Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Epigenetic and transgenerational reprogramming of brain development

Key Points

  • Neurodevelopmental programming is defined as the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development.

  • Epigenetic processes are also responsible for the reprogramming that occurs in response to environmental challenges, such as maternal stress or infection, making the organism more or less adaptive depending on the future environment and the challenges presented.

  • Developmental windows of susceptibility exist such that exposures occurring during these dynamic periods are more likely to produce marked and broad changes to the epigenome.

  • Alterations to the germ cell epigenome as a result of environmental influences throughout life can result in transgenerational transmission of traits that are able to increase or to decrease disease risk in future offspring.

  • Seemingly different environmental perturbations, such as maternal stress or infection, can produce similar neurodevelopmental changes and phenotypes, which suggests that common downstream cellular mechanisms are responsible for transmitting information from the in utero environment to the developing fetus.

  • Sex specificity of the parent and the offspring is also an important factor in determining the effect of the exposures and the epigenetic mechanisms involved.

Abstract

Neurodevelopmental programming — the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development — requires tight regulation of transcriptional processes. During prenatal and postnatal time periods, epigenetic processes fine-tune neurodevelopment towards an end product that determines how an organism interacts with and responds to exposures and experiences throughout life. Epigenetic processes also have the ability to reprogramme the epigenome in response to environmental challenges, such as maternal stress, making the organism more or less adaptive depending on the future challenges presented. Epigenetic marks generated within germ cells as a result of environmental influences throughout life can also shape future generations long before conception occurs.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Complex interactions between the maternal milieu, placenta and fetal compartments during gestation.
Figure 2: Modes of maternal and paternal transgenerational epigenetic transmission.
Figure 3: Programming of phenotypes and disease risk can skip generations.
Figure 4: Windows of vulnerability to environmental reprogramming in spermatogenesis.

References

  1. Bale, T. L. et al. Early life programming and neurodevelopmental disorders. Biol. Psychiatry 68, 314–319 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Curley, J. P., Jensen, C. L., Mashoodh, R. & Champagne, F. A. Social influences on neurobiology and behavior: epigenetic effects during development. Psychoneuroendocrinology 36, 352–371 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. McCarthy, M. M. & Nugent, B. M. Epigenetic contributions to hormonally mediated sexual differentiation of the brain. J. Neuroendocrinol. 25, 1133–1140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hodes, G. E. Sex, stress, and epigenetics: regulation of behavior in animal models of mood disorders. Biol. Sex Differ. 4, 1 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bohacek, J., Gapp, K., Saab, B. J. & Mansuy, I. M. Transgenerational epigenetic effects on brain functions. Biol. Psychiatry 73, 313–320 (2013).

    Article  PubMed  Google Scholar 

  6. Hales, C. N. & Barker, D. J. The thrifty phenotype hypothesis. Br. Med. Bull. 60, 5–20 (2001). In this paper, the thrifty phenotype hypothesis describes how a mismatch between fetal programming and the postnatal environment can result in disease risk.

    Article  CAS  PubMed  Google Scholar 

  7. Binder, E. B. & Nemeroff, C. B. The CRF system, stress, depression and anxiety-insights from human genetic studies. Mol. Psychiatry 15, 574–588 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Hackman, D. A., Farah, M. J. & Meaney, M. J. Socioeconomic status and the brain: mechanistic insights from human and animal research. Nature Rev. Neurosci. 11, 651–659 (2010).

    Article  CAS  Google Scholar 

  9. Sweatt, J. D. The emerging field of neuroepigenetics. Neuron 80, 624–632 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Glynn, L. M., Wadhwa, P. D., Dunkel-Schetter, C., Chicz-Demet, A. & Sandman, C. A. When stress happens matters: effects of earthquake timing on stress responsivity in pregnancy. Am. J. Obstet. Gynecol. 184, 637–642 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Deverman, B. E. & Patterson, P. H. Cytokines and CNS development. Neuron 64, 61–78 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Howerton, C. L. & Bale, T. L. Prenatal programing: at the intersection of maternal stress and immune activation. Horm. Behav. 62, 237–242 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Brown, A. S. Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev. Neurobiol. 72, 1272–1276 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Brown, A. S. et al. Prenatal infection and cavum septum pellucidum in adult schizophrenia. Schizophr. Res. 108, 285–287 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Brown, A. S. et al. Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia. Am. J. Psychiatry 166, 683–690 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Selevan, S. G., Kimmel, C. A. & Mendola, P. Identifying critical windows of exposure for children's health. Environ. Health Perspect. 108 (Suppl. 3), 451–455 (2000).

