Abstract
Neurological illnesses, including cognitive impairment, memory decline and dementia, affect over 50 million people worldwide, imposing a substantial burden on individuals and society. These disorders arise from a combination of genetic, environmental and experiential factors, with the latter two factors having the greatest impact during sensitive periods in development. In this Review, we focus on the contribution of adverse early-life experiences to aberrant brain maturation, which might underlie vulnerability to cognitive brain disorders. Specifically, we draw on recent robust discoveries from diverse disciplines, encompassing human studies and experimental models. These discoveries suggest that early-life adversity, especially in the perinatal period, influences the maturation of brain circuits involved in cognition. Importantly, new findings suggest that fragmented and unpredictable environmental and parental signals comprise a novel potent type of adversity, which contributes to subsequent vulnerabilities to cognitive illnesses via mechanisms involving disordered maturation of brain ‘wiring’.
Key points
-
A strong association exists between neurocognitive disorders and early-life adversity, and experimental animal models support a causal relationship, in addition to the critical effects of genetics and gene–environment interactions.
-
The emotional aspects of adversity, including unpredictability of environmental and parental signals, most profoundly influence cognitive outcomes.
-
Mechanistically, early-life adversity might disrupt the normal maturation of the brain circuits that underlie cognitive functions by modulating synaptic maturation and pruning.
-
Novel cross-species imaging and epigenomic technologies hold promise for identifying mechanisms, biomarkers and mechanism-based preventive approaches and interventions.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Prince, M. et al. World Alzheimer Report 2015. The global impact of dementia: an analysis of prevalence, incidence, cost and trends. Alzheimer’s Disease International https://www.alz.co.uk/research/world-report-2015 (2015).
Prince, M., Guerchet, M. & Prina, M. Policy Brief: the global impact of dementia 2013–2050. Alzheimer’s Disease International https://www.alz.co.uk/research/G8-policy-brief (2013).
Stern, Y. et al. Whitepaper: defining and investigating cognitive reserve, brain reserve, and brain maintenance. Alzheimers Dement. https://doi.org/10.1016/j.jalz.2018.07.219 (2018).
Revelas, M. et al. Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity. Mech. Ageing Dev. 175, 24–34 (2018).
Freudenberg-Hua, Y., Li, W. & Davies, P. The role of genetics in advancing precision medicine for Alzheimer’s disease — a narrative review. Front. Med. 5, 108 (2018).
Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 301, 386–389 (2003).
Klengel, T. & Binder, E. B. Epigenetics of stress-related psychiatric disorders and gene×environment interactions. Neuron 86, 1343–1357 (2015).
Brown, A. S., Susser, E. S., Lin, S. P., Neugebauer, R. & Gorman, J. M. Increased risk of affective disorders in males after second trimester prenatal exposure to the Dutch hunger winter of 1944–45. Br. J. Psychiatry 166, 601–606 (1995).
Eriksson, M., Räikkönen, K. & Eriksson, J. G. Early life stress and later health outcomes–findings from the Helsinki Birth Cohort Study. Am. J. Hum. Biol. 26, 111–116 (2014).
Lupien, S. J., McEwen, B. S., Gunnar, M. R. & Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10, 434–445 (2009).
Chen, Y. & Baram, T. Z. Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology 41, 197–206 (2016).
Novick, A. M. et al. The effects of early life stress on reward processing. J. Psychiatr. Res. 101, 80–103 (2018).
Raymond, C., Marin, M.-F., Majeur, D. & Lupien, S. Early child adversity and psychopathology in adulthood: HPA axis and cognitive dysregulations as potential mechanisms. Prog. Neuropsychopharmacol. Biol. Psychiatry 85, 152–160 (2018).
Millan, M. J. et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat. Rev. Drug Discov. 11, 141–168 (2012).
Osler, M., Avlund, K. & Mortensen, E. L. Socio-economic position early in life, cognitive development and cognitive change from young adulthood to middle age. Eur. J. Public Health 23, 974–980 (2013).
Sheridan, M. A. & McLaughlin, K. A. Dimensions of early experience and neural development: deprivation and threat. Trends Cogn. Sci. 18, 580–585 (2014).
Kaplan, G. A. et al. Childhood socioeconomic position and cognitive function in adulthood. Int. J. Epidemiol. 30, 256–263 (2001).
Melrose, R. J. et al. Early life development in a multiethnic sample and the relation to late life cognition. J. Gerontol. B Psychol. Sci. Soc. Sci. 70, 519–531 (2015).
Marden, J. R., Tchetgen Tchetgen, E. J., Kawachi, I. & Glymour, M. M. Contribution of socioeconomic status at 3 life-course periods to late-life memory function and decline: early and late predictors of dementia risk. Am. J. Epidemiol. 186, 805–814 (2017).
Elbejjani, M. et al. Life-course socioeconomic position and hippocampal atrophy in a prospective cohort of older adults. Psychosom. Med. 79, 14–23 (2017).
Staff, R. T., Hogan, M. J. & Whalley, L. J. The influence of childhood intelligence, social class, education and social mobility on memory and memory decline in late life. Age Ageing 47, 847–852 (2018).
Mosing, M. A., Lundholm, C., Cnattingius, S., Gatz, M. & Pedersen, N. L. Associations between birth characteristics and age-related cognitive impairment and dementia: a registry-based cohort study. PLOS Med. 15, e1002609 (2018).
Fors, S., Lennartsson, C. & Lundberg, O. Childhood living conditions, socioeconomic position in adulthood, and cognition in later life: exploring the associations. J. Gerontol. B Psychol. Sci. Soc. Sci. 64B, 750–757 (2009).
Everson-Rose, S. A., Mendes De Leon, C. F., Bienias, J. L., Wilson, R. S. & Evans, D. A. Early life conditions and cognitive functioning in later life. Am. J. Epidemiol. 158, 1083–1089 (2003).
Pollak, S. D. et al. Neurodevelopmental effects of early deprivation in postinstitutionalized children. Child Dev. 81, 224–236 (2010).
