Advertisement

Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene

      Background

      Childhood maltreatment and early trauma leave lasting imprints on neural mechanisms of cognition and emotion. With a rat model of infant maltreatment by a caregiver, we investigated whether early-life adversity leaves lasting epigenetic marks at the brain-derived neurotrophic factor (BDNF) gene in the central nervous system.

      Methods

      During the first postnatal week, we exposed infant rats to stressed caretakers that predominately displayed abusive behaviors. We then assessed DNA methylation patterns and gene expression throughout the life span as well as DNA methylation patterns in the next generation of infants.

      Results

      Early maltreatment produced persisting changes in methylation of BDNF DNA that caused altered BDNF gene expression in the adult prefrontal cortex. Furthermore, we observed altered BDNF DNA methylation in offspring of females that had previously experienced the maltreatment regimen.

      Conclusions

      These results highlight an epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Cicchetti D.
        • Toth S.L.
        Child maltreatment.
        Ann Rev Clin Psychol. 2005; 1: 409-438
        • De Bellis M.D.
        The psychobiology of neglect.
        Child Maltreat. 2005; 10: 150-172
        • Lee V.
        • Hoaken P.N.
        Cognition, emotion, and neurobiological development: Mediating the relation between maltreatment and aggression.
        Child Maltreat. 2007; 12: 281-298
        • Kaffman A.
        • Meaney M.J.
        Neurodevelopmental sequelae of postnatal maternal care in rodents: Clinical and research implications of molecular insights.
        J Child Psychol Psychiatry. 2007; 48: 224-244
        • Fumagalli F.
        • Molteni R.
        • Racagni G.
        • Riva M.A.
        Stress during development: Impact on neuroplasticity and relevance to psychopathology.
        Prog Neurobiol. 2007; 81: 197-217
        • Noble K.G.
        • Tottenham N.
        • Casey B.J.
        Neuroscience perspectives on disparities in school readiness and cognitive achievement.
        Future Child. 2005; 15: 71-89
        • Teicher M.H.
        • Andersen S.L.
        • Polcari A.
        • Anderson C.M.
        • Navalta C.P.
        • Kim D.M.
        The neurobiological consequences of early stress and childhood maltreatment.
        Neurosci Biobehav Rev. 2003; 27: 33-44
        • McEwen B.S.
        Physiology and neurobiology of stress and adaptation: central role of the brain.
        Physiol Rev. 2007; 87: 873-904
        • Bock J.
        • Gruss M.
        • Becker S.
        • Braun K.
        Experience-induced changes of dendritic spine densities in the prefrontal and sensory cortex: Correlation with developmental time windows.
        Cereb Cortex. 2005; 15: 802-808
        • Branchi I.
        The mouse communal nest: Investigating the epigenetic influences of the early social environment on brain and behavior development.
        Neurosci Biobehav Rev. 2008; ([published online ahead of print April 4])
        • Branchi I.
        • Francia N.
        • Alleva E.
        Epigenetic control of neurobehavioural plasticity: The role of neurotrophins.
        Behav Pharmacol. 2004; 15: 353-362
        • Fenoglio K.A.
        • Brunson K.L.
        • Baram T.Z.
        Hippocampal neuroplasticity induced by early-life stress: Functional and molecular aspects.
        Front Neuroendocrinol. 2006; 27: 180-192
        • Chahrour M.
        • Jung S.Y.
        • Shaw C.
        • Zhou X.
        • Wong S.T.C.
        • Qin J.
        • Zoghbi H.Y.
        MeCP2, a key contributor to neurological disease, activates and represses transcription.
        Science. 2008; 320: 1224-1229
        • Graff J.
        • Mansuy I.M.
        Epigenetic codes in cognition and behaviour.
        Behav Brain Res. 2008; 192: 70-87
        • Miranda T.B.
        • Jones P.A.
        DNA methylation: The nuts and bolts of repression.
        J Cell Physiol. 2007; 213: 384-390
        • Suzuki M.M.
        • Bird A.
        DNA methylation landscapes: Provocative insights from epigenomics.
        Nat Rev Genet. 2008; 9: 465-476
