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.

  • Review Article
  • Published:

Neurobiology of resilience to early life stress

Neuropsychopharmacology (2025)Cite this article

Subjects

Abstract

The early years of life are a critical period for brain development, encompassing high sensitivity to adverse experiences. Early life stress (ELS) is known to “scar” the brain and shape mental health trajectories later in life. Still, a great percentage of children faced with ELS develop adaptive competencies that maintain normal physiological and behavioral function across the lifespan, a process referred to as resilience. Work in humans and rodent models has demonstrated that resilience is an active process mediated largely by the induction of unique molecular, cellular, and circuit adaptations. In this review, we highlight evidence from rodent studies exploring the behavioral, circuit, cellular, and molecular effects of ELS and discuss resilient phenotypes that emerge from specific ELS paradigms. To this end, we focus on models comprising ELS exposure within pre-weening and adolescence. We next address critical factors that influence the effects of ELS, such as behavioral readouts, environmental conditions, or sex differences, and we compare these findings in light of human studies. Finally, we advocate for the use of novel and more sophisticated behavioral tasks for rodents that capture, at least in part, resilient phenotypes observed in humans and that can be directly linked to specific brain circuits.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Neurodevelopmental milestones in rodents and humans during postnatal life.
Fig. 2: Different rodent models of early life stress (ELS).
Fig. 3: Behavioral readouts for resilience to stress.
Fig. 4: Brain circuits of stress resilience and susceptibility to ELS.

Similar content being viewed by others

References

  1. Teicher MH, Samson JA. Annual research review: enduring neurobiological effects of childhood abuse and neglect. J Child Psychol Psychiatry. 2016;57:241–66.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Gee DG. Early adversity and development: parsing heterogeneity and identifying pathways of risk and resilience. Am J Psychiatry. 2021;178:998–1013.

    Article  PubMed  Google Scholar 

  3. Green JG, McLaughlin KA, Berglund PA, Gruber MJ, Sampson NA, Zaslavsky AM, et al. Childhood adversities and adult psychiatric disorders in the National Comorbidity Survey Replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry. 2010;67:113–23.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Kessler RC, McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, et al. Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys. Br J Psychiatry. 2010;197:378–85.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Scott KM, McLaughlin KA, Smith DA, Ellis PM. Childhood maltreatment and DSM-IV adult mental disorders: comparison of prospective and retrospective findings. Br J Psychiatry. 2012;200:469–75.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Walsh WA, Dawson J, Mattingly MJ. How are we measuring resilience following childhood maltreatment? Is the research adequate and consistent? What is the impact on research, practice, and policy?. Trauma Violence Abuse. 2010;11:27–41.

    Article  PubMed  Google Scholar 

  7. Yu W, Zhu F, Foo MD, Wiklund J. What does not kill you makes you stronger: entrepreneurs’ childhood adversity, resilience, and career success. J Bus Res. 2022;151:40–55.

    Article  Google Scholar 

  8. Bonanno GA. Loss, trauma, and human resilience: Have we underestimated the human capacity to thrive after extremely aversive events? Psychol Trauma Theory, Res Pract Policy. 2008;S:101–13.

    Article  Google Scholar 

  9. Bonanno GA, Papa A, O’Neill K. Loss and human resilience. Appl Prev Psychol. 2001;10:193–206.

    Article  Google Scholar 

  10. Southwick SM, Charney DS. Resilience: the science of mastering life’s greatest challenges. Cambridge: Cambridge University Press; 2012.

  11. Ryff C, Friedman E, Fuller-Rowell T, Love G, Miyamoto Y, Morozink J, et al. Varieties of resilience in MIDUS. Soc Pers Psychol Compass. 2012;6:792–806.

    Article  Google Scholar 

  12. Cromer KR, Sachs-Ericsson N. The association between childhood abuse, PTSD, and the occurrence of adult health problems: moderation via current life stress. J Trauma Stress. 2006;19:967–71.

    Article  PubMed  Google Scholar 

  13. Torres-Berrío A, Issler O, Parise EM, Nestler EJ. Unraveling the epigenetic landscape of depression: focus on early life stress. Dialogues Clin Neurosci. 2019;21:341–57.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Baram TZ, Davis EP, Obenaus A, Sandman CA, Small SL, Solodkin A, et al. Fragmentation and unpredictability of early-life experience in mental disorders. Am J Psychiatry. 2012;169:907–15.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Sheridan MA, McLaughlin KA. Dimensions of early experience and neural development: deprivation and threat. Trends Cogn Sci. 2014;18:580–85.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V. et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) study. Am J Prev Med. 1998;14:245–58.

    Article  CAS  PubMed  Google Scholar 

  17. Merrick MT, Ford DC, Ports KA, Guinn AS. Prevalence of adverse childhood experiences From the 2011-2014 behavioral risk factor surveillance system in 23 states. JAMA Pediatr. 2018;172:1038–44.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Hammen C. Adolescent depression: stressful interpersonal contexts and risk for recurrence. Curr Dir Psychol Sci. 2009;18:200–04.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Hammen C, Henry R, Daley SE. Depression and sensitization to stressors among young women as a function of childhood adversity. J Consult Clin Psychol. 2000;68:782–7.

    Article  CAS  PubMed  Google Scholar 

  20. Rudolph KD, Hammen C, Burge D, Lindberg N, Herzberg D, Daley SE. Toward an interpersonal life-stress model of depression: the developmental context of stress generation. Dev Psychopathol. 2000;12:215–34.

    Article  CAS  PubMed  Google Scholar 

  21. Teicher MH, Anderson CM, Ohashi K, Khan A, McGreenery CE, Bolger EA, et al. Differential effects of childhood neglect and abuse during sensitive exposure periods on male and female hippocampus. Neuroimage. 2018;169:443–52.

    Article  PubMed  Google Scholar 

  22. Dunn EC, Gilman SE, Willett JB, Slopen NB, Molnar BE. The impact of exposure to interpersonal violence on gender differences in adolescent-onset major depression: results from the National Comorbidity Survey Replication (NCS-R). Depress Anxiety. 2012;29:392–99.

    Article  PubMed  Google Scholar 

  23. Michael C, Gard AM, Tillem S, Hardi FA, Dunn EC, Smith ADAC, et al. Developmental timing of associations among parenting, brain architecture, and mental health. JAMA Pediatr. 2024;178:1326–36.

    Article  PubMed  Google Scholar 

  24. Jiang T, Yakin S, Crocker J, Way BM. Perceived social support-giving moderates the association between social relationships and interleukin-6 levels in blood. Brain Behav Immun. 2022;100:25–28.

    Article  CAS  PubMed  Google Scholar 

  25. Morozink JA, Friedman EM, Coe CL, Ryff CD. Socioeconomic and psychosocial predictors of interleukin-6 in the MIDUS national sample. Health Psychol. 2010;29:626–35.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Park AT, Tooley UA, Leonard JA, Boroshok AL, McDermott CL, Tisdall MD, et al. Early childhood stress is associated with blunted development of ventral tegmental area functional connectivity. Dev Cogn Neurosci. 2021;47:100909.

    Article  PubMed  Google Scholar 

  27. Marusak HA, Hatfield JRB, Thomason ME, Rabinak CA. Reduced ventral tegmental area–hippocampal connectivity in children and adolescents exposed to early threat. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:130–37.