Cohen, N. J., Lojkasek, M., Zadeh, Z. Y., Pugliese, M. & Kiefer, H. Children adopted from China: a prospective study of their growth and development. J. Child Psychol. Psychiatry 49, 458–468 (2008).
Johnson, D. E. et al. Growth and associations between auxology, caregiving environment, and cognition in socially deprived Romanian children randomized to foster vs ongoing institutional care. Arch. Pediatr. Adolesc. Med. 164, 507–516 (2010).
Loman, M. M., Wiik, K. L., Frenn, K. A., Pollak, S. D. & Gunnar, M. R. Postinstitutionalized children’s development: growth, cognitive, and language outcomes. J. Dev. Behav. Pediatr. 30, 426–434 (2009).
Nelson, C. A. et al. Cognitive recovery in socially deprived young children: the Bucharest Early Intervention Project. Science 318, 1937–1940 (2007).
van den Dries, L., Juffer, F., van Ijzendoorn, M. H. & Bakermans-Kranenburg, M. J. Infantsʼ physical and cognitive development after international adoption from foster care or institutions in China. J. Dev. Behav. Pediatr. 31, 144–150 (2010).
Pechtel, P. & Pizzagalli, D. A. Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology 214, 55–70 (2011).
Loman, M. M. et al. The effect of early deprivation on executive attention in middle childhood. J. Child Psychol. Psychiatry 54, 37–45 (2013).
McDermott, J. M., Westerlund, A., Zeanah, C. H., Nelson, C. A. & Fox, N. A. Early adversity and neural correlates of executive function: implications for academic adjustment. Dev. Cogn. Neurosci. 2, S59–S66 (2012).
Wiik, K. L. et al. Behavioral and emotional symptoms of post-institutionalized children in middle childhood. J. Child Psychol. Psychiatry 52, 56–63 (2011).
Lawler, J. & Gunnar, M. R. in Handbook of Early Child Education (ed. Pianta, R. C.) 457–479 (Guilford Press, 2012).
Huot, R. L., Plotsky, P. M., Lenox, R. H. & McNamara, R. K. Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats. Brain Res. 950, 52–63 (2002).
Molet, J. et al. Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome. Transl Psychiatry 6, e702 (2016).
Kohl, C. et al. Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice. Psychoneuroendocrinology 55, 128–143 (2015).
Sánchez, M. M., Hearn, E. F., Do, D., Rilling, J. K. & Herndon, J. G. Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys. Brain Res. 812, 38–49 (1998).
Pryce, C. R., Dettling, A., Spengler, M., Spaete, C. & Feldon, J. Evidence for altered monoamine activity and emotional and cognitive disturbance in marmoset monkeys exposed to early life stress. Ann. NY Acad. Sci. 1032, 245–249 (2004).
Bath, K. G. et al. Early life stress leads to developmental and sex selective effects on performance in a novel object placement task. Neurobiol. Stress 7, 57–67 (2017).
Roozendaal, B., Brunson, K. L., Holloway, B. L., McGaugh, J. L. & Baram, T. Z. Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc. Natl Acad. Sci. USA 99, 13908–13913 (2002).
Kosten, T. A. et al. Memory impairments and hippocampal modifications in adult rats with neonatal isolation stress experience. Neurobiol. Learn. Mem. 88, 167–176 (2007).
Guijarro, J. Z. et al. Effects of brief and long maternal separations on the HPA axis activity and the performance of rats on context and tone fear conditioning. Behav. Brain Res. 184, 101–108 (2007).
Raineki, C. et al. Functional emergence of the hippocampus in context fear learning in infant rats. Hippocampus 20, 1037–1046 (2010).
Hulshof, H. J. et al. Maternal separation decreases adult hippocampal cell proliferation and impairs cognitive performance but has little effect on stress sensitivity and anxiety in adult Wistar rats. Behav. Brain Res. 216, 552–560 (2011).
Lucassen, P. J. et al. Perinatal programming of adult hippocampal structure and function; emerging roles of stress, nutrition and epigenetics. Trends Neurosci. 36, 621–631 (2013).
Naninck, E. F. et al. Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice. Hippocampus 25, 309–328 (2015).
Brunson, K. L. et al. Mechanisms of late-onset cognitive decline after early-life stress. J. Neurosci. 25, 9328–9338 (2005).
Maras, P. M. & Baram, T. Z. Sculpting the hippocampus from within: stress, spines, and CRH. Trends Neurosci. 35, 315–324 (2012).
Franke, K., Gaser, C., Roseboom, T. J., Schwab, M. & de Rooij, S. R. Premature brain aging in humans exposed to maternal nutrient restriction during early gestation. Neuroimage 173, 460–471 (2018).
de Groot, R. H. et al. Prenatal famine exposure and cognition at age 59 years. Int. J. Epidemiol. 40, 327–337 (2011).
He, P. et al. Prenatal malnutrition and adult cognitive impairment: a natural experiment from the 1959–1961 Chinese famine. Br. J. Nutr. 120, 198–203 (2018).
Crookston, B. T., Forste, R., McClellan, C., Georgiadis, A. & Heaton, T. B. Factors associated with cognitive achievement in late childhood and adolescence: the young lives cohort study of children in Ethiopia, India, Peru, and Vietnam. BMC Pediatr. 14, 253 (2014).
Tottenham, N. et al. Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation. Dev. Sci. 13, 46–61 (2010).
Nelson, C. A., Bos, K., Gunnar, M. R. & Sonuga-Barke, E. J. S. V. The neurobiological toll of early human deprivation. Monogr. Soc. Res. Child Dev. 76, 127–146 (2011).
Callaghan, B. L. & Tottenham, N. The neuro-environmental loop of plasticity: a cross-species analysis of parental effects on emotion circuitry development following typical and adverse caregiving. Neuropsychopharmacology 41, 163–176 (2016).
Duncan, G. J., Yeung, W. J., Brooks-Gunn, J. & Smith, J. R. How much does childhood poverty affect the life chances of children? Am. Sociol. Rev. 63, 406–423 (1998).
Hackman, D. A. & Farah, M. J. Socioeconomic status and the developing brain. Trends Cogn. Sci. 13, 65–73 (2009).
