Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders

Clinical Epigenetics

Bernhard T. Baune³  Emma L. Harrison¹  Chris Murgatroyd²  Magdalene C. Jawahar³ 

[1] School of Medicine and Dentistry, James Cook University, Townsville City, Australia;School of HealthCare Science, Manchester Metropolitan University, Manchester, UK;Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide 5005, SA, Australia

关键词: Psychopathology;    Histone acetylation;    Stress-responsive genes;    DNA methylation;    Epigenetics;    Maternal separation;    Early life stress;   

Others  :  1234340
DOI  :  10.1186/s13148-015-0156-3

 received in 2015-09-18, accepted in 2015-11-08,  发布年份 2015

【 摘 要 】

Stressor exposure during early life has the potential to increase an individual’s susceptibility to a number of neuropsychiatric conditions such as mood and anxiety disorders and schizophrenia in adulthood. This occurs in part due to the dysfunctional stress axis that persists following early adversity impairing stress responsivity across life. The mechanisms underlying the prolonged nature of this vulnerability remain to be established. Alterations in the epigenetic signature of genes involved in stress responsivity may represent one of the neurobiological mechanisms. The overall aim of this review is to provide current evidence demonstrating changes in the epigenetic signature of candidate gene(s) in response to early environmental adversity. More specifically, this review analyses the epigenetic signatures of postnatal adversity such as childhood abuse or maltreatment and later-life psychopathology in human and animal models of early life stress. The results of this review shows that focus to date has been on genes involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and its correlation to subsequent neurobiology, for example, the role of glucocorticoid receptor gene. However, epigenetic changes in other candidate genes such as brain-derived neurotrophic factor (BDNF) and serotonin transporter are also implicated in early life stress (ELS) and susceptibility to adult psychiatric disorders. DNA methylation is the predominantly studied epigenetic mark followed by histone modifications specifically acetylation and methylation. Further, these epigenetic changes are cell/tissue-specific in regulating expression of genes, providing potential biomarkers for understanding the trajectory of early stress-induced susceptibility to adult psychiatric disorders.