    PubMed Central  PubMed  Google Scholar 

  28. Sinha R, Lacadie CM, Constable RT, Seo D. Dynamic neural activity during stress signals resilient coping. Proc Natl Acad Sci USA. 2016;113:8837–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. McEwen BS, Gray J, Nasca C. Recognizing resilience: learning from the effects of stress on the brain. Neurobiol Stress. 2015;1:1–11.

    Article  PubMed  Google Scholar 

  30. Norbury A, Seeley SH, Perez-Rodriguez MM, Feder A. Functional neuroimaging of resilience to trauma: convergent evidence and challenges for future research. Psychol Med. 2023;53:3293–305.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Libé-Philippot B, Vanderhaeghen P. Cellular and molecular mechanisms linking human cortical development and evolution. Annu Rev Genet. 2021;55:555–81.

    Article  PubMed  Google Scholar 

  32. Zeiss CJ. Comparative milestones in rodent and human postnatal central nervous system development. Toxicol Pathol. 2021;49:1368–73.

    Article  PubMed  Google Scholar 

  33. Wallace JL, Pollen AA. Human neuronal maturation comes of age: cellular mechanisms and species differences. Nat Rev Neurosci. 2024;25:7–29.

    Article  CAS  PubMed  Google Scholar 

  34. Prince GS, Reynolds M, Martina V, Sun H. Gene-environmental regulation of the postnatal post-mitotic neuronal maturation. Trends Genet. 2024;40:480–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Knudsen EI. Sensitive periods in the development of the brain and behavior. J Cogn Neurosci. 2004;16:1412–25.

    Article  PubMed  Google Scholar 

  36. Peña CJ. Early-life stress sensitizes response to future stress: evidence and mechanisms. Neurobiol Stress. 2025;35:100716.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979;3:79–83.

    Article  CAS  PubMed  Google Scholar 

  38. Sengupta P. The laboratory rat: relating its age with human’s. Int J Prev Med. 2013;4:624–30.

    PubMed Central  PubMed  Google Scholar 

  39. Berry KP, Nedivi E. Spine dynamics: Are they all the same? Neuron. 2017;96:43–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Kalemaki K, Velli A, Christodoulou O, Denaxa M, Karagogeos D, Sidiropoulou K. The developmental changes in intrinsic and synaptic properties of prefrontal neurons enhance local network activity from the second to the third postnatal weeks in mice. Cereb Cortex. 2021;32:3633–50.

    Article  Google Scholar 

  41. Rurak GM, Simard S, Freitas-Andrade M, Lacoste B, Charih F, Van Geel A, et al. Sex differences in developmental patterns of neocortical astroglia: a mouse translatome database. Cell Rep. 2022;38:110310.

    Article  CAS  PubMed  Google Scholar 

  42. Farhy-Tselnicker I, Allen NJ. Astrocytes, neurons, synapses: a tripartite view on cortical circuit development. Neural Dev. 2018;13:7.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science. 2016;353:aad8670.

    Article  PubMed  Google Scholar 

  44. Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF, Okamoto J, et al. Developmental Heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron. 2019;101:207–23.e10.

    Article  CAS  PubMed  Google Scholar 

  45. Kessaris N, Fogarty M, Iannarelli P, Grist M, Wegner M, Richardson WD. Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat Neurosci. 2006;9:173–9.

    Article  CAS  PubMed  Google Scholar 

  46. Teissier A, Le Magueresse C, Olusakin J, Andrade da Costa BLS, De Stasi AM, Bacci A, et al. Early-life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms. Mol Psychiatry. 2020;25:1159–74.

    Article  CAS  PubMed  Google Scholar 

  47. Wang C, Xue Y, Markovic T, Li H, Wang S, Zhong Y, et al. Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system. Nat Mater. 2025 https://doi.org/10.1038/s41563-024-02114-5.

  48. Solarz A, Majcher-Maślanka I, Chocyk A. Effects of early-life stress and sex on blood–brain barrier permeability and integrity in juvenile and adult rats. Dev Neurobiol. 2021;81:861–76.

    Article  CAS  PubMed  Google Scholar 

  49. Milbocker KA, Campbell TS, Collins N, Kim S, Smith IF, Roth TL, et al. Glia-driven brain circuit refinement is altered by early-life adversity: behavioral outcomes. Front Behav Neurosci. 2021;15:786234.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Nestler EJ, Russo SJ. Neurobiological basis of stress resilience. Neuron. 2024;112:1911–29.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN, et al. Mechanisms of stress in the brain. Nat Neurosci. 2015;18:1353–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Schmidt M, Enthoven L, van der Mark M, Levine S, de Kloet ER, Oitzl MS. The postnatal development of the hypothalamic–pituitary–adrenal axis in the mouse. Int J Dev Neurosci. 2003;21:125–32.

    Article  CAS  PubMed  Google Scholar 

  53. Bolton JL, Short AK, Othy S, Kooiker CL, Shao M, Gunn BG, et al. Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses. Cell Rep. 2022;38:110600.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Bolton JL, Short AK, Simeone KA, Daglian J, Baram TZ. Programming of stress-sensitive neurons and circuits by early-life experiences. Front Behav Neurosci. 2019;13:30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Anderson KN, Swedo EA, Trinh E, Ray CM, Krause KH, Verlenden JV, et al. Adverse childhood experiences during the COVID-19 pandemic and associations with poor mental health and suicidal behaviors among high school students—Adolescent Behaviors and Experiences Survey, United States, January-June 2021. MMWR Morb Mortal Wkly Rep. 2022;71:1301–05.

    Article  PubMed Central  PubMed  Google Scholar 

  56. Kessler RC, Amminger GP, Aguilar-Gaxiola S, Alonso J, Lee S, Üstün TB. Age of onset of mental disorders: a review of recent literature. Curr Opin Psychiatry. 2007;20:359-64

  57. Reynolds LM, Yetnikoff L, Pokinko M, Wodzinski M, Epelbaum JG, Lambert LC, et al. Early adolescence is a critical period for the maturation of inhibitory behavior. Cereb Cortex. 2018;29:3676–86.

    Article  PubMed Central  Google Scholar 

  58. Hoops D, Flores C. Making dopamine connections in adolescence. Trends Neurosci. 2017;40:709–19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Floresco SB. The nucleus accumbens: an interface between cognition, emotion, and action. Annu Rev Psychol. 2015;66:25–52.

    Article  PubMed  Google Scholar 

  60. Brenhouse HC, Andersen SL. Developmental trajectories during adolescence in males and females: a cross-species understanding of underlying brain changes. Neurosci Biobehav Rev. 2011;35:1687–703.

    Article  PubMed Central  PubMed  Google Scholar 

  61. Somerville LH, Hare T, Casey BJ. Frontostriatal maturation predicts cognitive control failure to appetitive cues in adolescents. J Cogn Neurosci. 2011;23:2123–34.

    Article  PubMed  Google Scholar 

  62. Klune CB, Goodpaster CM, Gongwer MW, Gabriel CJ, An J, Chen R, et al. Developmentally distinct architectures in top–down pathways controlling threat avoidance. Nat Neurosci. 2025;28:823–35.