Volkow, N. D. et al. The conception of the ABCD study: from substance use to a broad NIH collaboration. Dev. Cogn. Neurosci. 32, 4–7 (2018).
Karlsson, L. et al. Cohort profile: the Finnbrain Birth Cohort Study (FinnBrain). Int. J. Epidemiol. 47, 15–16j (2018).
Hermus, M. A. A. et al. Differences in optimality index between planned place of birth in a birth centre and alternative planned places of birth, a nationwide prospective cohort study in The Netherlands: results of the Dutch Birth Centre Study. BMJ Open 7, e016958 (2017).
Glynn, L. M. et al. Prenatal maternal mood patterns predict child temperament and adolescent mental health. J. Affect. Disord. 228, 83–90 (2018).
Davis, E. P. et al. Exposure to unpredictable maternal sensory signals influences cognitive development across species. Proc. Natl Acad. Sci. USA 114, 10390–10395 (2017).
Zannas, A. S. et al. Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol. 16, 266 (2015).
Wilson, R. S. et al. Socioeconomic characteristics of the community in childhood and cognition in old age. Exp. Aging Res. 31, 393–407 (2005).
González, H. M., Tarraf, W., Bowen, M. E., Johnson-Jennings, M. D. & Fisher, G. G. What do parents have to do with my cognitive reserve? Life course perspectives on twelve-year cognitive decline. Neuroepidemiology 41, 101–109 (2013).
Sha, T., Yan, Y. & Cheng, W. Associations of childhood socioeconomic status with mid-life and late-life cognition in Chinese middle-aged and older population based on a 5-year period cohort study. Int. J. Geriatr. Psychiatry 33, 1335–1345 (2018).
Luo, Y. & Waite, L. J. The impact of childhood and adult SES on physical, mental, and cognitive well-being in later life. J. Gerontol. B Psychol. Sci. Soc. Sci. 60, S93–S101 (2005).
Turrell, G. et al. Socioeconomic position across the lifecourse and cognitive function in late middle age. J. Gerontol. B Psychol. Sci. Soc. Sci. 57, S43–S51 (2002).
Zhang, Z., Gu, D. & Hayward, M. D. Early life influences on cognitive impairment among oldest old chinese. J. Gerontol. B Psychol. Sci. Soc. Sci. 63, S25–S33 (2008).
Chen, Z.-Y. et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314, 140–143 (2006).
Chen, Z.-Y., Bath, K., McEwen, B., Hempstead, B. & Lee, F. Impact of genetic variant BDNF (Val66Met) on brain structure and function. Novartis Found. Symp. 2008, 180–188 (2008).
Labermaier, C. et al. A polymorphism in the Crhr1 gene determines stress vulnerability in male mice. Endocrinology 155, 2500–2510 (2014).
Dedic, N. et al. Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood. Mol. Psychiatry 23, 533–543 (2018).
Danese, A. et al. The origins of cognitive deficits in victimized children: implications for neuroscientists and clinicians. Am. J. Psychiatry 174, 349–361 (2017).
Whalley, L. J. et al. How the 1932 and 1947 mental surveys of Aberdeen schoolchildren provide a framework to explore the childhood origins of late onset disease and disability. Maturitas 69, 365–372 (2011).
Davis, E. P. et al. Across continents and demographics, unpredictable maternal signals impact children’s neurodevelopment. EBioMedicine https://doi.org/10.1016/j.ebiom.2019.07.025 (2019).
Vegetabile, B. G., Stout-Oswald, S. A., Poggi Davis, E., Baram, T. Z. & Stern, H. S. Estimating the entropy rate of finite Markov chains with application to behavior studies. J. Educ. Behav. Stat. 44, 282–308 (2019).
Conte Center. Measuring unpredictable maternal sensory signals. UCI https://contecenter.uci.edu/measuring-unpredictable-maternal-sensory-signals/ (2019).
Nelson, E. D. & Monteggia, L. M. Epigenetics in the mature mammalian brain: effects on behavior and synaptic transmission. Neurobiol. Learn. Mem. 96, 53–60 (2011).
van Ijzendoorn, M. H., Bard, K. A., Bakermans-Kranenburg, M. J. & Ivan, K. Enhancement of attachment and cognitive development of young nursery-reared chimpanzees in responsive versus standard care. Dev. Psychobiol. 51, 173–185 (2009).
van Bodegom, M., Homberg, J. R. & Henckens, M. J. A. G. Modulation of the hypothalamic–pituitary–adrenal axis by early life stress exposure. Front. Cell. Neurosci. 11, 87 (2017).
Molet, J., Maras, P. M., Avishai-Eliner, S. & Baram, T. Z. Naturalistic rodent models of chronic early-life stress. Dev. Psychobiol. 56, 1675–1688 (2014).
Walker, C.-D. D. et al. Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential. Stress 20, 421–448 (2017).
Raineki, C., Cortés, M. R., Belnoue, L. & Sullivan, R. M. Effects of early-life abuse differ across development: infant social behavior deficits are followed by adolescent depressive-like behaviors mediated by the amygdala. J. Neurosci. 32, 7758–7765 (2012).
Sevelinges, Y., Sullivan, R. M., Messaoudi, B. & Mouly, A.-M. Neonatal odor-shock conditioning alters the neural network involved in odor fear learning at adulthood. Learn. Mem. 15, 649–656 (2008).
Oomen, C. A. et al. Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J. Neurosci. 30, 6635–6645 (2010).
Schaaf, M. J. et al. Correlation between hippocampal BDNF mRNA expression and memory performance in senescent rats. Brain Res. 915, 227–233 (2001).
Loi, M. et al. Effects of early-life stress on cognitive function and hippocampal structure in female rodents. Neuroscience 342, 101–119 (2017).
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).
Molet, J. et al. MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early-life adversity. Hippocampus 26, 1618–1632 (2016).
Wearick-Silva, L. E. et al. Running during adolescence rescues a maternal separation-induced memory impairment in female mice: potential role of differential exon-specific BDNF expression. Dev. Psychobiol. 59, 268–274 (2017).