【 授权许可】

   
2015 Jawahar et al.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]Green JG, McLaughlin KA, Berglund PA, Gruber MJ, Sampson NA, Zaslavsky AM, et al.: Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry 2010, 67(2):113-23.
• [2]Kessler RC, McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, et al.: Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys. Br J Psychiatry 2010, 197(5):378-85.
• [3]Bernet CZ, Stein MB: Relationship of childhood maltreatment to the onset and course of major depression in adulthood. Depress Anxiety 1999, 9(4):169-74.
• [4]Varese F, Smeets F, Drukker M, Lieverse R, Lataster T, Viechtbauer W, et al.: Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 2012, 38(4):661-71.
• [5]Scott KM, Von Korff M, Angermeyer MC, Benjet C, Bruffaerts R, de Girolamo G, et al.: Association of childhood adversities and early-onset mental disorders with adult-onset chronic physical conditions. Arch Gen Psychiatry 2011, 68(8):838-44.
• [6]Scott KM, Von Korff M, Alonso J, Angermeyer MC, Benjet C, Bruffaerts R, et al.: Childhood adversity, early-onset depressive/anxiety disorders, and adult-onset asthma. Psychosom Med 2008, 70(9):1035-43.
• [7]Gershon A, Sudheimer K, Tirouvanziam R, Williams LM, O’Hara R: The long-term impact of early adversity on late-life psychiatric disorders. Curr Psychiatry Rep 2013, 15(4):013-0352.
• [8]Kaplow JB, Widom CS: Age of onset of child maltreatment predicts long-term mental health outcomes. J Abnorm Psychol 2007, 116(1):176-87.
• [9]Schoedl AF, Costa MC, Mari JJ, Mello MF, Tyrka AR, Carpenter LL, et al.: The clinical correlates of reported childhood sexual abuse: an association between age at trauma onset and severity of depression and PTSD in adults. J Child Sex Abus 2010, 19(2):156-70.
• [10]Evans GW, Schamberg MA: Childhood poverty, chronic stress, and adult working memory. Proc Natl Acad Sci 2009, 30:2009.
• [11]Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al.: Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med 1998, 14(4):245-58.
• [12]Wise LA, Zierler S, Krieger N, Harlow BL: Adult onset of major depressive disorder in relation to early life violent victimisation: a case-control study. Lancet 2001, 358(9285):881-7.
• [13]Gershon A, Minor K, Hayward C: Gender, victimization, and psychiatric outcomes. Psychol Med 2008, 38(10):1377-91.
• [14]Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al.: Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003, 301(5631):386-9.
• [15]Buchmann AF, Hellweg R, Rietschel M, Treutlein J, Witt SH, Zimmermann US, et al.: BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: a prospective study. Eur Neuropsychopharmacol 2013, 23(8):902-9.
• [16]Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al.: Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 2008, 299(11):1291-305.
• [17]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(6):693-710.
• [18]Danese A, Pariante CM, Caspi A, Taylor A, Poulton R: Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A 2007, 104(4):1319-24.
• [19]McGowan P, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, et al.: Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009, 12(3):342-8.
• [20]Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al.: Epigenetic programming by maternal behavior. Nat Neurosci 2004, 7(8):847-54.
• [21]Franklin TB, Russig H, Weiss IC, Graff J, Linder N, Michalon A, et al.: Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 2010, 68(5):408-15.
• [22]McGowan PO, Szyf M: The epigenetics of social adversity in early life: implications for mental health outcomes. Neurobiol Dis 2010, 39(1):66-72.
• [23]Murgatroyd C, Patchev A, Wu Y, Micale V, Bockmuhl Y, Fischer D, et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci. 2009;12(12):1559–66. doi:10.038/nn.2436. Epub 009 Nov 8.
• [24]Holsboer F: The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000, 23(5):477-501.
• [25]Meynen G, Unmehopa UA, van Heerikhuize JJ, Hofman MA, Swaab DF, Hoogendijk WJ: Increased arginine vasopressin mRNA expression in the human hypothalamus in depression: A preliminary report. Biol Psychiatry 2006, 60(8):892-5.
• [26]Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF: Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994, 60(4):436-44.