  63. Nelson EE, Jarcho JM, Guyer AE. Social re-orientation and brain development: an expanded and updated view. Dev Cogn Neurosci. 2016;17:118–27.

    Article  PubMed  Google Scholar 

  64. Chein J, Albert D, O’Brien L, Uckert K, Steinberg L. Peers increase adolescent risk taking by enhancing activity in the brain’s reward circuitry. Dev Sci. 2011;14:F1–10.

    Article  PubMed Central  PubMed  Google Scholar 

  65. McCutcheon JE, Marinelli M. Age matters. Eur J Neurosci. 2009;29:997–1014.

    Article  PubMed Central  PubMed  Google Scholar 

  66. Ghasemi A, Jeddi S, Kashfi K. The laboratory rat: age and body weight matter. EXCLI J. 2021;20:1431–45.

    PubMed Central  PubMed  Google Scholar 

  67. Sturman DA, Moghaddam B. The neurobiology of adolescence: changes in brain architecture, functional dynamics, and behavioral tendencies. Neurosci Biobehav Rev. 2011;35:1704–12.

    Article  PubMed Central  PubMed  Google Scholar 

  68. Sisk CL, Zehr JL. Pubertal hormones organize the adolescent brain and behavior. Front Neuroendocrinol. 2005;26:163–74.

    Article  CAS  PubMed  Google Scholar 

  69. Sisk CL, Foster DL. The neural basis of puberty and adolescence. Nat Neurosci. 2004;7:1040–47.

    Article  CAS  PubMed  Google Scholar 

  70. Lewis EM, Barnett JF Jr., Freshwater L, Hoberman AM, Christian MS. Sexual maturation data for Crl Sprague-Dawley rats: criteria and confounding factors. Drug Chem Toxicol. 2002;25:437–58.

    Article  CAS  PubMed  Google Scholar 

  71. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013;106-107:1–16.

    Article  PubMed  Google Scholar 

  72. Yang Y, Cheng Z, Tang H, Jiao H, Sun X, Cui Q, et al. Neonatal maternal separation impairs prefrontal cortical myelination and cognitive functions in rats through activation of Wnt signaling. Cereb Cortex. 2017;27:2871–84.

    PubMed  Google Scholar 

  73. Casey BJ, Getz S, Galvan A. The adolescent brain. Dev Rev. 2008;28:62–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA. 2004;101:8174–79.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Kolk SM, Rakic P. Development of prefrontal cortex. Neuropsychopharmacology. 2022;47:41–57.

    Article  CAS  PubMed  Google Scholar 

  76. Chad JA, Lebel C. Can gray matter loss in early adolescence be explained by white matter growth? Hum Brain Mapp. 2024;45:e26758.

    Article  PubMed Central  Google Scholar 

  77. Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW. Mapping cortical change across the human life span. Nat Neurosci. 2003;6:309–15.

    Article  CAS  PubMed  Google Scholar 

  78. Manitt C, Mimee A, Eng C, Pokinko M, Stroh T, Cooper HM, et al. The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. J Neurosci. 2011;31:8381–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Cuesta S, Nouel D, Reynolds LM, Morgunova A, Torres-Berrío A, White A, et al. Dopamine axon targeting in the nucleus accumbens in adolescence requires Netrin-1. Front Cell Dev Biol. 2020;8:487.

    Article  PubMed Central  PubMed  Google Scholar 

  80. Vassilev P, Pantoja-Urban AH, Giroux M, Nouel D, Hernandez G, Orsini T, et al. Unique effects of social defeat stress in adolescent male mice on the Netrin-1/DCC pathway, prefrontal cortex dopamine and cognition. eNeuro. 2021;8:0045-21:ENEURO.0045-21.

  81. Majcher-Maślanka I, Solarz A, Wędzony K, Chocyk A. The effects of early-life stress on dopamine system function in adolescent female rats. Int J Dev Neurosci. 2017;57:24–33.

    Article  PubMed  Google Scholar 

  82. Chocyk A, Przyborowska A, Dudys D, Majcher I, Maćkowiak M, Wędzony K. The impact of maternal separation on the number of tyrosine hydroxylase-expressing midbrain neurons during different stages of ontogenesis. Neuroscience. 2011;182:43–61.

    Article  CAS  PubMed  Google Scholar 

  83. Tseng KY, O’Donnell P. Dopamine modulation of prefrontal cortical interneurons changes during adolescence. Cereb Cortex. 2007;17:1235–40.

    Article  PubMed  Google Scholar 

  84. Tseng KY, O’Donnell P. Dopamine–glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci. 2004;24:5131–39.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Murthy S, Gould E. Early life stress in rodents: animal models of illness or resilience? Front Behav Neurosci. 2018;12:157.

    Article  PubMed Central  PubMed  Google Scholar 

  86. Demaestri C, Gallo M, Mazenod E, Hong AT, Arora H, Short AK, et al. Resource scarcity but not maternal separation provokes unpredictable maternal care sequences in mice and both upregulate Crh-associated gene expression in the amygdala. Neurobiol Stress. 2022;20:100484.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Demaestri C, Pan T, Critz M, Ofray D, Gallo M, Bath KG. Type of early life adversity confers differential, sex-dependent effects on early maturational milestones in mice. Horm Behav. 2020;124:104763.

    Article  PubMed Central  PubMed  Google Scholar 

  88. Waters RC, Gould E. Early life adversity and neuropsychiatric disease: differential outcomes and translational relevance of rodent models. Front Syst Neurosci. 2022;16:860847.

    Article  PubMed Central  PubMed  Google Scholar 

  89. Ader R, Tatum R, Beels CC. Social factors affecting emotionality and resistance to disease in animals: I. Age of separation from the mother and susceptibility to gastric ulcers in the rat. J Comp Physiol Psychol. 1960;53:446–54.

    Article  CAS  PubMed  Google Scholar 

  90. Raineki C, Moriceau S, Sullivan RM. Developing a neurobehavioral animal model of infant attachment to an abusive caregiver. Biol Psychiatry. 2010;67:1137–45.

    Article  PubMed Central  PubMed  Google Scholar 

  91. Moriceau S, Shionoya K, Jakubs K, Sullivan RM. Early-life stress disrupts attachment learning: the role of amygdala corticosterone, locus ceruleus corticotropin releasing hormone, and olfactory bulb norepinephrine. J Neurosci. 2009;29:15745–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Moriceau S, Sullivan RM. Maternal presence serves as a switch between learning fear and attraction in infancy. Nat Neurosci. 2006;9:1004–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Raineki C, Cortés MR, Belnoue L, Sullivan RM. 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. 2012;32:7758–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. George ED, Bordner KA, Elwafi HM, Simen AA. Maternal separation with early weaning: a novel mouse model of early life neglect. BMC Neurosci. 2010;11:123.

    Article  PubMed Central  PubMed  Google Scholar 

  95. Gruss M, Braun K, Frey JU, Korz V. Maternal separation during a specific postnatal time window prevents reinforcement of hippocampal long-term potentiation in adolescent rats. Neuroscience. 2008;152:1–7.

    Article  CAS  PubMed  Google Scholar 

  96. Authement ME, Kodangattil JN, Gouty S, Rusnak M, Symes AJ, Cox BM, et al. Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling. Neuron. 2015;86:1240–52.