Arcego, D. M. et al. Early life adversities or high fat diet intake reduce cognitive function and alter BDNF signaling in adult rats: interplay of these factors changes these effects. Int. J. Dev. Neurosci. 50, 16–25 (2016).
de Lima, M. N. M. et al. Early life stress decreases hippocampal BDNF content and exacerbates recognition memory deficits induced by repeated D-amphetamine exposure. Behav. Brain Res. 224, 100–106 (2011).
Gatt, J. M. et al. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol. Psychiatry 14, 681–695 (2009).
Grassi-Oliveira, R., Stein, L. M., Lopes, R. P., Teixeira, A. L. & Bauer, M. E. Low plasma brain-derived neurotrophic factor and childhood physical neglect are associated with verbal memory impairment in major depression–a preliminary report. Biol. Psychiatry 64, 281–285 (2008).
Bath, K. G., Schilit, A. & Lee, F. S. Stress effects on BDNF expression: effects of age, sex, and form of stress. Neuroscience 239, 149–156 (2013).
Amso, D. & Scerif, G. The attentive brain: insights from developmental cognitive neuroscience. Nat. Rev. Neurosci. 16, 606–619 (2015).
Teicher, M. H., Samson, J. A., Anderson, C. M. & Ohashi, K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat. Rev. Neurosci. 17, 652–666 (2016).
Casey, B. J., Heller, A. S., Gee, D. G. & Cohen, A. O. Development of the emotional brain. Neurosci. Lett. 693, 29–34 (2019).
Chen, Y. et al. Converging, synergistic actions of multiple stress hormones mediate enduring memory impairments after acute simultaneous stresses. J. Neurosci. 36, 11295–11307 (2016).
Pattwell, S. S. et al. Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories. Nat. Commun. 7, 11475 (2016).
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
Gordon, J. Translational research: from research findings to transformative treatments. NIMH https://www.nimh.nih.gov/about/director/messages/2018/translational-research-from-research-findings-to-transformative-treatments.shtml (2018).
Krugers, H. J. et al. Early life adversity: lasting consequences for emotional learning. Neurobiol. Stress 6, 14–21 (2017).
Agidew, A. A. & Singh, K. N. Determinants of food insecurity in the rural farm households in South Wollo Zone of Ethiopia: the case of the Teleyayen sub-watershed. Agric. Food Econ. 6, 10 (2018).
Hodel, A. S. et al. Duration of early adversity and structural brain development in post-institutionalized adolescents. Neuroimage 105, 112–119 (2015).
Bale, T. L. et al. Early life programming and neurodevelopmental disorders. Biol. Psychiatry 68, 314–319 (2010).
Sandman, C. A. et al. Cortical thinning and neuropsychiatric outcomes in children exposed to prenatal adversity: a role for placental CRH? Am. J. Psychiatry 175, 471–479 (2018).
Sandman, C. A., Davis, E. P., Buss, C. & Glynn, L. M. Prenatal programming of human neurological function. Int. J. Pept. 2011, 837596 (2011).
Gee, D. G. et al. Maternal buffering of human amygdala-prefrontal circuitry during childhood but not during adolescence. Psychol. Sci. 25, 2067–2078 (2014).
Bowlby, J. Research into the origins of delinquent behaviour. Br. Med. J. 1, 570–573 (1950).
Hostinar, C. E. & Gunnar, M. R. The developmental effects of early life stress. Curr. Dir. Psychol. Sci. 22, 400–406 (2013).
Gunnar, M. R., Morison, S. J., Chisholm, K. & Schuder, M. Salivary cortisol levels in children adopted from Romanian orphanages. Dev. Psychopathol. 13, 611–628 (2001).
Gunnar, M. R. Reversing the effects of early deprivation after infancy: giving children families may not be enough. Front. Neurosci. 4, 170 (2010).
Masur, E. F., Flynn, V. & Eichorst, D. L. Maternal responsive and directive behaviours and utterances as predictors of children’s lexical development. J. Child Lang. 32, 63–91 (2005).
NICHD Early Care Research Network. Chronicity of maternal depressive symptoms, maternal sensitivity, and child functioning at 36 months. Dev. Psychol. 35, 1297–1310 (1999).
NICHD Early Care Research Network. Infant–mother attachment classification: risk and protection in relation to changing maternal caregiving quality. Dev. Psychol. 42, 38–58 (2006).
Hane, A. A., Henderson, H. A., Reeb-Sutherland, B. C. & Fox, N. A. Ordinary variations in human maternal caregiving in infancy and biobehavioral development in early childhood: a follow-up study. Dev. Psychobiol. 52, 558–567 (2010).
Belsky, J. & Fearon, R. M. P. Early attachment security, subsequent maternal sensitivity, and later child development: does continuity in development depend upon continuity of caregiving? Attach. Hum. Dev. 4, 361–387 (2002).
Weaver, I. C. G. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004).
Champagne, F. A., Francis, D. D., Mar, A. & Meaney, M. J. Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol. Behav. 79, 359–371 (2003).
Coates, D. L. & Lewis, M. Early mother–infant interaction and infant cognitive status as predictors of school performance and cognitive behavior in six-year-olds. Child Dev. 55, 1219 (1984).
Parker, K. J., Buckmaster, C. L., Justus, K. R., Schatzberg, A. F. & Lyons, D. M. Mild early life stress enhances prefrontal-dependent response inhibition in monkeys. Biol. Psychiatry 57, 848–855 (2005).
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).
Sánchez, 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).
Spencer-Booth, Y. & Hinde, R. A. The effects of 13 days maternal separation on infant rhesus monkeys compared with those of shorter and repeated separations. Anim. Behav. 19, 595–605 (1971).
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).
Meaney, M. J., Aitken, D. H., van Berkel, C., Bhatnagar, S. & Sapolsky, R. M. Effect of neonatal handling on age-related impairments associated with the hippocampus. Science 239, 766–768 (1988).
Gilles, E. E., Schultz, L. & Baram, T. Z. Abnormal corticosterone regulation in an immature rat model of continuous chronic stress. Pediatr. Neurol. 15, 114–119 (1996).