• [27]Murgatroyd C, Spengler D: Epigenetics of early child development. Front Psychiatry 2011, 2:16.
• [28]Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE, et al.: Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 2002, 7(1):118-22.
• [29]Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA: Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004, 306(5697):879-81.
• [30]Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, et al.: Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 2009, 14(7):681-95.
• [31]Cirulli F, Francia N, Berry A, Aloe L, Alleva E, Suomi SJ: Early life stress as a risk factor for mental health: role of neurotrophins from rodents to non-human primates. Neurosci Biobehav Rev 2009, 33(4):573-85.
• [32]Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM: Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 2002, 109(2):143-8.
• [33]Black IB: Trophic regulation of synaptic plasticity. J Neurobiol 1999, 41(1):108-18.
• [34]White KJ, Walline CC, Barker EL: Serotonin transporters: implications for antidepressant drug development. AAPS J 2005, 7(2):E421-33.
• [35]Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al.: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996, 274(5292):1527-31.
• [36]Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al.: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003, 112(2):257-69.
• [37]van der Doelen RH, Calabrese F, Guidotti G, Geenen B, Riva MA, Kozicz T, et al.: Early life stress and serotonin transporter gene variation interact to affect the transcription of the glucocorticoid and mineralocorticoid receptors, and the co-chaperone FKBP5, in the adult rat brain. Front Behav Neurosci 2014, 8:355.
• [38]Osterlund MK, Hurd YL: Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders. Prog Neurobiol 2001, 64(3):251-67.
• [39]Champagne FA, Weaver IC, Diorio J, Sharma S, Meaney MJ: Natural variations in maternal care are associated with estrogen receptor alpha expression and estrogen sensitivity in the medial preoptic area. Endocrinology 2003, 144(11):4720-4.
• [40]Pinheiro M, Ferraz-de-Paula V, Ribeiro A, Sakai M, Bernardi M, Palermo-Neto J: Long-term maternal separation differentially alters serum corticosterone levels and blood neutrophil activity in A/J and C57BL/6 mouse offspring. Neuroimmunomodulation 2011, 18(3):184-90.
• [41]Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA: Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 2002, 7(6):609-16.
• [42]George ED, Bordner KA, Elwafi HM, Simen AA: Maternal separation with early weaning: a novel mouse model of early life neglect. BMC Neurosci 2010, 11:123. BioMed Central Full Text
• [43]Weaver ICG, D’Alessio AC, Brown SE, Hellstrom IC, Dymov S, Sharma S, et al.: The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes. J Neurosci 2007, 27(7):1756-68.
• [44]Daniels WMU, Fairbairn L, Tilburg G, McEvoy C, Zigmond M, Russell V, et al.: Maternal separation alters nerve growth factor and corticosterone levels but not the DNA methylation status of the exon 1(7) glucocorticoid receptor promoter region. Metab Brain Dis 2009, 24(4):615-27.
• [45]Kember RL, Dempster EL, Lee TH, Schalkwyk LC, Mill J, Fernandes C: Maternal separation is associated with strain-specific responses to stress and epigenetic alterations to Nr3c1, Avp, and Nr4a1 in mouse. Brain Behav 2012, 2(4):455-67.
• [46]McGowan P, Suderman M, Sasaki A, Huang T, Hallett M, Meaney MJ, et al.: Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One 2011, 6(2):e14739.
• [47]Chen J, Evans A, Liu Y, Honda M, Saavedra J, Aguilera G: Maternal deprivation in rats is associated with corticotrophin-releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J Neuroendocrinol 2012, 24(7):1055-64.
• [48]Wang A, Nie W, Li H, Hou Y, Yu Z, Fan Q, et al.: Epigenetic upregulation of corticotrophin-releasing hormone mediates postnatal maternal separation-induced memory deficiency. PLoS One 2014, 9(4):e94394.
• [49]Rishi V, Bhattacharya P, Chatterjee R, Rozenberg J, Zhao J, Glass K, et al.: CpG methylation of half-CRE sequences creates C/EBPalpha binding sites that activate some tissue-specific genes. Proc Natl Acad Sci U S A 2010, 107(47):20311-6.
• [50]Zhang X, Odom DT, Koo SH, Conkright MD, Canettieri G, Best J, et al.: Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc Natl Acad Sci U S A 2005, 102(12):4459-64.