    PubMed  PubMed Central  Google Scholar 

  17. Rapoport, J. L., Addington, A. M., Frangou, S. & Psych, M. R. The neurodevelopmental model of schizophrenia: update 2005. Mol. Psychiatry 10, 434–449 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Meyer, U., Feldon, J. & Dammann, O. Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatr. Res. 69, 26R–33R (2011). This study examines the shared mechanistic link between neurodevelopmental disorders that are related to prenatal inflammation.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Morrison, K. E., Rodgers, A. B., Morgan, C. P. & Bale, T. L. Epigenetic mechanisms in pubertal brain maturation. Neuroscience 264, 7–24 (2013).

    Google Scholar 

  20. Davis, E. P., Sandman, C. A., Buss, C., Wing, D. A. & Head, K. Fetal glucocorticoid exposure is associated with preadolescent brain development. Biol. Psychiatry 74, 647–655 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Malter Cohen, M. et al. Early-life stress has persistent effects on amygdala function and development in mice and humans. Proc. Natl Acad. Sci. USA 110, 18274–18278 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bale, T. L. Sex differences in prenatal epigenetic programming of stress pathways. Stress 14, 348–356 (2011).

    Article  PubMed  Google Scholar 

  23. Susser, E., St Clair, D. & He, L. Latent effects of prenatal malnutrition on adult health: the example of schizophrenia. Ann. NY Acad. Sci. 1136, 185–192 (2008).

    Article  PubMed  Google Scholar 

  24. Stoner, R. et al. Patches of disorganization in the neocortex of children with autism. N. Engl. J. Med. 370, 1209–1219 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Avishai-Eliner, S., Brunson, K. L., Sandman, C. A. & Baram, T. Z. Stressed-out, or in (utero)? Trends Neurosci. 25, 518–524 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wadhwa, P. D., Sandman, C. A. & Garite, T. J. The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system. Prog. Brain Res. 133, 131–142 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Wadhwa, P. D., Sandman, C. A., Porto, M., Dunkel-Schetter, C. & Garite, T. J. The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation. Am. J. Obstet. Gynecol. 169, 858–865 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Khashan, A. S. et al. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch. Gen. Psychiatry 65, 146–152 (2008).

    Article  PubMed  Google Scholar 

  29. Atladottir, H. O. et al. Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study. Arch. Pediatr. Adolesc. Med. 164, 470–477 (2010).

    Article  PubMed  Google Scholar 

  30. Atladottir, H. O. et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. 40, 1423–1430 (2010).

    Article  PubMed  Google Scholar 

  31. Goines, P. E. et al. Increased midgestational IFNγ, IL-4 and IL-5 in women bearing a child with autism: a case-control study. Mol. Autism 2, 13 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Brown, A. S. & Susser, E. S. Prenatal nutritional deficiency and risk of adult schizophrenia. Schizophr. Bull. 34, 1054–1063 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Xu, M. Q. et al. Prenatal malnutrition and adult schizophrenia: further evidence from the 1959–1961 Chinese famine. Schizophr. Bull. 35, 568–576 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ravelli, G. P., Stein, Z. A. & Susser, M. W. Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 295, 349–353 (1976).

    Article  CAS  PubMed  Google Scholar 

  35. Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046–17049 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Van Lieshout, R. J., Taylor, V. H. & Boyle, M. H. Pre-pregnancy and pregnancy obesity and neurodevelopmental outcomes in offspring: a systematic review. Obes. Rev. 12, e548–e559 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Buss, C. et al. Impaired executive function mediates the association between maternal pre-pregnancy body mass index and child ADHD symptoms. PLoS ONE 7, e37758 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Howerton, C. L., Morgan, C. P., Fischer, D. B. & Bale, T. L. O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development. Proc. Natl Acad. Sci. USA 110, 5169–5174 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mao, J. et al. Contrasting effects of different maternal diets on sexually dimorphic gene expression in the murine placenta. Proc. Natl Acad. Sci. USA 107, 5557–5562 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Weaver, J. R., Susiarjo, M. & Bartolomei, M. S. Imprinting and epigenetic changes in the early embryo. Mamm. Genome 20, 532–543 (2009).