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).
Wang, X.-D. et al. Forebrain CRF1 modulates early-life stress-programmed cognitive deficits. J. Neurosci. 31, 13625–13634 (2011).
Herman, J. P. & Tasker, J. G. Paraventricular hypothalamic mechanisms of chronic stress adaptation. Front. Endocrinol. 7, 137 (2016).
Redish, A. D. & Gordon, J. A. (eds) Computational Psychiatry: New Perspectives on Mental Illness (MIT Press, 2016).
Bassett, D. S. & Sporns, O. Network neuroscience. Nat. Neurosci. 20, 353–364 (2017).
Espinosa, J. S. & Stryker, M. P. Development and plasticity of the primary visual cortex. Neuron 75, 230–249 (2012).
Khazipov, R. et al. Early motor activity drives spindle bursts in the developing somatosensory cortex. Nature 432, 758–761 (2004).
Hensch, T. K. Critical period mechanisms in developing visual cortex. Curr. Top. Dev. Biol. 69, 215–237 (2005).
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).
Singh-Taylor, A. et al. NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. Mol. Psychiatry 23, 648–657 (2018).
Gunn, B. G. et al. Dysfunctional astrocytic and synaptic regulation of hypothalamic glutamatergic transmission in a mouse model of early-life adversity: relevance to neurosteroids and programming of the stress response. J. Neurosci. 33, 19534–19554 (2013).
Eichenbaum, H. The role of the hippocampus in navigation is memory. J. Neurophysiol. 117, 1785–1796 (2017).
Wixted, J. T. et al. Coding of episodic memory in the human hippocampus. Proc. Natl Acad. Sci. USA 115, 1093–1098 (2018).
Squire, L. R., Genzel, L., Wixted, J. T. & Morris, R. G. Memory consolidation. Cold Spring Harb. Perspect. Biol. 7, a021766 (2015).
Zhang, J. et al. Mapping postnatal mouse brain development with diffusion tensor microimaging. Neuroimage 26, 1042–1051 (2005).
Nassar, R. et al. Gestational age is dimensionally associated with structural brain network abnormalities across development. Cereb. Cortex 29, 2102–2114 (2019).
Hodge, R. D. et al. Tbr2 expression in Cajal–Retzius cells and intermediate neuronal progenitors is required for morphogenesis of the dentate gyrus. J. Neurosci. 33, 4165–4180 (2013).
Nakahira, E. & Yuasa, S. Neuronal generation, migration, and differentiation in the mouse hippocampal primoridium as revealed by enhanced green fluorescent protein gene transfer by means of in utero electroporation. J. Comp. Neurol. 483, 329–340 (2005).
Kehoe, P. & Bronzino, J. D. Neonatal stress alters LTP in freely moving male and female adult rats. Hippocampus 9, 651–658 (1999).
Jackowski, A. et al. Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates. Psychiatry Res. 192, 37–44 (2011).
Lyons, D. M. et al. Early life stress and inherited variation in monkey hippocampal volumes. Arch. Gen. Psychiatry 58, 1145–1151 (2001).
Paus, T. in Handbook of Adolescent Psychology (eds. Lerner, M. & Steinberg, L.). 95–115 (John Wiley & Sons, 2009).
Braitenberg, V. & Schüz, A. in Cortex: Statistics and Geometry of Neuronal Connectivity 93–98 (Springer, 1998).
Shansky, R. M. & Woolley, C. S. Considering sex as a biological variable will be valuable for neuroscience research. J. Neurosci. 36, 11817–11822 (2016).
Eliot, L. & Richardson, S. S. Sex in context: limitations of animal studies for addressing human sex/gender neurobehavioral health disparities. J. Neurosci. 36, 11823–11830 (2016).
Valentino, R. J. & Bangasser, D. A. Sex-biased cellular signaling: molecular basis for sex differences in neuropsychiatric diseases. Dialogues Clin. Neurosci. 18, 385–393 (2016).
Regev, L. & Baram, T. Z. Corticotropin releasing factor in neuroplasticity. Front. Neuroendocrinol. 35, 171–179 (2014).
Avena-Koenigsberger, A., Misic, B. & Sporns, O. Communication dynamics in complex brain networks. Nat. Rev. Neurosci. 19, 17–33 (2017).
Wisse, L. E. M. et al. A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals? Hippocampus 27, 3–11 (2017).
Driessen, M. et al. Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization. Arch. Gen. Psychiatry 57, 1115 (2000).
Bremner, J. D. et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse — a preliminary report. Biol. Psychiatry 41, 23–32 (1997).
Stein, M. B., Koverola, C., Hanna, C., Torchia, M. G. & McClarty, B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol. Med. 27, 951–959 (1997).
Crossley, N. A. et al. Imaging social and environmental factors as modulators of brain dysfunction: time to focus on developing non-Western societies. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 4, 8–15 (2019).
Lenze, S. N., Xiong, C. & Sheline, Y. I. Childhood adversity predicts earlier onset of major depression but not reduced hippocampal volume. Psychiatry Res. Neuroimaging 162, 39–49 (2008).
Riem, M. M. E., Alink, L. R. A., Out, D., Van Ijzendoorn, M. H. & Bakermans-Kranenburg, M. J. Beating the brain about abuse: empirical and meta-analytic studies of the association between maltreatment and hippocampal volume across childhood and adolescence. Dev. Psychopathol. 27, 507–520 (2015).
Kim, D.-J. et al. Childhood poverty and the organization of structural brain connectome. Neuroimage 184, 409–416 (2019).
Buss, C., Davis, E. P., Muftuler, L. T., Head, K. & Sandman, C. A. High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6–9-year-old children. Psychoneuroendocrinology 35, 141–153 (2010).
Hatfield, T. et al. 71: Magnetic resonance imaging (MRI) shows long term changes in brain structure in preterm infants exposed to chorioamnionitis. Am. J. Obstet. Gynecol. 204, S41 (2011).