• [51]Murgatroyd C, Spengler D: Polycomb binding precedes early-life stress responsive DNA methylation at the Avp enhancer. PLoS One 2014, 9(3):e90277.
• [52]Roceri M, Cirulli F, Pressina C, Peretto P, Racagni G, Riva MA: Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biol Psychiatry 2004, 55(7):708-14.
• [53]Roth TL, Lubin FD, Funk A, Sweatt JD: Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 2009, 65(9):760-9.
• [54]Bai M, Zhu X, Zhang Y, Zhang S, Zhang L, Xue L, et al.: Abnormal hippocampal BDNF and miR-16 expression is associated with depression-like behaviors induced by stress during early life. PLoS One 2012, 7(10):e46921.
• [55]Kinnally EL, Tarara E, Mason W, Mendoza S, Abel K, Lyons L, et al.: Serotonin transporter expression is predicted by early life stress and is associated with disinhibited behavior in infant rhesus macaques. Genes Brain Behav 2010, 9(1):45-52.
• [56]Lee J-H, Kim B-T, Kim HJ, Kim JG, Ryu V, Kang D-W, et al.: Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation. Neurosci Res 2007, 58(1):32-9.
• [57]Kinnally EL, Capitanio JP, Leibel R, Deng L, LeDuc C, Haghighi F, et al.: Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes Brain Behav 2010, 9(6):575-82.
• [58]Kinnally EL, Feinberg C, Kim D, Ferguson K, Leibel R, Coplan JD, et al.: DNA methylation as a risk factor in the effects of early life stress. Brain Behav Immun 2011, 25(8):1548-53.
• [59]Champagne FA, Weaver ICG, Diorio J, Dymov S, Szyf M, Meaney MJ: Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology 2006, 147(6):2909.
• [60]Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA: Decreased glutamic acid decarboxylase 67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 2000, 57(3):237-45.
• [61]Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM: Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry 2002, 59(6):521-9.
• [62]Kundakovic M, Chen Y, Costa E, Grayson D: DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol 2007, 71(3):644-53.
• [63]Costa E, Dong E, Grayson DR, Ruzicka WB, Simonini MV, Veldic M, et al.: Epigenetic targets in GABAergic neurons to treat schizophrenia. Adv Pharmacol 2006, 54:95-117.
• [64]Fatemi SH, Earle JA, McMenomy T: Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry 2000, 5(6):654-63.
• [65]Guidotti A, Sharma R, Uzunov D, Costa E, Auta J, Davis JM, et al.: Decrease in Reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000, 57(11):1061-9.
• [66]Zhang T-Y, Hellstrom IC, Bagot R, Wen X, Diorio J, Meaney MJ: Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus. J Neurosci 2010, 30(39):13130-7.
• [67]Qin L, Tu W, Sun X, Zhang J, Chen Y, Zhao H: Retardation of neurobehavioral development and reelin down-regulation regulated by further DNA methylation in the hippocampus of the rat pups are associated with maternal deprivation. Behav Brain Res 2011, 217(1):142-7.
• [68]Aas M, Djurovic S, Athanasiu L, Steen NE, Agartz I, Lorentzen S, et al.: Serotonin transporter gene polymorphism, childhood trauma, and cognition in patients with psychotic disorders. Schizophr Bull 2012, 38(1):15-22.
• [69]Suderman M, McGowan PO, Sasaki A, Huang TC, Hallett MT, Meaney MJ, et al.: Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc Natl Acad Sci U S A 2012, 109(Suppl 2):17266-72.
• [70]Perroud N, Paoloni-Giacobino A, Prada P, Olie E, Salzmann A, Nicastro R, et al.: Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl Psychiatry 2011, 1:e59.
• [71]Tyrka AR, Price LH, Marsit C, Walters OC, Carpenter LL: Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS One 2012, 7(1):e30148.
• [72]Murgatroyd C, Quinn J, Sharp H, Pickles A, Hill J. Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene. Transl Psychiatry. 2015. In press.
• [73]Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A: The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am J Med Genet B Neuropsychiatr Genet 2008, 147B(5):543-9.
• [74]Beach SR, Brody GH, Todorov AA, Gunter TD, Philibert RA: Methylation at SLC6A4 is linked to family history of child abuse: an examination of the Iowa adoptee sample. Am J Med Genet B Neuropsychiatr Genet 2010, 153B(2):710-3.
• [75]Beach SR, Brody GH, Todorov AA, Gunter TD, Philibert RA: Methylation at 5HTT mediates the impact of child sex abuse on women’s antisocial behavior: an examination of the Iowa adoptee sample. Psychosom Med 2011, 73(1):83-7.
• [76]Kang HJ, Kim JM, Stewart R, Kim SY, Bae KY, Kim SW, et al.: Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression. Prog Neuropsychopharmacol Biol Psychiatry 2013, 44:23-8.
• [77]Naumova OY, Lee M, Koposov R, Szyf M, Dozier M, Grigorenko EL: Differential patterns of whole-genome DNA methylation in institutionalized children and children raised by their biological parents. Dev Psychopathol 2012, 24(1):143-55.
• [78]Labonte B, Yerko V, Gross J, Mechawar N, Meaney MJ, Szyf M, et al.: Differential glucocorticoid receptor exon 1(B), 1(C), and 1(H) expression and methylation in suicide completers with a history of childhood abuse. Biol Psychiatry 2012, 72(1):41-8.
• [79]Borghol N, Suderman M, McArdle W, Racine A, Hallett M, Pembrey M, et al.: Associations with early-life socio-economic position in adult DNA methylation. Int J Epidemiol 2012, 41(1):62-74.
• [80]Mehta D, Klengel T, Conneely KN, Smith AK, Altmann A, Pace TW, et al.: Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc Natl Acad Sci U S A 2013, 110(20):8302-7.
• [81]Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, et al.: Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet 2011, 156B(6):700-8.
• [82]Champagne FA, Meaney MJ: Transgenerational effects of social environment on variations in maternal care and behavioral response to novelty. Behav Neurosci 2007, 121(6):1353-63.
• [83]Levine A, Worrell TR, Zimnisky R, Schmauss C: Early life stress triggers sustained changes in histone deacetylase expression and histone H4 modifications that alter responsiveness to adolescent antidepressant treatment. Neurobiol Dis 2012, 45(1):488-98.
• [84]Massart R, Suderman M, Provencal N, Yi C, Bennett AJ, Suomi S, et al.: Hydroxymethylation and DNA methylation profiles in the prefrontal cortex of the non-human primate rhesus macaque and the impact of maternal deprivation on hydroxymethylation. Neuroscience 2014, 268:139-48.
• [85]Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RCS, et al.: Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology 2006, 31(1):47-57.
• [86]Ikegame T, Bundo M, Murata Y, Kasai K, Kato T, Iwamoto K: DNA methylation of the BDNF gene and its relevance to psychiatric disorders. J Hum Genet 2013, 58(7):434-8.
• [87]Kundakovic M, Gudsnuk K, Herbstman JB, Tang D, Perera FP, Champagne FA: DNA methylation of BDNF as a biomarker of early-life adversity. Proc Natl Acad Sci U S A 2014, 112(22):6807-13.
• [88]Martinowich K, Lu B: Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 2008, 33(1):73-83.
• [89]Madhav TR, Pei Q, Zetterstrom TS: Serotonergic cells of the rat raphe nuclei express mRNA of tyrosine kinase B (trkB), the high-affinity receptor for brain derived neurotrophic factor (BDNF). Brain Res Mol Brain Res 2001, 93(1):56-63.
• [90]Solum DT, Handa RJ: Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J Neurosci 2002, 22(7):2650-9.
• [91]Provencal N, Suderman MJ, Guillemin C, Massart R, Ruggiero A, Wang D, et al.: The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. J Neurosci 2012, 32(44):15626-42.
• [92]Khulan B, Manning JR, Dunbar DR, Seckl JR, Raikkonen K, Eriksson JG, et al.: Epigenomic profiling of men exposed to early-life stress reveals DNA methylation differences in association with current mental state. Transl Psychiatry 2014, 4:e448.
• [93]Labonte B, Suderman M, Maussion G, Navaro L, Yerko V, Mahar I, et al.: Genome-wide epigenetic regulation by early-life trauma. Arch Gen Psychiatry 2012, 69(7):722-31.
• [94]Levine S: Infantile experience and resistance to physiological stress. Science 1957, 126(3270):405.
• [95]Laban O, Markovic B, Dimitruevic M, Jankovic B: Maternal deprivation and early weaning modulate experimental allergic encephalomyelitis in the rat. Brain Behav Immun 1995, 9(1):9-19.
• [96]Plotsky P, Meaney M: Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res 1993, 18(3):195-200.
• [97]Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, et al.: Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 1997, 277(5332):1659.
• [98]McGowan PO, Sasaki A, Huang TC, Unterberger A, Suderman M, Ernst C, et al.: Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS One 2008, 3(5):e2085.