    Article  PubMed  Google Scholar 

  41. Mueller, B. R. & Bale, T. L. Impact of prenatal stress on long term body weight is dependent on timing and maternal sensitivity. Physiol. Behav. 88, 605–614 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Mueller, B. R. & Bale, T. L. Sex-specific programming of offspring emotionality after stress early in pregnancy. J. Neurosci. 28, 9055–9065 (2008). This study identifies sex-specific changes in the placenta in response to early gestational stress that are associated with changes in offspring neurodevelopment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Brunton, P. J. & Russell, J. A. Prenatal social stress in the rat programmes neuroendocrine and behavioural responses to stress in the adult offspring: sex-specific effects. J. Neuroendocrinol. 22, 258–271 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Brunton, P. J. & Russell, J. A. Allopregnanolone and suppressed hypothalamo–pituitary–adrenal axis stress responses in late pregnancy in the rat. Stress 14, 6–12 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Weinstock, M. Gender differences in the effects of prenatal stress on brain development and behaviour. Neurochem. Res. 32, 1730–1740 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Kapoor, A., Kostaki, A., Janus, C. & Matthews, S. G. The effects of prenatal stress on learning in adult offspring is dependent on the timing of the stressor. Behav. Brain Res. 197, 144–149 (2009).

    Article  PubMed  Google Scholar 

  47. Kapoor, A., Leen, J. & Matthews, S. G. Molecular regulation of the hypothalamic–pituitary–adrenal axis in adult male guinea pigs after prenatal stress at different stages of gestation. J. Physiol. 586, 4317–4326 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schneider, M. L., Moore, C. F., Kraemer, G. W., Roberts, A. D. & DeJesus, O. T. The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model. Psychoneuroendocrinology 27, 285–298 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Kapoor, A. & Matthews, S. G. Short periods of prenatal stress affect growth, behaviour and hypothalamo–pituitary–adrenal axis activity in male guinea pig offspring. J. Physiol. 566, 967–977 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mueller, B. R. & Bale, T. L. Early prenatal stress impact on coping strategies and learning performance is sex dependent. Physiol. Behav. 91, 55–65 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Lemaire, V., Koehl, M., Le Moal, M. & Abrous, D. N. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc. Natl Acad. Sci. USA 97, 11032–11037 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Darnaudery, M. & Maccari, S. Epigenetic programming of the stress response in male and female rats by prenatal restraint stress. Brain Res. Rev. 57, 571–585 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Weinstock, M. Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog. Neurobiol. 65, 427–451 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Coe, C. L. et al. Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys. Biol. Psychiatry 54, 1025–1034 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Welberg, L. A., Seckl, J. R. & Holmes, M. C. Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour. Neuroscience 104, 71–79 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Welberg, L. A. & Seckl, J. R. Prenatal stress, glucocorticoids and the programming of the brain. J. Neuroendocrinol. 13, 113–128 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Ward, I. L. Prenatal stress feminizes and demasculinizes the behavior of males. Science 175, 82–84 (1972). This is one of the first studies to determine the importance of sex-specific neurodevelopmental programming that can be disrupted by maternal stress.

    Article  CAS  PubMed  Google Scholar 

  58. Ward, I. L. & Stehm, K. E. Prenatal stress feminizes juvenile play patterns in male rats. Physiol. Behav. 50, 601–605 (1991).

    Article  CAS  PubMed  Google Scholar 

  59. Baron-Cohen, S. et al. Elevated fetal steroidogenic activity in autism. Mol. Psychiatry 20, 369–376 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Moore, L. et al. Serum testosterone levels are related to cognitive function in men with schizophrenia. Psychoneuroendocrinology 38, 1717–1728 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Lombardo, M. V. et al. Fetal testosterone influences sexually dimorphic gray matter in the human brain. J. Neurosci. 32, 674–680 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gur, R. E. et al. A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in schizophrenia. Biol. Psychiatry 55, 512–517 (2004). This paper reports the dysmasculinization of limbic brain regions in men with schizophrenia.