Sandman, C. A., Buss, C., Head, K. & Davis, E. P. Fetal exposure to maternal depressive symptoms is associated with cortical thickness in late childhood. Biol. Psychiatry 77, 324–334 (2015).
Curran, M. M., Sandman, C. A., Poggi Davis, E., Glynn, L. M. & Baram, T. Z. Abnormal dendritic maturation of developing cortical neurons exposed to corticotropin releasing hormone (CRH): insights into effects of prenatal adversity? PLOS ONE 12, e0180311 (2017).
Hibar, D. P. et al. Novel genetic loci associated with hippocampal volume. Nat. Commun. 8, 13624 (2017).
Feldman, H. M., Yeatman, J. D., Lee, E. S., Barde, L. H. F. & Gaman-Bean, S. Diffusion tensor imaging: a review for pediatric researchers and clinicians. J. Dev. Behav. Pediatr. 31, 346–356 (2010).
Mori, S. & Zhang, J. Principles of diffusion tensor imaging and its applications to basic neuroscience research. Neuron 51, 527–539 (2006).
Sorg, C. et al. Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proc. Natl Acad. Sci. USA 104, 18760–18765 (2007).
Greicius, M. D., Srivastava, G., Reiss, A. L. & Menon, V. Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc. Natl Acad. Sci. USA 101, 4637–4642 (2004).
Tahmasian, M. et al. Based on the network degeneration hypothesis: separating individual patients with different neurodegenerative syndromes in a preliminary hybrid PET/MR study. J. Nucl. Med. 57, 410–415 (2016).
Seeley, W. W., Crawford, R. K., Zhou, J., Miller, B. L. & Greicius, M. D. Neurodegenerative diseases target large-scale human brain networks. Neuron 62, 42–52 (2009).
Pievani, M., de Haan, W., Wu, T., Seeley, W. W. & Frisoni, G. B. Functional network disruption in the degenerative dementias. Lancet Neurol. 10, 829–843 (2011).
Landfield, P. W., McGaugh, J. L. & Lynch, G. Impaired synaptic potentiation processes in the hippocampus of aged, memory-deficient rats. Brain Res. 150, 85–101 (1978).
Riley, J. D. et al. Network specialization during adolescence: hippocampal effective connectivity in boys and girls. Neuroimage 175, 402–412 (2018).
Yassa, M. A., Muftuler, L. T. & Stark, C. E. L. Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo. Proc. Natl Acad. Sci. USA 107, 12687–12691 (2010).
Leal, S. L. & Yassa, M. A. Neurocognitive aging and the hippocampus across species. Trends Neurosci. 38, 800–812 (2015).
Kim, D.-J. et al. Prenatal maternal cortisol has sex-specific associations with child brain network properties. Cereb. Cortex 27, 5230–5241 (2017).
Luo, L., Callaway, E. M. & Svoboda, K. Genetic dissection of neural circuits: a decade of progress. Neuron 98, 865 (2018).
Roth, B. L. DREADDs for neuroscientists. Neuron 89, 683–694 (2016).
Kim, C. K., Adhikari, A. & Deisseroth, K. Integration of optogenetics with complementary methodologies in systems neuroscience. Nat. Rev. Neurosci. 18, 222–235 (2017).
Lomvardas, S. & Maniatis, T. Histone and DNA modifications as regulators of neuronal development and function. Cold Spring Harb. Perspect. Biol. 8, a024208 (2016).
Zocchi, L. & Sassone-Corsi, P. Joining the dots: from chromatin remodeling to neuronal plasticity. Curr. Opin. Neurobiol. 20, 432–440 (2010).
Baker-Andresen, D., Ratnu, V. S. & Bredy, T. W. Dynamic DNA methylation: a prime candidate for genomic metaplasticity and behavioral adaptation. Trends Neurosci. 36, 3–13 (2013).
Sweatt, J. The epigenetic basis of individuality. Curr. Opin. Behav. Sci. 25, 51–56 (2019).
Hwang, J.-Y., Aromolaran, K. A. & Zukin, R. S. The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat. Rev. Neurosci. 18, 347–361 (2017).
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).
Bale, T. L. Epigenetic and transgenerational reprogramming of brain development. Nat. Rev. Neurosci. 16, 332–344 (2015).
Lipovich, L. et al. Activity-dependent human brain coding/noncoding gene regulatory networks. Genetics 192, 1133–1148 (2012).
Szyf, M. Epigenetics, a key for unlocking complex CNS disorders? Therapeutic implications. Eur. Neuropsychopharmacol. 25, 682–702 (2015).
Turecki, G. The molecular bases of the suicidal brain. Nat. Rev. Neurosci. 15, 802–816 (2014).
Provencal, N. et al. The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. J. Neurosci. 32, 15626–15642 (2012).
Provençal, N. & Binder, E. B. The effects of early life stress on the epigenome: from the womb to adulthood and even before. Exp. Neurol. 268, 10–20 (2015).
Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621–628 (2008).
Maze, I. et al. Analytical tools and current challenges in the modern era of neuroepigenomics. Nat. Neurosci. 17, 1476–1490 (2014).
Peixoto, L. et al. How data analysis affects power, reproducibility and biological insight of RNA-seq studies in complex datasets. Nucleic Acids Res. 43, 7664–7674 (2015).
Verbitsky, M. et al. Altered hippocampal transcript profile accompanies an age-related spatial memory deficit in mice. Learn. Mem. 11, 253–260 (2004).
Gray, J. D. et al. Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice. Mol. Psychiatry 23, 904–913 (2018).
Ahmadiyeh, N., Slone-Wilcoxon, J. L., Takahashi, J. S. & Redei, E. E. Maternal behavior modulates X-linked inheritance of behavioral coping in the defensive burying test. Biol. Psychiatry 55, 1069–1074 (2004).
Peña, C. J. et al. Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science 356, 1185–1188 (2017).
Patterson, K. P. et al. Enduring memory impairments provoked by developmental febrile seizures are mediated by functional and structural effects of neuronal restrictive silencing factor. J. Neurosci. 37, 3799–3812 (2017).