    Article  CAS  PubMed  Google Scholar 

  97. Sullivan RM, Landers M, Yeaman B, Wilson DA. Good memories of bad events in infancy. Nature. 2000;407:38–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Peña CJ, Kronman HG, Walker DM, Cates HM, Bagot RC, Purushothaman I, et al. Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science. 2017;356:1185–88.

    Article  PubMed Central  PubMed  Google Scholar 

  99. Peña CJ, Nestler EJ, Bagot RC. Environmental programming of susceptibility and resilience to stress in adulthood in male mice. Front Behav Neurosci. 2019;13:40.

    Article  PubMed Central  PubMed  Google Scholar 

  100. Huot RL, Gonzalez ME, Ladd CO, Thrivikraman KV, Plotsky PM. Foster litters prevent hypothalamic-pituitary-adrenal axis sensitization mediated by neonatal maternal separation. Psychoneuroendocrinology. 2004;29:279–89.

    Article  CAS  PubMed  Google Scholar 

  101. Gilles EE, Schultz L, Baram TZ. Abnormal corticosterone regulation in an immature rat model of continuous chronic stress. Pediatr Neurol. 1996;15:114–19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Ivy AS, Brunson KL, Sandman C, Baram TZ. Dysfunctional nurturing behavior in rat dams with limited access to nesting material: a clinically relevant model for early-life stress. Neuroscience. 2008;154:1132–42.

    Article  CAS  PubMed  Google Scholar 

  103. Rice CJ, Sandman CA, Lenjavi MR, Baram TZ. A novel mouse model for acute and long-lasting consequences of early life stress. Endocrinology. 2008;149:4892–900.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Birnie MT, Baram TZ. The evolving neurobiology of early-life stress. Neuron. 2025;113:1474–90

  105. Molet J, Heins K, Zhuo X, Mei YT, Regev L, Baram TZ, et al. Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome. Transl Psychiatry. 2016;6:e702.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Eck SR, Ardekani CS, Salvatore M, Luz S, Kim ED, Rogers CM, et al. The effects of early life adversity on growth, maturation, and steroid hormones in male and female rats. Eur J Neurosci. 2020;52:2664–80.

    Article  PubMed  Google Scholar 

  107. Sanchez EO, Bavley CC, Deutschmann AU, Carpenter R, Peterson DR, Karbalaei R. et al. “Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes”: Correction. Proc Natl Acad Sci USA. 2022;119:1

    Google Scholar 

  108. Peña CJ, Smith M, Ramakrishnan A, Cates HM, Bagot RC, Kronman HG, et al. Early life stress alters transcriptomic patterning across reward circuitry in male and female mice. Nat Commun. 2019;10:5098.

    Article  PubMed Central  PubMed  Google Scholar 

  109. Kronman H, Torres-Berrío A, Sidoli S, Issler O, Godino A, Ramakrishnan A, et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nat Neurosci. 2021;24:667–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Balouek JA, McLain CA, Minerva AR, Rashford RL, Bennett SN, Rogers FD, et al. Reactivation of early-life stress-sensitive neuronal ensembles contributes to lifelong stress hypersensitivity. J Neurosci. 2023;43:5996–6009.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Bennett SN, Chang AB, Rogers FD, Jones P, Peña CJ. Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior. Horm Behav. 2024;159:105472.

    Article  CAS  PubMed  Google Scholar 

  112. Parel ST, Bennett SN, Cheng CJ, Timmermans OC, Fiori LM, Turecki G, et al. Transcriptional signatures of early-life stress and antidepressant treatment efficacy. Proc Natl Acad Sci USA. 2023;120:e2305776120.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Guayasamin M, Depaauw-Holt LR, Adedipe II, Ghenissa O, Vaugeois J, Duquenne M, et al. Early-life stress induces persistent astrocyte dysfunction associated with fear generalisation. eLife. 2025;13:RP99988.

    Article  PubMed Central  PubMed  Google Scholar 

  114. Torres-Berrío A, Estill M, Patel V, Ramakrishnan A, Kronman H, Minier-Toribio A, et al. Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress. Neuron. 2024;112:2973–89.e10.

    Article  PubMed  Google Scholar 

  115. Curley JP, Champagne FA. Influence of maternal care on the developing brain: mechanisms, temporal dynamics and sensitive periods. Front Neuroendocrinol. 2016;40:52–66.

    Article  PubMed  Google Scholar 

  116. Champagne FA, Francis DD, Mar A, Meaney MJ. Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol Behav. 2003;79:359–71.

    Article  CAS  PubMed  Google Scholar 

  117. Lapp HE, Salazar M, Champagne FA. Postnatal rearing environment alters pup cues for caregiver-offspring interactions. Horm Behav. 2024;165:105630.

    Article  PubMed  Google Scholar 

  118. van der Zee YY, Eijssen LMT, Mews P, Ramakrishnan A, Alvarez K, Lardner CK, et al. Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression. Mol Psychiatry. 2022;27:4536–49.

    Article  PubMed Central  PubMed  Google Scholar 

  119. Jensen Peña C, Champagne FA. Implications of temporal variation in maternal care for the prediction of neurobiological and behavioral outcomes in offspring. Behav Neurosci. 2013;127:33–46.

    Article  PubMed  Google Scholar 

  120. Hisey EE, Fritsch EL, Newman EL, Ressler KJ, Kangas BD, Carlezon WA. Early life stress in male mice blunts responsiveness in a translationally-relevant reward task. Neuropsychopharmacology. 2023;48:1752–59.

    Article  PubMed Central  PubMed  Google Scholar 

  121. Pantoja-Urbán AH, Richer S, Mittermaier A, Giroux M, Nouel D, Hernandez G, et al. Gains and losses: resilience to social defeat stress in adolescent female mice. Biol Psychiatry. 2024;95:37–47.

    Article  PubMed  Google Scholar 

  122. Mayeaux MR, Newman EL, Ressler KJ, Hisey EE. Chronic social defeat stress in early adolescent male mice. J Vis Exp. 2025;215:e67113.

  123. Krishnan V, Han M-H, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.

    Article  CAS  PubMed  Google Scholar 

  124. Golden SA, Covington HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Pantoja-Urbán AH, Richer S, Giroux M, Nouel D, Flores C. Social defeat stress model for adolescent C57BL/6 male and female mice. J Vis Exp. 2024;205:e66455.

  126. Shen M, Song Z, Wang J-H. microRNA and mRNA profiles in the amygdala are associated with stress-induced depression and resilience in juvenile mice. Psychopharmacology. 2019;236:2119–42.

    Article  CAS  PubMed  Google Scholar 

  127. Gyles TM, Nestler EJ, Parise EM. Advancing preclinical chronic stress models to promote therapeutic discovery for human stress disorders. Neuropsychopharmacology. 2024;49:215–26.

    Article  PubMed  Google Scholar 

  128. Stedenfeld KA, Clinton SM, Kerman IA, Akil H, Watson SJ, Sved AF. Novelty-seeking behavior predicts vulnerability in a rodent model of depression. Physiol Behav. 2011;103:210–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Porsolt RD, Bertin A, Jalfre M. Behavioural despair” in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol. 1978;51:291–94.

