature OL cells. This was paralleled by an increased expression of transcription factor MASH1, which is involved in the terminal differentiation of the OL, suggesting that CA may trigger an increased maturation, or bias the populations of OL cells toward a more mature phenotype. Some of these effects, which were absent in the brain of depressed suicides with no history of CA, were also found to recover with age, suggesting that changes in the balance of the OL may reflect a transient adaptive mechanism triggered by early-life adversity. In conclusion, our results indicate that CA in depressed suicides is associated with an imbalance of the OL in the ventromedial prefrontal white matter, an effect that could lead to myelin remodeling and long-term connectivity changes within the limbic network.
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References
Nemeroff CB. Paradise lost: the neurobiological and clinical consequences of child abuse and neglect. Neuron 2016; 89: 892–909.
Pechtel P, Pizzagalli DA. Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology 2011; 214: 55–70.
Gilbert R, Widom CS, Browne K, Fergusson D, Webb E, Janson S. Burden and consequences of child maltreatment in high-income countries. Lancet 2009; 373: 68–81.
Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW. Mapping cortical change across the human life span. Nat Neurosci 2003; 6: 309–315.
Nagy Z, Westerberg H, Klingberg T. Maturation of white matter is associated with the development of cognitive functions during childhood. J Cogn Neurosci 2004; 16: 1227–1233.
Peters BD, Ikuta T, Derosse P, John M, Burdick KE, Gruner P et al. Age-related differences in white matter tract microstructure are associated with cognitive performance from childhood to adulthood. Biol Psychiatry 2014; 75: 248–256.
Fields RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci 2008; 31: 361–370.
Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 2014; 344: 1252304.
Tomlinson L, Leiton CV, Colognato H. Behavioral experiences as drivers of oligodendrocyte lineage dynamics and myelin plasticity. Neuropharmacology 2015; 110: 548–562.
Hart H, Rubia K. Neuroimaging of child abuse: a critical review. Front Hum Neurosci 2012; 6: 1–24.
Lu S, Wei Z, Gao W, Wu W, Liao M, Zhang Y et al. White matter integrity alterations in young healthy adults reporting childhood trauma: a diffusion tensor imaging study. Aust N Z J Psychiatry 2013; 47: 1183–1190.
Bick J, Zhu T, Stamoulis C, Fox Na, Zeanah C, Nelson CE. Effect of early institutionalization and foster care on long-term white matter development: a randomized clinical trial. JAMA Pediatr 2015; 169: 211–219.
Peng H, Ning Y, Zhang Y, Yang H, Zhang L, He Z et al. White-matter density abnormalities in depressive patients with and without childhood neglect: a voxel-based morphometry (VBM) analysis. Neurosci Lett 2013; 550: 23–28.
Huang H, Gundapuneedi T, Rao U. White matter disruptions in adolescents exposed to childhood maltreatment and vulnerability to psychopathology. Neuropsychopharmacology 2012; 37: 2693–2701.
Daniels JK, Lamke J-P, Gaebler M, Walter H, Scheel M. White matter integrity and its relationship to Ptsd and childhood trauma-a systematic review and meta-analysis. Depress Anxiety 2013; 30: 207–216.
Hanson JL, Knodt AR, Brigidi BD, Hariri AR. Lower structural integrity of the uncinate fasciculus is associated with a history of child maltreatment and future psychological vulnerability to stress. Dev Psychopathol 2015; 27: 1611–1619.
Jedd K, Hunt RH, Cicchetti D, Hunt E, Cowell RA, Rogosch FA et al. Long-term consequences of childhood maltreatment: Altered amygdala functional connectivity. Dev Psychopathol 2015; 27: 1577–1589.
Howell BR, McCormack KM, Grand AP, Sawyer NT, Zhang X, Maestripieri D et al. Brain white matter microstructure alterations in adolescent rhesus monkeys exposed to early life stress: associations with high cortisol during infancy. Biol Mood Anxiety Disord 2013; 3: 21.
SĂ¡nchez MM, Hearn EF, Do D, Rilling JK, Herndon JG. Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys. Brain Res 1998; 812: 38–49.