Schulmann, A. et al. Blocking NRSF function rescues spatial memory impaired by early-life adversity and reveals unexpected underlying transcriptional programs. SSRN Electron. J. https://doi.org/10.2139/ssrn.3284454 (2018).
Gray, J. D., Kogan, J. F., Marrocco, J. & McEwen, B. S. Genomic and epigenomic mechanisms of glucocorticoids in the brain. Nat. Rev. Endocrinol. 13, 661–673 (2017).
Wang, X. D. et al. Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nat. Neurosci. 16, 706–713 (2013).
Roth, T. L., Lubin, F. D., Funk, A. J. & Sweatt, J. D. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol. Psychiatry 65, 760–769 (2009).
Klengel, T. et al. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat. Neurosci. 16, 33–41 (2013).
Meaney, M. J. et al. Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev. Neurosci. 18, 49–72 (1996).
Uchida, S. et al. Early life stress enhances behavioral vulnerability to stress through the activation of REST4-mediated gene transcription in the medial prefrontal cortex of rodents. J. Neurosci. 30, 15007–15018 (2010).
Bhansali, P., Dunning, J., Singer, S. E., David, L. & Schmauss, C. Early life stress alters adult serotonin 2c receptor pre-mRNA editing and expression of the subunit of the heterotrimeric G-protein Gq. J. Neurosci. 27, 1467–1473 (2007).
Xu, Z. & Taylor, J. A. Genome-wide age-related DNA methylation changes in blood and other tissues relate to histone modification, expression and cancer. Carcinogenesis 35, 356–364 (2014).
Alisch, R. S. et al. Age-associated DNA methylation in pediatric populations. Genome Res. 22, 623–632 (2012).
Florath, I., Butterbach, K., Müller, H., Bewerunge-Hudler, M. & Brenner, H. Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. Hum. Mol. Genet. 23, 1186–1201 (2014).
Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).
Smith, A. K. et al. DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am. J. Med. Genet. B Neuropsychiatr. Genet. 168, 36–44 (2015).
Tylee, D. S., Kawaguchi, D. M. & Glatt, S. J. On the outside, looking in: a review and evaluation of the comparability of blood and brain “-omes”. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162, 595–603 (2013).
Degerman, S. et al. Maintained memory in aging is associated with young epigenetic age. Neurobiol. Aging 55, 167–171 (2017).
Marioni, R. E. et al. The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. Int. J. Epidemiol. 44, 1388–1396 (2015).
Levine, M. E. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10, 573–591 (2018).
Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
Nemoda, Z. et al. Maternal depression is associated with DNA methylation changes in cord blood T lymphocytes and adult hippocampi. Transl. Psychiatry 5, e545 (2015).
Peter, C. J. et al. DNA methylation signatures of early childhood malnutrition associated with impairments in attention and cognition. Biol. Psychiatry 80, 765–774 (2016).
Eipel, M. et al. Epigenetic age predictions based on buccal swabs are more precise in combination with cell type-specific DNA methylation signatures. Aging 8, 1034–1048 (2016).
Schwaiger, M. et al. Altered stress-induced regulation of genes in monocytes in adults with a history of childhood adversity. Neuropsychopharmacology 41, 2530–2540 (2016).
Urdinguio, R. G. et al. Longitudinal study of DNA methylation during the first 5 years of life. J. Transl. Med. 14, 160 (2016).
Jiang, S. et al. Intra-individual methylomics detects the impact of early-life adversity. Life Sci. Alliance 2, e201800204 (2019).
Child and Adolescent Health Measurement Initiative. 2011–2012 national survey of children’s health (CAHMI, 2013).
Hoynes, H., Schanzenbach, D. W. & Almond, D. Long-run impacts of childhood access to the safety net. Am. Econ. Rev. 106, 903–934 (2016).
Shaefer, H. L. et al. A universal child allowance: a plan to reduce poverty and income instability among children in the United States. RSF 4, 22–42 (2018).
Josselyn, S. A. & Frankland, P. W. Infantile amnesia: a neurogenic hypothesis. Learn. Mem. 19, 423–433 (2012).
Collie, R. & Hayne, H. Deferred imitation by 6- and 9-month-old infants: more evidence for declarative memory. Dev. Psychobiol. 35, 83–90 (1999).
Hayne, H. & Herbert, J. Verbal cues facilitate memory retrieval during infancy. J. Exp. Child Psychol. 89, 127–139 (2004).
Evans, G. W. & Fuller-Rowell, T. E. Childhood poverty, chronic stress, and young adult working memory: the protective role of self-regulatory capacity. Dev. Sci. 16, 688–696 (2013).
Kavanaugh, B. C., Dupont-Frechette, J. A., Jerskey, B. A. & Holler, K. A. Neurocognitive deficits in children and adolescents following maltreatment: neurodevelopmental consequences and neuropsychological implications of traumatic stress. Appl. Neuropsychol. Child 6, 64–78 (2016).
Tan, H. M., Wills, T. J. & Cacucci, F. The development of spatial and memory circuits in the rat. Wiley Interdiscip. Rev. Cogn. Sci. 8, e1424 (2016).
Alberini, C. M. & Travaglia, A. Infantile amnesia: a critical period of learning to learn and remember. J. Neurosci. 37, 5783–5795 (2017).
Avishai-Eliner, S. Stressed-out, or in (utero)? Trends Neurosci. 25, 518–524 (2002).
Short, A. K., Maras, P. M., Pham, A. L., Ivy, A. S. & Baram, T. Z. Short-term block of CRH receptor in adults mitigates age-related memory impairments provoked by early-life adversity. bioRxiv https://doi.org/10.1101/714451 (2019).
Werker, J. F. & Hensch, T. K. Critical periods in speech perception: new directions. Annu. Rev. Psychol. 66, 173–196 (2015).
Sun, H. et al. Early seizures prematurely unsilence auditory synapses to disrupt thalamocortical critical period plasticity. Cell Rep. 23, 2533–2540 (2018).
Takesian, A. E., Bogart, L. J., Lichtman, J. W. & Hensch, T. K. Inhibitory circuit gating of auditory critical-period plasticity. Nat. Neurosci. 21, 218–227 (2018).