    Article  CAS  PubMed  Google Scholar 

  130. Samuels BA, Hen R. Novelty-suppressed feeding in the mouse. In: Gould TD, editor. Mood and anxiety related phenotypes in mice: characterization using behavioral tests, Vol. II. Totowa, NJ: Humana Press; 2011. p. 107–21.

  131. Blasco-Serra A, González-Soler EM, Cervera-Ferri A, Teruel-Martí V, Valverde-Navarro AA. A standardization of the Novelty-Suppressed Feeding Test protocol in rats. Neurosci Lett. 2017;658:73–8.

    Article  CAS  PubMed  Google Scholar 

  132. Kulkarni SK, Singh K, Bishnoi M. Elevated zero maze: a paradigm to evaluate antianxiety effects of drugs. Methods Find Exp Clin Pharmacol. 2007;29:343–8.

    Article  CAS  PubMed  Google Scholar 

  133. Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc. 2007;2:322–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  134. Bogdanova OV, Kanekar S, D’Anci KE, Renshaw PF. Factors influencing behavior in the forced swim test. Physiol Behav. 2013;118:227–39.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  135. Berton O, McClung CA, DiLeone RJ, Krishnan V, Renthal W, Russo SJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864–68.

    Article  CAS  PubMed  Google Scholar 

  136. Durand-de Cuttoli R, Martínez-Rivera FJ, Li L, Minier-Toribio A, Holt LM, Cathomas F, et al. Distinct forms of regret linked to resilience versus susceptibility to stress are regulated by region-specific CREB function in mice. Sci Adv. 2022;8:eadd5579.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Durand-de Cuttoli R, Martínez-Rivera FJ, Li L, Minier-Toribio A, Dong Z, Cai DJ, et al. A double hit of social and economic stress in mice precipitates changes in decision-making strategies. Biol Psychiatry. 2024;96:67–78.

    Article  PubMed  Google Scholar 

  138. Li L, Durand-de Cuttoli R, Aubry AV, Burnett CJ, Cathomas F, Parise LF, et al. Social trauma engages lateral septum circuitry to occlude social reward. Nature. 2023;613:696–703.

    Article  CAS  PubMed  Google Scholar 

  139. Kangas BD, Ang Y-S, Short AK, Baram TZ, Pizzagalli DA. Computational modeling differentiates learning rate from reward sensitivity deficits produced by early-life adversity in a rodent touchscreen probabilistic reward task. Biol Psychiatry Glob Open Sci. 2024;4:100362.

    Article  PubMed Central  PubMed  Google Scholar 

  140. Kangas BD, Short AK, Luc OT, Stern HS, Baram TZ, Pizzagalli DA. A cross-species assay demonstrates that reward responsiveness is enduringly impacted by adverse, unpredictable early-life experiences. Neuropsychopharmacology. 2022;47:767–75.

    Article  PubMed  Google Scholar 

  141. Diehl MM, Bravo-Rivera C, Quirk GJ. The study of active avoidance: a platform for discussion. Neurosci Biobehav Rev. 2019;107:229–37.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. Bolton JL, Molet J, Regev L, Chen Y, Rismanchi N, Haddad E, et al. Anhedonia following early-life adversity involves aberrant interaction of reward and anxiety circuits and is reversed by partial silencing of amygdala corticotropin-releasing hormone gene. Biol Psychiatry. 2018;83:137–47.

    Article  CAS  PubMed  Google Scholar 

  143. Demaestri C, Pisciotta M, Altunkeser N, Berry G, Hyland H, Breton J, et al. Central amygdala CRF+ neurons promote heightened threat reactivity following early life adversity in mice. Nat Commun. 2024;15:5522.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  144. Lepack AE, Bagot RC, Peña CJ, Loh Y-HE, Farrelly LA, Lu Y, et al. Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior. Proc Natl Acad Sci. 2016;113:12562–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  145. Geiger LT, Balouek J-A, Farrelly LA, Chen AS, Tang M, Bennett SN, et al. Early-life stress alters chromatin modifications in VTA to prime stress sensitivity. bioRxiv [Preprint]. 2024. https://www.biorxiv.org/content/10.1101/2024.03.14.584631v1.

  146. Rashford RL, DeBerardine M, Kim HJJ, Arzouni N, Hirschfield LW, Oke OM, et al. Early-life stress alters postnatal chromatin development in the nucleus accumbens. bioRxiv [Preprint]. 2024. https://www.biorxiv.org/content/10.1101/2024.04.12.589272v1.

  147. Parel ST, Peña CJ. Genome-wide signatures of early-life stress: influence of sex. Biol Psychiatry. 2022;91:36–42.

    Article  CAS  PubMed  Google Scholar 

  148. Singh-Taylor A, Molet J, Jiang S, Korosi A, Bolton JL, Noam Y, et al. NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. Mol Psychiatry. 2018;23:648–57.

    Article  CAS  PubMed  Google Scholar 

  149. Shi D-D, Zhang Y-D, Ren Y-Y, Peng S-Y, Yuan T-F, Wang Z. Predictable maternal separation confers adult stress resilience via the medial prefrontal cortex oxytocin signaling pathway in rats. Mol Psychiatry. 2021;26:7296–307.

    Article  CAS  PubMed  Google Scholar 

  150. Hegde A, Suresh S, Mitra R. Early-life short-term environmental enrichment counteracts the effects of stress on anxiety-like behavior, brain-derived neurotrophic factor and nuclear translocation of glucocorticoid receptors in the basolateral amygdala. Sci Rep. 2020;10:14053.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  151. Borba LA, Broseghini LDR, Manosso LM, de Moura AB, Botelho MEM, Arent CO, et al. Environmental enrichment improves lifelong persistent behavioral and epigenetic changes induced by early-life stress. J Psychiatr Res. 2021;138:107–16.

    Article  PubMed Central  PubMed  Google Scholar 

  152. Stairs DJ, Chacho NM, Wunsch C, Pipitone L, Dravid SM. Environmental enrichment increases cue-dependent freezing and behavioral despair but decreases anxiety-like behavior in rats. Pharmacol Biochem Behav. 2020;196:172979.

    Article  CAS  PubMed  Google Scholar 

  153. Xu H, Li B, Li L, Fan Z, Gong X, Wu L, et al. Environmental enrichment mitigates PTSD-like behaviors in adult male rats exposed to early life stress by regulating histone acetylation in the hippocampus and amygdala. J Psychiatr Res. 2022;155:120–36.

    Article  PubMed  Google Scholar 

  154. Connors EJ, Migliore MM, Pillsbury SL, Shaik AN, Kentner AC. Environmental enrichment models a naturalistic form of maternal separation and shapes the anxiety response patterns of offspring. Psychoneuroendocrinology. 2015;52:153–67.

    Article  CAS  PubMed  Google Scholar 

  155. Rule L, Yang J, Watkin H, Hall J, Brydges NM. Environmental enrichment rescues survival and function of adult-born neurons following early life stress. Mol Psychiatry. 2021;26:1898–908.