        • Brown S.E.
        • Weaver I.C.G.
        • Meaney M.J.
        • Szyf M.
        Regional-specific global cytosine methylation and DNA methyltransferase expression in the adult rat hippocampus.
        Neurosci Letters. 2008; 440: 49-53
        • Kangaspeska S.
        • Stride B.
        • Metivier R.
        • Polycarpou-Schwarz M.
        • Ibberson D.
        • Carmouche R.P.
        • et al.
        Transient cyclical methylation of promoter DNA.
        Nature. 2008; 452: 112-115
        • Metivier R.
        • Gallais R.
        • Tiffoche C.
        • Le Peron C.
        • Jurkowska R.Z.
        • Carmouche R.P.
        • et al.
        Cyclical DNA methylation of a transcriptionally active promoter.
        Nature. 2008; 452: 45-50
        • Siegmund K.D.
        • Connor C.M.
        DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons.
        PLoS ONE. 2007; 2: e895
        • Bailey C.H.
        • Kandel E.R.
        • Si K.
        The persistence of long-term memory: A molecular approach to self-sustaining changes in learning-induced synaptic growth.
        Neuron. 2004; 44: 49-57
        • Bredy T.W.
        • Wu H.
        • Crego C.
        • Zellhoefer J.
        • Sun Y.E.
        • Barad M.
        Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear.
        Learn Mem. 2007; 14: 268-276
        • Fischer A.
        • Sananbenesi F.
        • Wang X.
        • Dobbin M.
        • Tsai L.-H.
        Recovery of learning and memory is associated with chromatin remodeling.
        Nature. 2007; 447: 178-182
        • Korzus E.
        • Rosenfeld M.G.
        • Mayford M.
        CBP histone acetyltransferase activity is a critical component on memory consolidation.
        Neuron. 2004; 42: 961-972
        • Lubin F.D.
        • Roth T.L.
        • Sweatt J.D.
        Epigenetic regulation of bdnf gene transcription in the consolidation of fear memory.
        J Neurosci. 2008; 28: 10576-10586
        • Miller C.A.
        • Sweatt J.D.
        Covalent modification of DNA regulates memory formation.
        Neuron. 2007; 53: 857-869
        • Nelson E.D.
        • Kavalali E.T.
        • Monteggia L.M.
        Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation.
        J Neurosci. 2008; 28: 395-406
        • Tang A.C.
        • Zou B.
        • Reeb B.C.
        • Connor J.A.
        An epigenetic induction of a right-shift in hippocampal asymmetry: Selectivity for short- and long-term potentiation but not post-tetanic potentiation.
        Hippocampus. 2008; 18: 5-10
        • Tsankova N.
        • Berton O.
        • Renthal W.
        • Kumar A.
        • Neve R.
        • Nestler E.
        Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action.
        Nat Neurosci. 2006; 9: 519-525
        • Weaver I.C.G.
        • Cervoni N.
        • Champagne F.A.
        • D'Alessio A.C.
        • Sharma S.
        • Seckl J.R.
        • et al.
        Epigenetic programming by maternal behavior.
        Nat Neurosci. 2004; 7: 847-854
        • Mill J.
        • Tang T.
        • Kaminsky Z.
        • Khare T.
        • Yazdanpanah S.
        • Bouchard L.
        • et al.
        Epigenomic profiling reveals DNA-methylation changes associated with major psychosis.
        Am J Human Gen. 2008; 82: 696-711
        • Tsankova N.
        • Renthal W.
        • Kumar A.
        • Nestler E.J.
        Epigenetic regulation in psychiatric disorders.
        Nat Rev Neurosci. 2007; 8: 355-367
        • Costa E.
        • Chen Y.
        • Davis J.
        • Dong E.
        • Noh J.S.
        • Tremolizzo L.
        REELIN and schizophrenia: A disease at the interface of the genome and the epigenome.
        Mol Intervent. 2002; 2: 47-57
        • Guidotti A.
        • Ruzicka W.
        • Grayson D.R.
        • Veldic M.
        • Pinna G.
        • Davis J.M.
        • Costa E.
        S-adenosyl methionine and DNA methyltransferase-1 mRNA overexpression in psychosis.
        Neuroreport. 2007; 18: 57-60
        • McGowan P.O.
        • Sasaki A.
        • Huang T.C.T.
        • 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: e2085
        • Ivy A.S.
        • Brunson K.L.
        • Sandman C.