Trachtenberg, J. T. & Stryker, M. P. Rapid anatomical plasticity of horizontal connections in the developing visual cortex. J. Neurosci. 21, 3476–3482 (2001).
Amaral, D. G. & Dent, J. A. Development of the mossy fibers of the dentate gyrus: I. A light and electron microscopic study of the mossy fibers and their expansions. J. Comp. Neurol. 195, 51–86 (1981).
Henze, D., Urban, N. & Barrionuevo, G. The multifarious hippocampal mossy fiber pathway: a review. Neuroscience 98, 407–427 (2000).
Cotman, C. W., Berchtold, N. C. & Christie, L.-A. A. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464–472 (2007).
Nichol, K. E., Parachikova, A. I. & Cotman, C. W. Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse. Behav. Brain Res. 184, 124–132 (2007).
Nichol, K., Deeny, S. P., Seif, J., Camaclang, K. & Cotman, C. W. Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice. Alzheimers Dement. 5, 287–294 (2009).
Segal, S. K., Cotman, C. W. & Cahill, L. F. Exercise-induced noradrenergic activation enhances memory consolidation in both normal aging and patients with amnestic mild cognitive impairment. J. Alzheimers Dis. 32, 1011–1018 (2012).
Guitar, N. A., Connelly, D. M., Nagamatsu, L. S., Orange, J. B. & Muir-Hunter, S. W. The effects of physical exercise on executive function in community-dwelling older adults living with Alzheimer’s-type dementia: a systematic review. Ageing Res. Rev. 47, 159–167 (2018).
Roberts, C. E., Phillips, L. H., Cooper, C. L., Gray, S. & Allan, J. L. Effect of different types of physical activity on activities of daily living in older adults: systematic review and meta-analysis. J. Aging Phys. Act. 25, 653–670 (2017).
Snigdha, S., de Rivera, C., Milgram, N. W. & Cotman, C. W. Exercise enhances memory consolidation in the aging brain. Front. Aging Neurosci. 6, 3 (2014).
Baram, T. Z. & Bolton, J. L. Parental smartphone use and children’s mental outcomes: a neuroscience perspective. Neuropsychopharmacology 44, 239–240 (2019).
Galimberti, I., Bednarek, E., Donato, F. & Caroni, P. EphA4 signaling in juveniles establishes topographic specificity of structural plasticity in the hippocampus. Neuron 65, 627–642 (2010).
Donato, F., Jacobsen, R. I., Moser, M.-B. & Moser, E. I. Stellate cells drive maturation of the entorhinal-hippocampal circuit. Science 355, eaai8178 (2017).
Hong, S., Dissing-Olesen, L. & Stevens, B. New insights on the role of microglia in synaptic pruning in health and disease. Curr. Opin. Neurobiol. 36, 128–134 (2016).
Baram, T. Z., Donato, F. & Holmes, G. L. Construction and disruption of spatial memory networks during development. Learn. Mem. 26, 206–218 (2019).
Glynn, L. M. & Baram, T. Z. The influence of unpredictable, fragmented parental signals on the developing brain. Front. Neuroendocrinol. 53, 100736 (2019).
Stanton, M. E. & Levine, S. Inhibition of infant glucocorticoid stress response: specific role of maternal cues. Dev. Psychobiol. 23, 411–426 (1990).
Suchecki, D., Nelson, D. Y., Oers, H. Van & Levine, S. Activation and inhibition of the hypothalamic–pituitary–adrenal axis of the neonatal rat: effects of maternal deprivation. Psychoneuroendocrinology 20, 169–182 (1995).
Schmidt, M. V. et al. The postnatal development of the hypothalamic-pituitary-adrenal axis in the mouse. Int. J. Dev. Neurosci. 21, 125–132 (2003).
Yi, S. J. & Baram, T. Z. Corticotropin-releasing hormone mediates the response to cold stress in the neonatal rat without compensatory enhancement of the peptide’s gene expression. Endocrinology 135, 2364–2368 (1994).
Dent, G. W., Smith, M. A. & Levine, S. Rapid induction of corticotropin-releasing hormone gene transcription in the paraventricular nucleus of the developing rat. Endocrinology 141, 1593–1598 (2000).
Bohacek, J. & Mansuy, I. M. in Epigenetics and Neuroendocrinology (eds. Spengler, D. & Binder, E.) 79–119 (Springer, 2016).
Herringa, R. Commentary: Paediatric post-traumatic stress disorder from a neurodevelopmental network perspective: reflections on Weems et al. (2019). J. Child Psychol. Psychiatry 60, 409–411 (2019).
Acknowledgements
The authors’ work has been supported by NIH grants NS28912, NS35439, NS108296, MH73136 and MH096889, and by the Hewitt Foundation for Biomedical Research.
Reviewer information
Nature Reviews Neurology thanks R. Herringa and other anonymous reviewer(s) for their contribution to the peer review of this work.
Author information
Authors and Affiliations
Contributions
Both authors researched data for the article, wrote the article and reviewed and edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Short, A.K., Baram, T.Z. Early-life adversity and neurological disease: age-old questions and novel answers. Nat Rev Neurol 15, 657–669 (2019). https://doi.org/10.1038/s41582-019-0246-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41582-019-0246-5
This article is cited by
-
Early-life influenza A (H1N1) infection independently programs brain connectivity, HPA AXIS and tissue-specific gene expression profiles
Scientific Reports (2024)
-
Early-life prefrontal cortex inhibition and early-life stress lead to long-lasting behavioral, transcriptional, and physiological impairments
Molecular Psychiatry (2024)
-
Early life adversity as a risk factor for cognitive impairment and Alzheimer’s disease
Translational Neurodegeneration (2023)
-
Design of the Think PHRESH longitudinal cohort study: Neighborhood disadvantage, cognitive aging, and Alzheimer’s disease risk in disinvested, Black neighborhoods
BMC Public Health (2023)
-
Early life factors and structural brain network in children with overweight/obesity: The ActiveBrains project
Pediatric Research (2023)