    Article  PubMed  Google Scholar 

  156. Soares RO, Rorato RC, Padovan D, Lachat J-J, Antunes-Rodrigues J, Elias LLK, et al. Environmental enrichment reverses reduction in glucocorticoid receptor expression in the hippocampus of and improves behavioral responses of anxiety in early malnourished rats. Brain Res. 2015;1600:32–41.

    Article  CAS  PubMed  Google Scholar 

  157. de Lima RMS, da Mata MJ, Santos JCPD, Costa L, Marques VHM, Bento LVDS, et al. Exploring the role of environmental enrichment and early life adversity on emotional development. Behav Brain Res. 2024;472:115147.

    Article  PubMed  Google Scholar 

  158. Ma Y-N, Yang C-J, Zhang C-C, Sun Y-X, Yao X-D, Liu X, et al. Prefrontal parvalbumin interneurons mediate CRHR1-dependent early-life stress-induced cognitive deficits in adolescent male mice. Mol Psychiatry. 2024;30:2407–26.

  159. Joushi S, Esmaeilpour K, Masoumi-Ardakani Y, Esmaeili-Mahani S, Sheibani V. Effects of short environmental enrichment on early-life adversity induced cognitive alternations in adolescent rats. J Neurosci Res. 2021;99:3373–91.

    Article  CAS  PubMed  Google Scholar 

  160. Francis DD, Diorio J, Plotsky PM, Meaney MJ. Environmental enrichment reverses the effects of maternal separation on stress reactivity. J Neurosci. 2002;22:7840–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  161. Sadeghi M, Peeri M, Hosseini MJ. Adolescent voluntary exercise attenuated hippocampal innate immunity responses and depressive-like behaviors following maternal separation stress in male rats. Physiol Behav. 2016;163:177–83.

    Article  CAS  PubMed  Google Scholar 

  162. Wearick-Silva LE, Marshall P, Viola TW, Centeno-Silva A, de Azeredo LA, Orso R, 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. 2017;59:268–74.

    Article  CAS  PubMed  Google Scholar 

  163. Fuentes IM, Jones BM, Brake AD, Pierce AN, Eller OC, Supple RM, et al. Voluntary wheel running improves outcomes in an early life stress-induced model of urologic chronic pelvic pain syndrome in male mice. Pain. 2021;162:1681–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  164. Masrour FF, Peeri M, Azarbayjani MA, Hosseini M-J. Voluntary exercise during adolescence mitigated negative the effects of maternal separation stress on the depressive-like behaviors of adult male rats: role of NMDA receptors. Neurochem Res. 2018;43:1067–74.

    Article  CAS  PubMed  Google Scholar 

  165. Abbink MR, Naninck EFG, Lucassen PJ, Korosi A. Early-life stress diminishes the increase in neurogenesis after exercise in adult female mice. Hippocampus. 2017;27:839–44.

    Article  CAS  PubMed  Google Scholar 

  166. Huang H, Wang Q, Guan X, Zhang X, Zhang Y, Cao J, et al. Effects of enriched environment on depression and anxiety-like behavior induced by early life stress: a comparison between different periods. Behav Brain Res. 2021;411:113389.

    Article  CAS  PubMed  Google Scholar 

  167. Khalil MH. Environmental enrichment: a systematic review on the effect of a changing spatial complexity on hippocampal neurogenesis and plasticity in rodents, with considerations for translation to urban and built environments for humans. Front Neurosci. 2024;18:1368411.

    Article  PubMed Central  PubMed  Google Scholar 

  168. Koe AS, Ashokan A, Mitra R. Short environmental enrichment in adulthood reverses anxiety and basolateral amygdala hypertrophy induced by maternal separation. Transl Psychiatry. 2016;6:e729

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  169. Ke Z, Yip SP, Li L, Zheng XX, Tong KY. The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: a rat brain ischemia model. PLoS ONE. 2011;6:e16643.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  170. Campbell EJ, Mitchell CS, Adams CD, Yeoh JW, Hodgson DM, Graham BA, et al. Chemogenetic activation of the lateral hypothalamus reverses early life stress-induced deficits in motivational drive. Eur J Neurosci. 2017;46:2285–96.

    Article  PubMed  Google Scholar 

  171. Gildawie KR, Wang K, Budge KE, Byrnes EM. Effects of maternal separation on effort-based responding for sucrose are associated with c-Fos expression in the nucleus accumbens core. Neuroscience. 2024;537:174–88.

    Article  CAS  PubMed  Google Scholar 

  172. Pizzagalli DA, Iosifescu D, Hallett LA, Ratner KG, Fava M. Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. J Psychiatr Res. 2008;43:76–87.

    Article  PubMed Central  PubMed  Google Scholar 

  173. Pechtel P, Lyons-Ruth K, Anderson CM, Teicher MH. Sensitive periods of amygdala development: the role of maltreatment in preadolescence. Neuroimage. 2014;97:236–44.

    Article  PubMed  Google Scholar 

  174. Frodl T, Reinhold E, Koutsouleris N, Reiser M, Meisenzahl EM. Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression. J Psychiatr Res. 2010;44:799–807.

    Article  PubMed  Google Scholar 

  175. Samplin E, Ikuta T, Malhotra AK, Szeszko PR, Derosse P. Sex differences in resilience to childhood maltreatment: effects of trauma history on hippocampal volume, general cognition and subclinical psychosis in healthy adults. J Psychiatr Res. 2013;47:1174–9.

    Article  PubMed Central  PubMed  Google Scholar 

  176. Everaerd D, Gerritsen L, Rijpkema M, Frodl T, van Oostrom I, Franke B, et al. Sex modulates the interactive effect of the serotonin transporter gene polymorphism and childhood adversity on hippocampal volume. Neuropsychopharmacology. 2012;37:1848–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Underwood MD, Bakalian MJ, Escobar T, Kassir S, Mann JJ, Arango V. Early-life adversity, but not suicide, is associated with less prefrontal cortex gray matter in adulthood. Int J Neuropsychopharmacol. 2019;22:349–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  178. Andersen SL, Tomada A, Vincow ES, Valente E, Polcari A, Teicher MH. Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. J Neuropsychiatry Clin Neurosci. 2008;20:292–301.

    Article  PubMed Central  PubMed  Google Scholar 

  179. Admon R, Milad MR, Hendler T. A causal model of post-traumatic stress disorder: disentangling predisposed from acquired neural abnormalities. Trends Cogn Sci. 2013;17:337–47.

    Article  PubMed  Google Scholar 

  180. Yan CG, Rincón-Cortés M, Raineki C, Sarro E, Colcombe S, Guilfoyle DN. et al. Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring. Transl Psychiatry. 2017;7:e1005

    Article  PubMed Central  PubMed  Google Scholar 

  181. Johnson FK, Delpech J-C, Thompson GJ, Wei L, Hao J, Herman P, et al. Amygdala hyper-connectivity in a mouse model of unpredictable early life stress. Transl Psychiatry. 2018;8:49.

    Article  PubMed Central  PubMed  Google Scholar 

  182. Honeycutt JA, Demaestri C, Peterzell S, Silveri MM, Cai X, Kulkarni P, et al. Altered corticolimbic connectivity reveals sex-specific adolescent outcomes in a rat model of early life adversity. eLife. 2020;9:e52651.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  183. Ishikawa J, Nishimura R, Ishikawa A. Early-life stress induces anxiety-like behaviors and activity imbalances in the medial prefrontal cortex and amygdala in adult rats. Eur J Neurosci. 2015;41:442–53.