    Article  PubMed  Google Scholar 

  63. Fenoglio, K. A. et al. Enduring, handling-evoked enhancement of hippocampal memory function and glucocorticoid receptor expression involves activation of the corticotropin-releasing factor type 1 receptor. Endocrinology 146, 4090–4096 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Fenoglio, K. A., Brunson, K. L. & Baram, T. Z. Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects. Front. Neuroendocrinol. 27, 180–192 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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. Neuroscience 154, 1132–1142 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Ivy, A. S. et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J. Neurosci. 30, 13005–13015 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Korosi, A. & Baram, T. Z. Plasticity of the stress response early in life: mechanisms and significance. Dev. Psychobiol. 52, 661–670 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Korosi, A. et al. Early-life experience reduces excitation to stress-responsive hypothalamic neurons and reprograms the expression of corticotropin-releasing hormone. J. Neurosci. 30, 703–713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McClelland, S., Korosi, A., Cope, J., Ivy, A. & Baram, T. Z. Emerging roles of epigenetic mechanisms in the enduring effects of early-life stress and experience on learning and memory. Neurobiol. Learn. Mem. 96, 79–88 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Rice, C. J., Sandman, C. A., Lenjavi, M. R. & Baram, T. Z. A novel mouse model for acute and long-lasting consequences of early life stress. Endocrinology 149, 4892–4900 (2008). This novel and reproducible model shows how disruptions in maternal care can manifest in reprogramming of offspring stress pathways in the brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ladd, C. O. et al. Long-term behavioral and neuroendocrine adaptations to adverse early experience. Prog. Brain Res. 122, 81–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Liu, D. et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic–pituitary–adrenal responses to stress. Science 277, 1659–1662 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Meaney, M. J. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu. Rev. Neurosci. 24, 1161–1192 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Weaver, I. C. et al. Epigenetic programming by maternal behavior. Nature Neurosci. 7, 847–854 (2004). This important paper was the first to establish epigenetic mechanisms in the developing brain that were altered by the quality of maternal care.

    Article  CAS  PubMed  Google Scholar 

  75. Barha, C. K., Pawluski, J. L. & Galea, L. A. Maternal care affects male and female offspring working memory and stress reactivity. Physiol. Behav. 92, 939–950 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Sanchez, M. M., Ladd, C. O. & Plotsky, P. M. Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models. Dev. Psychopathol. 13, 419–449 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Caldji, C. et al. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc. Natl Acad. Sci. USA 95, 5335–5340 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Weaver, I. C., Diorio, J., Seckl, J. R., Szyf, M. & Meaney, M. J. Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Ann. NY Acad. Sci. 1024, 182–212 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Korosi, A. & Baram, T. Z. The pathways from mother's love to baby's future. Front. Behav. Neurosci. 3, 27 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Graham, Y. P., Heim, C., Goodman, S. H., Miller, A. H. & Nemeroff, C. B. The effects of neonatal stress on brain development: implications for psychopathology. Dev. Psychopathol. 11, 545–565 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Lyons, D. M., Martel, F. L., Levine, S., Risch, N. J. & Schatzberg, A. F. Postnatal experiences and genetic effects on squirrel monkey social affinities and emotional distress. Horm. Behav. 36, 266–275 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Barr, C. S. et al. Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques. Proc. Natl Acad. Sci. USA 101, 12358–12363 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neurosci. 12, 342–348 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Vukojevic, V. et al. Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors. J. Neurosci. 34, 10274–10284 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Koshy, T. S., Sara, V. R., King, T. L. & Lazarus, L. The influence of protein restriction imposed at various stages of pregnancy on fetal and placental development. Growth 39, 497–506 (1975).

    CAS  PubMed  Google Scholar 

  86. Vucetic, Z. et al. Early life protein restriction alters dopamine circuitry. Neuroscience 168, 359–370 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Pankevich, D. E., Teegarden, S. L., Hedin, A. D., Jensen, C. L. & Bale, T. L. Caloric restriction experience reprograms stress and orexigenic pathways and promotes binge eating. J. Neurosci. 30, 16399–16407 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Teegarden, S. L. & Bale, T. L. Decreases in dietary preference produce increased emotionality and risk for dietary relapse. Biol. Psychiatry 61, 1021–1029 (2007).