        • Baram T.Z.
        Dysfunctional nurturing behavior in rat dams with limited access to nesting material: A clinically relevant model for early-life stress.
        Neurosci. 2008; 154: 1132-1142
        • Roth T.L.
        • Sullivan R.M.
        Memory of early maltreatment: Neonatal behavioral and neural correlates of maternal maltreatment within the context of classical conditioning.
        Biol Psychiatry. 2005; 57: 823-831
        • Livak K.
        • Schmittgen T.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
        Methods. 2001; 25: 402-408
        • Pfaffl M.
        A new mathematical model for relative quantification in real-time RT-PCR.
        Nucleic Acids Res. 2001; 29: e45
        • Lippmann M.
        • Bress A.
        • Nemeroff C.B.
        • Plotsky P.M.
        • Monteggia L.M.
        Long-term behavioural and molecular alterations associated with maternal separation in rats.
        Eur J Neurosci. 2007; 25: 3091-3098
        • Nair A.
        • Vadodaria K.C.
        • Banerjee S.B.
        • Benekareddy M.
        • Dias B.G.
        • Duman R.S.
        • Vaidya V.A.
        Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus.
        Neuropsychopharmacol. 2007; 32: 1504-1519
        • Duman R.S.
        • Monteggia L.M.
        A neurotrophic model for stress-related mood disorders.
        Biol Psychiatry. 2006; 59: 1116-1127
        • Shelton R.C.
        The molecular neurobiology of depression.
        Psychiat Clin N Am. 2007; 30: 1-11
        • Weickert C.S.
        • Hyde T.M.
        • Lipska B.K.
        • Herman M.M.
        • Weinberger D.R.
        • Kleinman J.E.
        Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia.
        Mol Psychiatry. 2003; 8: 592-610
        • Aid T.
        • Kazantseva A.
        • Piirsoo M.
        • Palm K.
        • Timmusk T.
        Mouse and rat BDNF gene structure and expression revisited.
        J Neurosci Res. 2007; 85: 525-535
        • Liu Q.-R.
        • Lu L.
        • Zhu X.-G.
        • Gong J.-P.
        • Shaham Y.
        • Uhl G.R.
        Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine.
        Brain Res. 2006; 1067: 1-12
        • Sathanoori M.
        • Dias B.G.
        • Nair A.R.
        • Banerjee S.B.
        • Tole S.
        • Vaidya V.A.
        Differential regulation of multiple brain-derived neurotrophic factor transcripts in the postnatal and adult rat hippocampus during development, and in response to kainate administration.
        Brain Res Mol Brain Res. 2004; 130: 170-177
        • Martinowich K.
        • Hattori D.
        • Wu H.
        • Fouse S.
        • He F.
        • Hu Y.
        • et al.
        DNA Methylation-related chromatin remodeling in activity-dependent bdnf gene regulation.
        Science. 2003; 302: 890-893
        • Dennis K.E.
        • Levitt P.
        Regional expression of brain derived neurotrophic factor (BDNF) is correlated with dynamic patterns of promoter methylation in the developing mouse forebrain.
        Mol Brain Res. 2005; 140: 1-9
        • Maisonpierre P.C.
        • Belluscio L.
        • Friedman B.
        • Alderson R.F.
        • Wiegand S.J.
        • Furth M.E.
        • et al.
        NT-3, BDNF, and NGF in the developing rat nervous system: Parallel as well as reciprocal patterns of expression.
        Neuron. 1990; 5: 501-509
        • Herz J.
        • Chen Y.
        Reelin, lipoprotein receptors and synaptic plasticity.
        Nat Rev Neurosci. 2006; 7: 850-859
        • Weaver I.
        • Meaney M.J.
        • Szyf M.
        Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood.
        Proc Natl Acad Sci U S A. 2006; 103: 3480-3485
        • Cheng J.C.
        • Matsen C.B.
        • Gonzales F.A.
        • Ye W.
        • Greer S.
        • Marquez V.E.
        • et al.
        Inhibition of DNA methylation and reactivation of silenced genes by zebularine.
        J Natl Cancer Inst. 2003; 95: 399-409
        • Barreto G.
        • Schafer A.
        • Marhold J.
        • Stach D.
        • Swaminathan S.K.
        • Handa V.
        • et al.
        Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation.
        Nature. 2007; 445: 671-675
        • Detich N.
        • Bovenzi
        • Szyf M.
        Valproate induces replication-independent active DNA demethylation.
        J Biol Chem. 2003; 278: 27586-27592
        • Kress C.
        • Thomassin H.
        • Grange T.
        Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks.
        PNAS. 2006; 103: 11112-11117
        • Champagne F.A.
        Epigenetic mechanisms and the transgenerational effects of maternal care.
        Front Neuroendocrinol. 2008; 29: 386-397
        • Fleming A.S.
        • Kraemer G.W.
        • Gonzalez A.
        • Lovic V.
        • Rees S.
        • Melo A.
        Mothering begets mothering: The transmission of behavior and its neurobiology across generations.
        Pharmacol Biochem Behav. 2002; 73: 61-75
        • Lovic V.
        • Gonzalez A.
        • Fleming A.S.
        Maternally separated rats show deficits in maternal care in adulthood.
        Dev Psychobiol. 2001; 39: 19-33
        • Maestripieri D.
        • Lindell S.G.
        • Higley J.D.
        Intergenerational transmission of maternal behavior in rhesus macaques and its underlying mechanisms.
        Dev Psychobiol. 2007; 49: 165-171
        • Sanchez M.M.
        The impact of early adverse care on HPA axis development: Nonhuman primate models.
        Horm Behav. 2006; 50: 623-631
        • Febo M.
        • Numan M.
        • Ferris C.F.
        Functional magnetic resonance imaging shows oxytocin activates brain regions associated with mother-pup bonding during suckling.
        J Neurosci. 2005; 25: 11637-11644
        • Hernandez-Gonzalez M.
        • Navarro-Meza M.
        • Prieto-Beracoechea C.A.
        • Guevara M.A.
        Electrical activity of prefrontal cortex and ventral tegmental area during rat maternal behavior.
        Behav Proc. 2005; 70: 132-143
        • Numan M.
        Motivational systems and the neural circuitry of maternal behavior in the rat.
        Dev Psychobiol. 2007; 49: 12-21
        • Darnaudéry M.
        • Maccari S.
        Epigenetic programming of the stress response in male and female rats by prenatal restraint stress.
        Brain Res Rev. 2008; 57: 571-585
        • Moles A.
        • Rizzi R.
        • D'Amota F.R.
        Postnatal stress in mice: Does “stressing” the mother have the same effect as “stressing” the pups?.
        Dev Psychobiol. 2004; 44: 230-237
        • Champagne F.
        • Weaver I.
        • Diorio J.
        • Dymov S.
        • Szyf M.
        • Meaney M.J.
        Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring.
        Endocrinol. 2006; 147: 2909-2915
        • Champagne F.A.
        • Curley J.P.
        Epigenetic mechanisms mediating the long-term effects of maternal care on development.
        Neurosci Biobehav Rev. 2008; ([published online ahead of print January 18])
        • Jirtle R.L.
        • Skinner M.K.
        Environmental epigenomics and disease susceptibility.
        Nat Rev Genet. 2007; 8: 253-262
        • McLeod J.
        • Sinal C.J.
        • Perrot-Sinal T.S.
        Evidence for non-genomic transmission of ecological information via maternal behavior in female rats.
        Genes Brain Behav. 2007; 6: 19-29
        • Richards E.J.
        Inherited epigenetic variation—revisiting soft inheritance.
        Nat Rev Genet. 2006; 7: 395-401
        • Szyf M.
        • Weaver I.
        • Meaney M.
        Maternal care, the epigenome and phenotypic differences in behavior.
        Reproductive Toxicol. 2007; 24: 9-19
        • Oberlander T.F.
        • Weinberg J.
        • Papsdorf M.
        • Grunau R.
        • Misri S.
        • Devlin A.M.
        Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses.
        Epigenetics. 2008; 3: 97-106
        • Novikova S.I.
        • He F.
        • Bai J.
        • Cutrufello N.J.
        • Lidow M.S.
        • Undieh A.S.
        Maternal cocaine administration in mice alters DNA methylation and gene expression in hippocampal neurons of neonatal and prepubertal offspring.
        PLoS ONE. 2008; 3: e1919
        • Mueller B.R.
        • Bale T.L.
        Sex-specific programming of offspring emotionality after stress early in pregnancy.
        J Neurosci. 2008; 28: 9055-9065