    Article  PubMed  Google Scholar 

  184. Cody CR, de la Villarmois EA, Fernandez AM, Lardizabal J, McKnight C, Tseng K, et al. Effects of early life adversity and adolescent basolateral amygdala activity on corticolimbic connectivity and anxiety behaviors. bioRxiv [Preprint]. 2024. https://www.biorxiv.org/content/10.1101/2024.03.26.586708v1.full.

  185. Hultman R, Ulrich K, Sachs BD, Blount C, Carlson DE, Ndubuizu N, et al. Brain-wide electrical spatiotemporal dynamics encode depression vulnerability. Cell. 2018;173:166–80.e14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  186. Birnie MT, Short AK, de Carvalho GB, Taniguchi L, Gunn BG, Pham AL, et al. Stress-induced plasticity of a CRH/GABA projection disrupts reward behaviors in mice. Nat Commun. 2023;14:1088.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  187. Spyrka J, Gugula A, Rak A, Tylko G, Hess G, Blasiak A. Early life stress-induced alterations in the activity and morphology of ventral tegmental area neurons in female rats. Neurobiol Stress. 2020;13:100250.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  188. Buthmann JL, Miller JG, Uy JP, Coury SM, Jo B, Gotlib IH. Early life stress predicts trajectories of emotional problems and hippocampal volume in adolescence. Eur Child Adolesc Psychiatry. 2024;33:2331–42.

    Article  PubMed  Google Scholar 

  189. Ruiz R, Roque A, Pineda E, Licona-Limón P, José Valdéz-Alarcón J, Lajud N. Early life stress accelerates age-induced effects on neurogenesis, depression, and metabolic risk. Psychoneuroendocrinology. 2018;96:203–11.

    Article  PubMed  Google Scholar 

  190. Dixon R, Malave L, Thompson R, Wu S, Li Y, Sadik N, et al. Sex-specific and developmental effects of early life adversity on stress reactivity are rescued by postnatal knockdown of 5-HT1A autoreceptors. Neuropsychopharmacology. 2025;50:507–18.

    Article  CAS  PubMed  Google Scholar 

  191. Kos A, Lopez JP, Bordes J, de Donno C, Dine J, Brivio E, et al. Early life adversity shapes social subordination and cell type-specific transcriptomic patterning in the ventral hippocampus. Sci Adv. 2023;9:eadj3793.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  192. Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016;17:487–500.

    Article  CAS  PubMed  Google Scholar 

  193. Baram TZ, Birnie MT. Enduring memory consequences of early-life stress/adversity: structural, synaptic, molecular and epigenetic mechanisms. Neurobiol Stress. 2024;33:100669.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  194. Peña CJ. Epigenetic regulation of developmental plasticity and response to stress. Neuropsychopharmacology. 2026.

  195. Yim YY, Teague CD, Nestler EJ. In vivo locus-specific editing of the neuroepigenome. Nat Rev Neurosci. 2020;21:471–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  196. Walker DM, Zhou X, Cunningham AM, Lipschultz AP, Ramakrishnan A, Cates HM, et al. Sex-specific transcriptional changes in response to adolescent social stress in the brain’s reward circuitry. Biol Psychiatry. 2022;91:118–28.

    Article  CAS  PubMed  Google Scholar 

  197. Walker DM, Zhou X, Cunningham AM, Ramakrishnan A, Cates HM, Lardner CK, et al. Crystallin Mu in medial amygdala mediates the effect of social experience on cocaine seeking in males but not in females. Biol Psychiatry. 2022;92:895–906.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  198. Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212–22.

    Article  PubMed  Google Scholar 

  199. Rahman MF, McGowan PO. Cell-type-specific epigenetic effects of early life stress on the brain. Transl Psychiatry. 2022;12:326.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  200. Orso R, Creutzberg KC, Lumertz FS, Kestering-Ferreira E, Stocchero BA, Perrone MK, et al. A systematic review and multilevel meta-analysis of the prenatal and early life stress effects on rodent microglia, astrocyte, and oligodendrocyte density and morphology. Neurosci Biobehav Rev. 2023;150:105202.

    Article  PubMed  Google Scholar 

  201. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  202. Dayananda KK, Ahmed S, Wang D, Polis B, Islam R, Kaffman A. Early life stress impairs synaptic pruning in the developing hippocampus. Brain Behav Immun. 2023;107:16–31.

    Article  PubMed  Google Scholar 

  203. Hoeijmakers L, Ruigrok SR, Amelianchik A, Ivan D, van Dam AM, Lucassen PJ, et al. Early-life stress lastingly alters the neuroinflammatory response to amyloid pathology in an Alzheimer’s disease mouse model. Brain Behav Immun. 2017;63:160–75.

    Article  CAS  PubMed  Google Scholar 

  204. Depaauw-Holt LR, Hamane S, Peyrard S, Rogers B, Fulton S, Bosson A, et al. Astrocyte glucocorticoid receptors mediate sex-specific changes in activity following stress. bioRxiv [Preprint]. 2024. https://www.biorxiv.org/content/10.1101/2024.09.17.613499v1.

  205. Tanti A, Kim JJ, Wakid M, Davoli MA, Turecki G, Mechawar N. Child abuse associates with an imbalance of oligodendrocyte-lineage cells in ventromedial prefrontal white matter. Mol Psychiatry. 2018;23:2018–28.

    Article  CAS  PubMed  Google Scholar 

  206. Wu X, Ding Z, Fan T, Wang K, Li S, Zhao J, et al. Childhood social isolation causes anxiety-like behaviors via the damage of blood-brain barrier in amygdala in female mice. Front Cell Dev Biol. 2022;10:943067.

    Article  PubMed Central  PubMed  Google Scholar 

  207. Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  208. Shirtcliff EA, Allison AL, Armstrong JM, Slattery MJ, Kalin NH, Essex MJ. Longitudinal stability and developmental properties of salivary cortisol levels and circadian rhythms from childhood to adolescence. Dev Psychobiol. 2012;54:493–502.

    Article  CAS  PubMed  Google Scholar 

  209. Owens M, Herbert J, Jones PB, Sahakian BJ, Wilkinson PO, Dunn VJ, et al. Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms. Proc Natl Acad Sci USA. 2014;111:3638–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  210. Khandaker GM, Stochl J, Zammit S, Goodyer I, Lewis G, Jones PB. Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: a longitudinal cohort study. Psychol Med. 2018;48:1514–22.

    Article  CAS  PubMed  Google Scholar 

  211. Chu AL, Stochl J, Lewis G, Zammit S, Jones PB, Khandaker GM. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav Immun. 2019;76:74–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  212. Iob E, Kirschbaum C, Steptoe A. Persistent depressive symptoms, HPA-axis hyperactivity, and inflammation: the role of cognitive-affective and somatic symptoms. Mol Psychiatry. 2020;25:1130–40.