    Article  PubMed  Google Scholar 

  89. Teegarden, S. L. & Bale, T. L. Effects of stress on dietary preference and intake are dependent on access and stress sensitivity. Physiol. Behav. 93, 713–723 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Teegarden, S. L., Scott, A. N. & Bale, T. L. Early life exposure to a high fat diet promotes long-term changes in dietary preferences and central reward signaling. Neuroscience 162, 924–932 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Will, M. J., Franzblau, E. B. & Kelley, A. E. Nucleus accumbens μ-opioids regulate intake of a high-fat diet via activation of a distributed brain network. J. Neurosci. 23, 2882–2888 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Pecina, S., Cagniard, B., Berridge, K. C., Aldridge, J. W. & Zhuang, X. Hyperdopaminergic mutant mice have higher “wanting” but not “liking” for sweet rewards. J. Neurosci. 23, 9395–9402 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cottrell, E. C., Holmes, M. C., Livingstone, D. E., Kenyon, C. J. & Seckl, J. R. Reconciling the nutritional and glucocorticoid hypotheses of fetal programming. FASEB J. 26, 1866–1874 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Lesage, J., Blondeau, B., Grino, M., Breant, B. & Dupouy, J. P. Maternal undernutrition during late gestation induces fetal overexposure to glucocorticoids and intrauterine growth retardation, and disturbs the hypothalamo–pituitary–adrenal axis in the newborn rat. Endocrinology 142, 1692–1702 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Lingas, R., Dean, F. & Matthews, S. G. Maternal nutrient restriction (48 h) modifies brain corticosteroid receptor expression and endocrine function in the fetal guinea pig. Brain Res. 846, 236–242 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Cottrell, E. C. & Seckl, J. R. Prenatal stress, glucocorticoids and the programming of adult disease. Front. Behav. Neurosci. 3, 19 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Seckl, J. R. & Holmes, M. C. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology. Nature Clin. Pract. Endocrinol. Metab. 3, 479–488 (2007).

    Article  CAS  Google Scholar 

  98. Welberg, L. A., Thrivikraman, K. V. & Plotsky, P. M. Chronic maternal stress inhibits the capacity to up-regulate placental 11β-hydroxysteroid dehydrogenase type 2 activity. J. Endocrinol. 186, R7–R12 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Grayson, B. E. et al. Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet. Endocrinology 151, 1622–1632 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sullivan, E. L. et al. Chronic consumption of a high-fat diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like behavior in nonhuman primate offspring. J. Neurosci. 30, 3826–3830 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bilbo, S. D. & Tsang, V. Enduring consequences of maternal obesity for brain inflammation and behavior of offspring. FASEB J. 24, 2104–2115 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Frias, A. E. et al. Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition. Endocrinology 152, 2456–2464 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Shen, Q. et al. The role of pro-inflammatory factors in mediating the effects on the fetus of prenatal undernutrition: implications for schizophrenia. Schizophr. Res. 99, 48–55 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Ilievski, V., Lu, S. J. & Hirsch, E. Activation of toll-like receptors 2 or 3 and preterm delivery in the mouse. Reprod. Sci. 14, 315–320 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Hsiao, E. Y. & Patterson, P. H. Placental regulation of maternal–fetal interactions and brain development. Dev. Neurobiol. 72, 1317–1326 (2012).

    Article  PubMed  Google Scholar 

  106. Malkova, N. V., Yu, C. Z., Hsiao, E. Y., Moore, M. J. & Patterson, P. H. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun. 26, 607–616 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bilbo, S. D. & Schwarz, J. M. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front. Behav. Neurosci. 3, 14 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Bronson, S. L. & Bale, T. L. Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment. Endocrinology 155, 2635–2646 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Hsiao, E. Y. & Patterson, P. H. Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain Behav. Immun. 25, 604–615 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Lucassen, P. J. et al. Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11β-hydroxysteroid dehydrogenase type 2. Eur. J. Neurosci. 29, 97–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Mairesse, J. et al. Maternal stress alters endocrine function of the feto-placental unit in rats. Am. J. Physiol. Endocrinol. Metab. 292, E1526–E1533 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Garbett, K. A., Hsiao, E. Y., Kalman, S., Patterson, P. H. & Mirnics, K. Effects of maternal immune activation on gene expression patterns in the fetal brain. Transl. Psychiatry 2, e98 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hodge, D. R. et al. Interleukin-6 regulation of the human DNA methyltransferase (HDNMT) gene in human erythroleukemia cells. J. Biol. Chem. 276, 39508–39511 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Howerton, C. L. & Bale, T. L. Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction. Proc. Natl Acad. Sci. USA 111, 9639–9644 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Dunn, G. A., Morgan, C. P. & Bale, T. L. Sex-specificity in transgenerational epigenetic programming. Horm. Behav. 59, 290–295 (2011).

    Article  PubMed  Google Scholar 

  116. Pembrey, M. E. et al. Sex-specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14, 159–166 (2006).

    Article  PubMed  Google Scholar 

  117. Kaati, G., Bygren, L. O. & Edvinsson, S. Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur. J. Hum. Genet. 10, 682–688 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Pembrey, M., Saffery, R. & Bygren, L. O. Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J. Med. Genet. 51, 563–572 (2014). This is a comprehensive review that covers the field of transgenerational epigenetics in relation to human health and disease.