Hercher C, Turecki G, Mechawar N. Through the looking glass: examining neuroanatomical evidence for cellular alterations in major depression. J Psychiatr Res 2009; 43: 947–961.
Tham MW, Woon PS, Sum MY, Lee T-S, Sim K. White matter abnormalities in major depression: evidence from post-mortem, neuroimaging and genetic studies. J Affect Disord 2011; 132: 26–36.
Fields RD. A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci 2015; 16: 756–767.
Arnett HA, Fancy SPJ, Alberta JA, Zhao C, Plant SR, Kaing S et al. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 2004; 306: 2111–2115.
Franklin RJM, ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 2008; 9: 839–855.
Dugas JC, Tai YC, Speed TP, Ngai J, Barres BA. Functional genomic analysis of oligodendrocyte differentiation. J Neurosci 2006; 26: 10967–10983.
Moyon S, Huynh JL, Dutta D, Zhang F, Ma D, Yoo S et al. Functional characterization of DNA methylation in the oligodendrocyte lineage. Cell Rep 2016; 15: 748–760.
Liu J, Casaccia P. Epigenetic regulation of oligodendrocyte identity. Trends Neurosci 2010; 33: 193–201.
Li H, He Y, Richardson WD, Casaccia P. Two-tier transcriptional control of oligodendrocyte differentiation. Curr Opin Neurobiol 2009; 19: 479–485.
Myers-Schulz B, Koenigs M. Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders. Mol Psychiatry 2012; 17: 132–141.
Dumais A, Lesage AD, Alda M, Rouleau G, Dumont M, Chawky N et al. Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. Am J Psychiatry 2005; 162: 2116–2124.
Bifulco A, Brown GW, Lillie A, Jarvis J. Memories of childhood neglect and abuse: corroboration in a series of sisters. J Child Psychol Psychiatry 1997; 38: 365–374.
Bifulco A, Brown GW, Harris TO. Childhood Experience of Care and Abuse (CECA): a retrospective interview measure. J Child Psychol Psychiatry 1994; 35: 1419–1435.
Brewin CR, Andrews B, Gotlib IH. Psychopathology and early experience: a reappraisal of retrospective reports. Psychol Bull 1993; 113: 82–98.
Conner KR, Conwell Y, Duberstein PR. The validity of proxy-based data in suicide research: a study of patients 50 years of age and older who attempted suicide. II. Life events, social support and suicidal behavior. Acta Psychiatr Scand 2001; 104: 452–457.
Hawton K, Appleby L, Platt S, Foster T, Cooper J, Malmberg A et al. The psychological autopsy approach to studying suicide: a review of methodological issues. J Affect Disord 1998; 50: 269–276.
Kelly TM, Mann JJ. Validity of DSM-III-R diagnosis by psychological autopsy: a comparison with clinician ante-mortem diagnosis. Acta Psychiatr Scand 1996; 94: 337–343.
Brent DA, Perper JA, Moritz G, Allman CJ, Roth C, Schweers J et al. The validity of diagnoses obtained through the psychological autopsy procedure in adolescent suicide victims: use of family history. Acta Psychiatr Scand 1993; 87: 118–122.
Mai JK, Paxinos G, Voss T Atlas of the Human Brain. Elsevier Academy Press: Cambridge, MA, USA, 2008.
Fruttiger M, Karlsson L, Hall AC, Abramsson A, Calver AR, Boström H et al. Defective oligodendrocyte development and severe hypomyelination in PDGF-A knockout mice. Development 1999; 126: 457–467.
Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha FalcĂ£o A, Xiao L et al. Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 2016; 352: 1326–1329.
Nishiyama A, Lin X-H, Giese N, Heldin C-H, Stallcup WB. Co-localization of NG2 proteoglycan and PDGF ?-receptor on O2A progenitor cells in the developing rat brain. J Neurosci Res 1996; 43: 299–314.
Zhou Q, Wang S, Anderson DJ. Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 2000; 25: 331–343.
Lu QR, Yuk D, Alberta JA, Zhu Z, Pawlitzky I, Chan J et al. Sonic hedgehog—regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 2000; 25: 317–329.