    Article  PubMed  Google Scholar 

  213. Colich NL, Kircanski K, Foland-Ross LC, Gotlib IH. HPA-axis reactivity interacts with stage of pubertal development to predict the onset of depression. Psychoneuroendocrinology. 2015;55:94–101.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  214. King LS, Colich NL, LeMoult J, Humphreys KL, Ordaz SJ, Price AN, et al. The impact of the severity of early life stress on diurnal cortisol: the role of puberty. Psychoneuroendocrinology. 2017;77:68–74.

    Article  CAS  PubMed  Google Scholar 

  215. Humphreys KL, Moore SR, Davis EG, MacIsaac JL, Lin DTS, Kobor MS, et al. DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis. Transl Psychiatry. 2019;9:245.

    Article  PubMed Central  PubMed  Google Scholar 

  216. Yousufzai MIuA, Harmatz ES, Shah M, Malik MO, Goosens KA. Ghrelin is a persistent biomarker for chronic stress exposure in adolescent rats and humans. Transl Psychiatry. 2018;8:74.

    Article  PubMed Central  PubMed  Google Scholar 

  217. Biltz RG, Sawicki CM, Sheridan JF, Godbout JP. The neuroimmunology of social-stress-induced sensitization. Nat Immunol. 2022;23:1527–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  218. Carboni L, Becchi S, Piubelli C, Mallei A, Giambelli R, Razzoli M, et al. Early-life stress and antidepressants modulate peripheral biomarkers in a gene–environment rat model of depression. Prog Neuro Psychopharmacol Biol Psychiatry. 2010;34:1037–48.

    Article  CAS  Google Scholar 

  219. Short AK, Weber R, Kamei N, Wilcox Thai C, Arora H, Mortazavi A, et al. Individual longitudinal changes in DNA-methylome identify signatures of early-life adversity and correlate with later outcome. Neurobiol Stress. 2024;31:100652.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  220. Lussier AA, Smith BJ, Fisher J, Luo M, Cerutti J, Schneper L, et al. DNA methylation mediates the link between adversity and depressive symptoms. Nat Ment Health. 2024;2:1476–85.

    Article  Google Scholar 

  221. Kaufman J, Wymbs NF, Montalvo-Ortiz JL, Orr C, Albaugh MD, Althoff R, et al. Methylation in OTX2 and related genes, maltreatment, and depression in children. Neuropsychopharmacology. 2018;43:2204–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  222. Issler O, Haramati S, Paul Evan D, Maeno H, Navon I, Zwang R, et al. MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron. 2014;83:344–60.

    Article  CAS  PubMed  Google Scholar 

  223. Lopez JP, Fiori LM, Cruceanu C, Lin R, Labonte B, Cates HM, et al. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes. Nat Commun. 2017;8:15497.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  224. Torres-Berrío A, Lopez JP, Bagot RC, Nouel D, Dal Bo G, Cuesta S, et al. DCC confers susceptibility to depression-like behaviors in humans and mice and is regulated by miR-218. Biol Psychiatry. 2017;81:306–15.

    Article  PubMed  Google Scholar 

  225. Torres-Berrío A, Morgunova A, Giroux M, Cuesta S, Nestler EJ, Flores C. miR-218 in adolescence predicts and mediates vulnerability to stress. Biol Psychiatry. 2021;89:911–19.

    Article  PubMed  Google Scholar 

  226. Torres-Berrío A, Nouel D, Cuesta S, Parise EM, Restrepo-Lozano JM, Larochelle P, et al. MiR-218: a molecular switch and potential biomarker of susceptibility to stress. Mol Psychiatry. 2020;25:951–64.

    Article  PubMed  Google Scholar 

  227. Muir J, Iyer ES, Tse Y-C, Sorensen J, Wu S, Eid RS, et al. Sex-biased neural encoding of threat discrimination in nucleus accumbens afferents drives suppression of reward behavior. Nat Neurosci. 2024;27:1966–76.

    Article  CAS  PubMed  Google Scholar 

  228. Giovanniello JR, Paredes N, Wiener A, Ramírez-Armenta K, Oragwam C, Uwadia HO, et al. A dual-pathway architecture for stress to disrupt agency and promote habit. Nature. 2025;640:722–31.

  229. Mathis A, Mamidanna P, Cury KM, Abe T, Murthy VN, Mathis MW, et al. DeepLabCut: markerless pose estimation of user-defined body parts with deep learning. Nat Neurosci. 2018;21:1281–89.

    Article  CAS  PubMed  Google Scholar 

  230. Parise EM, Gyles TM, Godino A, Sial OK, Browne CJ, Parise LF, et al. Sex-specific regulation of stress susceptibility by the astrocytic gene Htra1. bioRxiv [Preprint]. 2024. https://pubmed.ncbi.nlm.nih.gov/38659771/.

  231. Sardar D, Cheng Y-T, Woo J, Choi D-J, Lee Z-F, Kwon W, et al. Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation. Science. 2023;380:eade0027.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  232. Fulton SL, Bendl J, Di Salvo G, Fullard JF, Al-Kachak A, Lepack AE, et al. Major-depressive-disorder-associated dysregulation of ZBTB7A in orbitofrontal cortex promotes astrocyte-mediated stress susceptibility. Neuron. 2025 https://doi.org/10.1016/j.neuron.2025.05.023.

  233. Badimon A, Strasburger HJ, Ayata P, Chen X, Nair A, Ikegami A, et al. Negative feedback control of neuronal activity by microglia. Nature. 2020;586:417–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  234. Chan KL, Poller WC, Swirski FK, Russo SJ. Central regulation of stress-evoked peripheral immune responses. Nat Rev Neurosci. 2023;24:591–604.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Nicola Hawes, Carlos Torres-Berrío, and Jill Gregory at the Icahn School of Medicine at Mount Sinai for assistance with figure preparation.

Funding

This work was supported by grants from the National Institute of Mental Health (R01MH129306 to EJN and R01MH129643 to CJP), the Hope for Depression Research Foundation (to EJN), the Charles Hood Foundation (to ATB), and the New York Stem Cell Foundation (to CJP). CJP is a New York Stem Cell Foundation Robertson Investigator. ATB is supported by the Massachusetts General Hospital Lurie Center for Autism, Department of Pediatrics, and Center for Diversity and Inclusion.

Author information

Authors and Affiliations

  1. Lurie Center for Autism at Massachusetts General Hospital, Boston, MA, USA

    Angélica Torres-Berrío & Alessandro Bortolami

  2. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Angélica Torres-Berrío & Alessandro Bortolami

  3. Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA

    Catherine J. Peña

  4. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Eric J. Nestler

Authors
  1. Angélica Torres-Berrío
    View author publications

    Search author on:PubMed Google Scholar

  2. Alessandro Bortolami
    View author publications

    Search author on:PubMed Google Scholar

  3. Catherine J. Peña
    View author publications

    Search author on:PubMed Google Scholar

  4. Eric J. Nestler
    View author publications

    Search author on:PubMed Google Scholar

Contributions

ATB and EJN designed the review timeline. ATB, AB, CJP, and EJN wrote the manuscript. All authors discussed, commented on, and edited the paper.

Corresponding authors

Correspondence to Angélica Torres-Berrío or Eric J. Nestler.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torres-Berrío, A., Bortolami, A., Peña, C.J. et al. Neurobiology of resilience to early life stress. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02158-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41386-025-02158-4

This article is cited by

Search

Advanced search

Quick links