    Article  PubMed  Google Scholar 

  119. Morgan, C. P. & Bale, T. L. Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage. J. Neurosci. 31, 11748–11755 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Franklin, T. B. et al. Epigenetic transmission of the impact of early stress across generations. Biol. Psychiatry 68, 408–415 (2010).

    Article  PubMed  Google Scholar 

  121. King, V. et al. Maternal obesity has little effect on the immediate offspring but impacts on the next generation. Endocrinology 154, 2514–2524 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Dunn, G. A. & Bale, T. L. Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice. Endocrinology 150, 4999–5009 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Dunn, G. A. & Bale, T. L. Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology 152, 2228–2236 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jimenez-Chillaron, J. C. et al. Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58, 460–468 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Thamotharan, M. et al. Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring. Am. J. Physiol. Endocrinol. Metab. 292, E1270–E1279 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Burdge, G. C. et al. Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br. J. Nutr. 97, 435–439 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Boney, C. M., Verma, A., Tucker, R. & Vohr, B. R. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 115, e290–e296 (2005).

    Article  PubMed  Google Scholar 

  128. McCurdy, C. E. et al. Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J. Clin. Invest. 119, 323–335 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Sullivan, E. L., Smith, M. S. & Grove, K. L. Perinatal exposure to high-fat diet programs energy balance, metabolism and behavior in adulthood. Neuroendocrinology 93, 1–8 (2011). This paper examines the sex-specific neurodevelopmental programming and resulting increased anxiety in the non-human primate that follows exposure to a maternal high-fat diet during pregnancy.

    Article  CAS  PubMed  Google Scholar 

  130. Tamashiro, K. L., Terrillion, C. E., Hyun, J., Koenig, J. I. & Moran, T. H. Prenatal stress or high-fat diet increases susceptibility to diet-induced obesity in rat offspring. Diabetes 58, 1116–1125 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Shiell, A. W., Campbell, D. M., Hall, M. H. & Barker, D. J. Diet in late pregnancy and glucose-insulin metabolism of the offspring 40 years later. BJOG 107, 890–895 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Dietz, D. M. & Nestler, E. J. From father to offspring: paternal transmission of depressive-like behaviors. Neuropsychopharmacology 37, 311–312 (2012).

    Article  PubMed  Google Scholar 

  133. Dias, B. G. & Ressler, K. J. Parental olfactory experience influences behavior and neural structure in subsequent generations. Naure Neurosci. 17, 89–96 (2014). This is a comprehensive examination, in adult male mice, of epigenetic changes in germ cells that occur in response to exposure to an odour cue in fear conditioning that is related to reprogramming of offspring brain and behaviour.

    CAS  Google Scholar 

  134. Rodgers, A. B., Morgan, C. P., Bronson, S. L., Revello, S. & Bale, T. L. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J. Neurosci. 33, 9003–9012 (2013). This paper identifies important changes in specific sperm miRNAs produced by chronic stress in adult mice that correlate with programming of offspring stress reactivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ng, S. F. et al. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467, 963–966 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Vassoler, F. M., White, S. L., Schmidt, H. D., Sadri-Vakili, G. & Pierce, R. C. Epigenetic inheritance of a cocaine-resistance phenotype. Nature Neurosci. 16, 42–47 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Carone, B. R. et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Anway, M. D., Cupp, A. S., Uzumcu, M. & Skinner, M. K. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Anderson, L. M. et al. Preconceptional fasting of fathers alters serum glucose in offspring of mice. Nutrition 22, 327–331 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. Jenkins, T. G. & Carrell, D. T. The sperm epigenome and potential implications for the developing embryo. Reproduction 143, 727–734 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. van Os, J. & Selten, J. P. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. Br. J. Psychiatry 172, 324–326 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. Gerardin, P. et al. Depression during pregnancy: is the developmental impact earlier in boys? A prospective case-control study. J. Clin. Psychiatry 72, 378–387 (2010).

    Article  PubMed  Google Scholar 

  143. Newschaffer, C. J. et al. The epidemiology of autism spectrum disorders. Annu. Rev. Publ. Health 28, 235–258 (2007).

    Article  Google Scholar 

  144. Beversdorf, D. Q. et al. Timing of prenatal stressors and autism. J. Autism Dev. Disord. 35, 471–478 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Sandman, C. A., Glynn, L. M. & Davis, E. P. Is there a viability–vulnerability tradeoff? Sex differences in fetal programming. J. Psychosomat. Res. 75, 327–335 (2013).