Rowitch DH. Glial specification in the vertebrate neural tube. Nat Rev Neurosci 2004; 5: 409–419.
Hack MA, Saghatelyan A, de Chevigny A, Pfeifer A, Ashery-Padan R, Lledo P-M et al. Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci 2005; 8: 865–872.
Guo F, Maeda Y, Ma J, Delgado M, Sohn J, Miers L et al. Macroglial plasticity and the origins of reactive astroglia in experimental autoimmune encephalomyelitis. J Neurosci 2011; 31: 11914–11928.
Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL et al. The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. J Neuropathol Exp Neurol 2004; 63: 499–509.
Schwab ME, Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigenfor monoclonal antibody IN-1. Nature 2000; 403: 434–439.
Kuhlmann T, Remington L, Maruschak B, Owens T, BrĂ¼ck W. Nogo-A is a reliable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions. J Neuropathol Exp Neurol 2007; 66: 238–246.
Kuhlmann T, Miron V, Cui Q, Cuo Q, Wegner C, Antel J et al. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 2008; 131: 1749–1758.
Bhat RV, Axt KJ, Fosnaugh JS, Smith KJ, Johnson KA, Hill DE et al. Expression of the APC tumor suppressor protein in oligodendroglia. Glia 1996; 17: 169–174.
Lang J, Maeda Y, Bannerman P, Xu J, Horiuchi M, Pleasure D et al. Adenomatous polyposis coli regulates oligodendroglial development. J Neurosci 2013; 33: 3113–3130.
Yeung MSY, Zdunek S, Bergmann O, Bernard S, Salehpour M, Alkass K et al. Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 2014; 159: 766–774.
Burgess A, Vigneron S, Brioudes E, Labbé J-C, Lorca T, Castro A. Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance. Proc Natl Acad Sci USA 2010; 107: 12564–12569.
Nishiyama A, Komitova M, Suzuki R, Zhu X. Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci 2009; 10: 9–22.
Nakatani H, Martin E, Hassani H, Clavairoly A, Maire CL, Viadieu A et al. Ascl1/Mash1 promotes brain oligodendrogenesis during myelination and remyelination. J Neurosci 2013; 33: 9752–9768.
Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 2008; 33: 693–710.
Matsusue Y, Horii-Hayashi N, Kirita T, Nishi M. Distribution of corticosteroid receptors in mature oligodendrocytes and oligodendrocyte progenitors of the adult mouse brain. J Histochem Cytochem 2014; 62: 211–226.
Chetty S, Friedman AR, Taravosh-Lahn K, Kirby ED, Mirescu C, Guo F et al. Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus. Mol Psychiatry 2014;: 1–9.
Wennström M, Hellsten J, Ekstrand J, Lindgren H, Tingström A. Corticosterone-induced inhibition of gliogenesis in rat hippocampus is counteracted by electroconvulsive seizures. Biol Psychiatry 2006; 59: 178–186.
Alonso G. Prolonged corticosterone treatment of adult rats inhibits the proliferation of oligodendrocyte progenitors present throughout white and gray matter regions of the brain. Glia 2000; 31: 219–231.
Heim C, Mletzko T, Purselle D, Musselman DL, Nemeroff CB. The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol Psychiatry 2008; 63: 398–405.
Makinodan M, Rosen KM, Ito S, Corfas G. A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 2012; 337: 1357–1360.
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: 1621–1623.
Jahn O, Tenzer S, Werner HB. Myelin proteomics: molecular anatomy of an insulating sheath. Mol Neurobiol 2009; 40: 55–72.
Rajkowska G, Mahajan G, Maciag D, Sathyanesan M, Iyo AH, Moulana M et al. Oligodendrocyte morphometry and expression of myelin—Related mRNA in ventral prefrontal white matter in major depressive disorder. J Psychiatr Res 2015; 65: 53–62.
Parras CM, Hunt C, Sugimori M, Nakafuku M, Rowitch D, Guillemot F. The proneural gene Mash1 specifies an early population of telencephalic oligodendrocytes. J Neurosci 2007; 27: 4233–4242.
Sugimori M, Nagao M, Parras CM, Nakatani H, Lebel M, Guillemot F et al. Ascl1 is required for oligodendrocyte development in the spinal cord. Development 2008; 135: 1271–1281.
Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, Miyachi H et al. Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science 2013; 342: 1203–1208.
Ross SE, Greenberg ME, Stiles CD. Basic helix-loop-helix factors in cortical development. Neuron 2003; 39: 13–25.
Vue TY, Kim EJ, Parras CM, Guillemot F, Johnson JE. Ascl1 controls the number and distribution of astrocytes and oligodendrocytes in the gray matter and white matter of the spinal cord. Development 2014; 141: 3721–3731.
Wang J, Pol SU, Haberman AK, Wang C, O’Bara Ma, Sim FJ. Transcription factor induction of human oligodendrocyte progenitor fate and differentiation. Proc Natl Acad Sci USA 2014; 111: E2885–E2894.
Braun SMG, Pilz G-A, Machado RAC, Moss J, Becher B, Toni N et al. Programming hippocampal neural stem/progenitor cells into oligodendrocytes enhances remyelination in the adult brain after injury. Cell Rep 2015; 11: 1679–1685.
Kondo T, Raff M. Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development 2000; 127: 2989–2998.
Mei F, Wang H, Liu S, Niu J, Wang L, He Y et al. Stage-specific deletion of Olig2 conveys opposing functions on differentiation and maturation of oligodendrocytes. J Neurosci 2013; 33: 8454–8462.
Kitada M, Rowitch DH. Transcription factor co-expression patterns indicate heterogeneity of oligodendroglial subpopulations in adult spinal cord. Glia 2006; 54: 35–46.
DeSantis SM, Baker NL, Back SE, Spratt E, Ciolino JD, Moran-Santa Maria M et al. Gender differences in the effect of early life trauma on hypothalamic-pituitary-adrenal axis functioning. Depress Anxiety 2011; 28: 383–392.
Seltzer LJ, Ziegler T, Connolly MJ, Prososki AR, Pollak SD. Stress-induced elevation of oxytocin in maltreated children: evolution, neurodevelopment, and social behavior. Child Dev 2014; 85: 501–512.
Perrin JS, Leonard G, Perron M, Pike GB, Pitiot A, Richer L et al. Sex differences in the growth of white matter during adolescence. Neuroimage 2009; 45: 1055–1066.
Paus T, Toro R. Could sex differences in white matter be explained by g ratio? Front Neuroanat 2009; 3: 14.
Ugwu ID, Amico F, Carballedo A, Fagan AJ, Frodl T. Childhood adversity, depression, age and gender effects on white matter microstructure: a DTI study. Brain Struct Funct 2015; 220: 1997–2009.
Gokhan S. Combinatorial profiles of oligodendrocyte-selective classes of transcriptional regulators differentially modulate myelin basic protein gene expression. J Neurosci 2005; 25: 8311–8321.
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: 941–956.
Hanson JL, Adluru N, Chung MK, Alexander AL, Davidson RJ, Pollak SD. Early neglect is associated with alterations in white matter integrity and cognitive functioning. Child Dev 2013; 84: 1566–1578.
van Harmelen A-L, van Tol M-J, van der Wee NJA, Veltman DJ, Aleman A, Spinhoven P et al. Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment. Biol Psychiatry 2010; 68: 832–838.
Acknowledgments
A Tanti is supported by fellowships from the Fonds de Recherche du Québec-Santé (FRQ-S) and from TD (Youth Mental Health). This work was supported by operating grants from the AFSP (SRG-0-088-1), ERA-NET NEURON (FRQ-S), and CIHR (MOP-111022) to N Mechawar, who was a CIHR New Investigator and FRQS Chercheur-boursier Junior 2 during the course of the study. We thank Liam O’Leary for his artwork contribution (Figure 1b) and the Douglas-Bell Canada Brain Bank staff for their precious collaboration.
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Tanti, A., Kim, J.J., Wakid, M. et al. Child abuse associates with an imbalance of oligodendrocyte-lineage cells in ventromedial prefrontal white matter. Mol Psychiatry 23, 2018–2028 (2018). https://doi.org/10.1038/mp.2017.231
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DOI: https://doi.org/10.1038/mp.2017.231
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