    Article  Google Scholar 

  146. Smith, S. E., Li, J., Garbett, K., Mirnics, K. & Patterson, P. H. Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. 27, 10695–10702 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Morgan, C. P. & Bale, T. L. Sex differences in microRNA regulation of gene expression: no smoke, just miRs. Biol. Sex Differ. 3, 22 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Cowell, P. E., Kostianovsky, D. J., Gur, R. C., Turetsky, B. I. & Gur, R. E. Sex differences in neuroanatomical and clinical correlations in schizophrenia. Am. J. Psychiatry 153, 799–805 (1996).

    Article  CAS  PubMed  Google Scholar 

  149. McCarthy, M. M. et al. The epigenetics of sex differences in the brain. J. Neurosci. 29, 12815–12823 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Nugent, B. M. & McCarthy, M. M. Epigenetic underpinnings of developmental sex differences in the brain. Neuroendocrinology 93, 150–158 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Westberry, J. M., Trout, A. L. & Wilson, M. E. Epigenetic regulation of estrogen receptor-α gene expression in the mouse cortex during early postnatal development. Endocrinology 151, 731–740 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Kurian, J. R., Olesen, K. M. & Auger, A. P. Sex differences in epigenetic regulation of the estrogen receptor-α promoter within the developing preoptic area. Endocrinology 151, 2297–2305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Murray, E. K., Hien, A., de Vries, G. J. & Forger, N. G. Epigenetic control of sexual differentiation of the bed nucleus of the stria terminalis. Endocrinology 150, 4241–4247 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. McCarthy, M. M. Molecular aspects of sexual differentiation of the rodent brain. Psychoneuroendocrinology 19, 415–427 (1994).

    Article  CAS  PubMed  Google Scholar 

  155. Bale, T. L. Stress sensitivity and the development of affective disorders. Horm. Behav. 50, 529–533 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Bale, T. L. Neuroendocrine and immune influences on the CNS: it's a matter of sex. Neuron 64, 13–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  157. Cryan, J. F. & Dinan, T. G. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature Rev. Neurosci. 13, 701–712 (2012).

    Article  CAS  Google Scholar 

  158. Dinan, T. G. & Cryan, J. F. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology 37, 1369–1378 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Clarke, G. et al. The microbiome–gut–brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18, 666–673 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Borrelli, E., Nestler, E. J., Allis, C. D. & Sassone-Corsi, P. Decoding the epigenetic language of neuronal plasticity. Neuron 60, 961–974 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Colvis, C. M. et al. Epigenetic mechanisms and gene networks in the nervous system. J. Neurosci. 25, 10379–10389 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Tsankova, N., Renthal, W., Kumar, A. & Nestler, E. J. Epigenetic regulation in psychiatric disorders. Nature Rev. Neurosci. 8, 355–367 (2007).

    Article  CAS  Google Scholar 

  163. Day, J. J. et al. DNA methylation regulates associative reward learning. Nature Neurosci. 16, 1445–1452 (2013).

    Article  CAS  PubMed  Google Scholar 

  164. Roth, T. L. & Sweatt, J. D. Regulation of chromatin structure in memory formation. Curr. Opin. Neurobiol. 19, 336–342 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sweatt, J. D. Experience-dependent epigenetic modifications in the central nervous system. Biol. Psychiatry 65, 191–197 (2009).

    Article  PubMed  Google Scholar 

  166. Zovkic, I. B., Guzman-Karlsson, M. C. & Sweatt, J. D. Epigenetic regulation of memory formation and maintenance. Learn. Mem. 20, 61–74 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zovkic, I. B. & Sweatt, J. D. Epigenetic mechanisms in learned fear: implications for PTSD. Neuropsychopharmacology 38, 77–93 (2013).

    Article  CAS  PubMed  Google Scholar 

  168. Mahgoub, M. & Monteggia, L. M. A role for histone deacetylases in the cellular and behavioral mechanisms underlying learning and memory. Learn. Mem. 21, 564–568 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Adachi, M. & Monteggia, L. M. Decoding transcriptional repressor complexes in the adult central nervous system. Neuropharmacology 80, 45–52 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Lester, B. M. et al. Behavioral epigenetics. Ann. NY Acad. Sci. 1226, 14–33 (2011).

    Article  PubMed  Google Scholar 

  171. Morrison, K. E., Rodgers, A. B., Morgan, C. P. & Bale, T. L. Epigenetic mechanisms in pubertal brain maturation. Neuroscience 264, 17–24 (2014).

    Article  CAS  PubMed  Google Scholar 

  172. Waddington, C. H. Canalization of development and genetic assimilation of acquired characters. Nature 183, 1654–1655 (1959). This paper laid the foundation for the field of epigenetic programming by defining the 'epigenetic landscape'.

    Article  CAS  PubMed  Google Scholar 

  173. Berger, S. L., Kouzarides, T., Shiekhattar, R. & Shilatifard, A. An operational definition of epigenetics. Genes Dev. 23, 781–783 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Drake, A. J., Walker, B. R. & Seckl, J. R. Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R34–R38 (2005).

    Article  CAS  PubMed  Google Scholar 

  175. O'Regan, D., Welberg, L. L., Holmes, M. C. & Seckl, J. R. Glucocorticoid programming of pituitary–adrenal function: mechanisms and physiological consequences. Semin. Neonatol. 6, 319–329 (2001).

    Article  CAS  PubMed  Google Scholar 

  176. Nyirenda, M. J., Welberg, L. A. & Seckl, J. R. Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids — fetal effect or maternal influence? J. Endocrinol. 170, 653–660 (2001).

    Article  CAS  PubMed  Google Scholar 

  177. Heller, E. A. et al. Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nature Neurosci. 17, 1720–1727 (2014).

    Article  CAS  PubMed  Google Scholar 

  178. Brunner, A. M., Nanni, P. & Mansuy, I. M. Epigenetic marking of sperm by post-translational modification of histones and protamines. Epigenetics Chromatin 7, 2 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Bale, T. L. Lifetime stress experience: transgenerational epigenetics and germ cell programming. Dialogues Clin. Neurosci. 16, 297–305 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Kotaja, N. & Sassone-Corsi, P. The chromatid body: a germ-cell-specific RNA-processing centre. Nature Rev. Mol. Cell Biol. 8, 85–90 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the US National Institutes of Health MH099910, MH104184, MH091258, MH087597 and MH073030.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tracy L. Bale.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Glossary

Birth cohort studies

Longitudinal prospective studies in which pregnancies are followed through birth and into childhood to correlate the risk for given outcomes with specified experiences or exposures during gestation. These cohorts of individuals differ from other epidemiological studies in which the outcome measures are mainly retrospective.

Biomarkers

Specific biochemical, molecular, anatomical or physiological characteristics that are used to predict, measure or indicate the presence or progress of disease or the effects of treatment.

Executive function

A set of cognitive abilities that include inhibition (resisting habits, temptations or distractions), switching (adjusting to change) and working memory (mentally holding and using information).

Stress responsiveness

Behavioural or physiological measures in response to a stress provocation. In all mammals, the physiological hypothalamic–pituitary–adrenal stress axis is the standard measure of stress experience. Behavioural changes in response to stress or threat can also be examined as an indication of stress state.

Imprinted gene

A gene expressed from only one allele in a manner that depends on the parent of origin and that is regulated by DNA methylation.

Hypothalamic–pituitary–adrenal stress axis

(HPA stress axis). The neuroendocrine core of the stress system. Its activation results in the release of corticotropin-releasing factor from the hypothalamus, adrenocorticotropic hormone from the pituitary and cortisol (corticosterone in rats and mice) from the adrenal glands.

Endophenotypes

Quantifiable phenotypes with an assumed intermediate role in the pathway from genes to complex phenotypes. It is thought that the action of an endophenotype is easier to understand biologically and genetically than the action of the complex phenotype of primary interest. They enable the examination of specific aspects of complex human diseases in animal models.

Barnes maze

A spatial learning and memory task in which the animal is placed on a large, open table that has holes around the circumference. Only one of the holes has an escape tunnel, and the animal must learn to use distal cues to identify this hole and escape in the shortest possible time. Learning in this task involves the hippocampus.

Microglia

Glia of mesodermal origin and the resident macrophages of the CNS.

Social defeat

A behavioural model in which rodents (predominantly males) are repeatedly exposed to a more aggressive conspecific. The outcomes of these confrontations are repeated losses for the subject. This exposure is then followed by a period of housing the defeated animal in close proximity to the aggressor to establish the conditioning.

Pre-pulse inhibition

A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a pre-pulse) before being presented with the startling stimulus. Deficits in pre-pulse inhibition have been observed in patients with schizophrenia.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bale, T. Epigenetic and transgenerational reprogramming of brain development. Nat Rev Neurosci 16, 332–344 (2015). https://doi.org/10.1038/nrn3818

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3818

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing