Early life adversity influences brain development through neuroendocrine, immune, and microbiota-related mechanisms: A review
References
- Alcantara-Alonso V, Amaya MI, Matamoros-Trejo G, de Gortari P. Altered functionality of the corticotrophin-releasing hormone receptor-2 in the hypothalamic paraventricular nucleus of hyperphagic maternally separated rats. Neuropeptides 63, 75–82, 2017.
- Alcantara-Alonso V, Garcia-Luna C, Soberanes-Chavez P, Estrada-Camarena E, de Gortari P. Two adverse early life events induce differential changes in brain CRH and serotonin systems in rats along with hyperphagia and depression. J Integr Neurosci 23, 41, 2024.
- Anza S, Heistermann M, Ostner J, Schulke O. Early prenatal but not postnatal glucocorticoid exposure is associated with enhanced HPA axis activity into adulthood in a wild primate. Proc Biol Sci 292, 20242418, 2025.
- Arnett MG, Pan MS, Doak W, Cyr PE, Muglia LM, Muglia LJ. The role of glucocorticoid receptor-dependent activity in the amygdala central nucleus and reversibility of early-life stress programmed behavior. Transl Psychiatry 5, e542, 2015.
- Aulinas A, Lawson EA. The oxytocin system and implications for oxytocin deficiency in hypothalamic-pituitary disease. Endocr Rev 46, 518–548, 2025.
- Azad MB, Lissitsyn Y, Miller GE, Becker AB, HayGlass KT, Kozyrskyj AL. Influence of socioeconomic status trajectories on innate immune responsiveness in children. PLoS One 7, e38669, 2012.
- Bakos J, Zatkova M, Bacova Z, Ostatnikova D. The role of hypothalamic neuropeptides in neurogenesis and neurito-genesis. Neural Plast 2016, 3276383, 2016.
- Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry 21, 642–649, 2016.
- Beurel E, Medina-Rodriguez EM, Jope RS. Targeting the adaptive immune system in depression: focus on T helper 17 cells. Pharmacol Rev 74, 373–386, 2022.
- Beurel E, Nemeroff CB. Early life adversity, microbiome, and inflammatory responses. Biomolecules 14, 802. 2024.
- Bilbo SD, Schwarz JM. The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33, 267–286, 2012.
- Birmaher B, Rabin BS, Garcia MR, Jain U, Whiteside TL, Williamson DE, al-Shabbout M, Nelson BC, Dahl RE, Ryan ND. Cellular immunity in depressed, conduct disorder, and normal adolescents: role of adverse life events. J Am Acad Child Adolesc Psychiatry, 33, 671–678, 1994.
- Bland ST, Beckley JT, Young S, Tsang V, Watkins LR, Maier SF, Bilbo SD. Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain. Brain Behav Immun 24, 329–338, 2010.
- Bonetti Bertagna N, Favoretto CA, Rodolpho BT, Righi T, Loss CM, Morais IBM, Vrechi TAM, Erustes AG, Pereira GJS, Miguel TT, Cruz FC. The impact of maternal separation stress on the CRFergic system in the extended amygdala and its relevance to acute stress-induced ethanol consumption in mice. Alcohol 130, 40–56, 2026.
- Bukatova S, Reichova A, Bacova Z, Bakos J. Neonatal oxytocin treatment alters levels of precursor and mature BDNF forms and modifies the expression of neuronal markers in the male rat hippocampus. Neuropeptides 102, 102384, 2023.
- Callaghan BL, Fields A, Gee DG, Gabard-Durnam L, Caldera C, Humphreys KL, Goff B, Flannery J, Telzer EH, Shapiro M, Tottenham N. Mind and gut: Associations between mood and gastrointestinal distress in children exposed to adversity. Dev Psychopathol 32, 309–328, 2020.
- Carlson AL, Xia K, Azcarate-Peril MA, Goldman BD, Ahn M, Styner MA, Thompson AL, Geng X, Gilmore JH, Knickmeyer RC. Infant gut microbiome associated with cognitive development. Biol Psychiatry 83, 148–159, 2018.
- Catale C, Carola V, Viscomi MT. Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research. Neural Regen Res 17, 1971–1972, 2022.
- Chen Y, Baram TZ. Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology 41, 197–206, 2016.
- Coley EJL, Mayer EA, Osadchiy V, Chen Z, Subramanyam V, Zhang Y, Hsiao EY, Gao K, Bhatt R, Dong T, Vora P, Naliboff B, Jacobs JP, Gupta A. Early life adversity predicts brain-gut alterations associated with increased stress and mood. Neurobiol Stress 15, 100348, 2021.
- Cong X, Henderson WA, Graf J, McGrath JM. Early life experience and gut microbiome: the brain-gut-microbiota signaling system. Adv Neonatal Care 15, 314–323, quiz E1-2, 2015.
- Counotte J, Drexhage HA, Wijkhuijs JM, Pot-Kolder R, Bergink V, Hoek HW, Veling W. Th17/T regulator cell balance and NK cell numbers in relation to psychosis liability and social stress reactivity. Brain Behav Immun 69, 408–417, 2018.
- Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O’Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG. The microbiota-gut-brain axis. Physiol Rev 99, 1877–2013, 2019.
- Cunningham K, Mengelkoch S, Gassen J, Hill SE. Early life adversity, inflammation, and immune function: An initial test of adaptive response models of immunological programming. Dev Psychopathol 34, 539–555, 2022. Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol 16, 461–478, 2019.
- de Almeida Magalhaes T, Correia D, de Carvalho LM, Damasceno S, Brunialti Godard AL. Maternal separation affects expression of stress response genes and increases vulnerability to ethanol consumption. Brain Behav 8, e00841, 2017.
- Derks NA, Krugers HJ, Hoogenraad CC, Joels M, Sarabdjitsingh RA. Effects of early life stress on synaptic plasticity in the developing hippocampus of male and female Rats. PLoS One 11, e0164551, 2016.
- Duffy KA, McLaughlin KA, Green PA. Early life adversity and health-risk behaviors: proposed psychological and neural mechanisms. Ann N Y Acad Sci, 1428, 151–169, 2018.
- Elwenspoek MMC, Hengesch X, Leenen FAD, Schritz A, Sias K, Schaan VK, Meriaux SB, Schmitz S, Bonnemberger F, Schachinger H, Vogele C, Turner JD, Muller CP. Proinflammatory T cell status associated with early life adversity. J Immunol 199, 4046–4055, 2017.
- Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, Schwierzeck V, Utermohlen O, Chun E, Garrett WS, McCoy KD, Diefenbach A, Staeheli P, Stecher B, Amit I, Prinz M. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18, 965–977, 2015.
- Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiol Stress 7, 124–136, 2017.
- Garay PA, McAllister AK. Novel roles for immune molecules in neural development: implications for neurodevelop-mental disorders. Front Synaptic Neurosci 2, 136, 2010.
- Garvin MM, Kar U, Kooiker CL, Bolton JL. Deletion of the microglial phagocytic receptor MerTK mimics early-life adversity-induced changes in synapses and behavior in male mice. Brain Behav Immun 133, 106246, 2026.
- Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, Green G, Dionne D, Nguyen L, Marshall JL, Chen F, Zhang F, Kaplan T, Regev A, Schwartz M. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat Neurosci 23, 701–706, 2020.
- Havranek T, Zatkova M, Lestanova Z, Bacova Z, Mravec B, Hodosy J, Strbak V, Bakos J. Intracerebroventricular oxytocin administration in rats enhances object recognition and increases expression of neurotrophins, microtubule-associated protein 2, and synapsin I. J Neurosci Res 93, 893–901, 2015.
- Herman JP, Cullinan WE. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20, 78–84, 1997.
- Hillerer KM, Reber SO, Neumann ID, Slattery DA. Exposure to chronic pregnancy stress reverses peripartum-associated adaptations: implications for postpartum anxiety and mood disorders. Endocrinology 152, 3930–3940, 2011.
- Howland MA, Sandman CA, Glynn LM. Developmental origins of the human hypothalamic-pituitary-adrenal axis. Expert Rev Endocrinol Metab 12, 321–339, 2017.
- Howland MA. Recalibration of the stress response system over adult development: Is there a perinatal recalibration period? Dev Psychopathol 35, 2315–2337, 2023.
- Jappy D, Sokolov R, Dobryakova Y, Krut V, Maltseva K, Fedulina A, Smirnov I, Rozov A. Early-life stress differentially affects CA3 synaptic inputs converging on apical and basal dendrites of CA1 pyramidal neurons. Front Neural Circuits 19, 1533791, 2025.
- Jezova D, Skultetyova I, Tokarev DI, Bakos P, Vigas M. Vasopressin and oxytocin in stress. Ann N Y Acad Sci, 771, 192–203, 1995.
- Jiang L, Xue L, Juruena MF. The impact of early life stress on the hypothalamic-pituitary-adrenal axis in unipolar major depression: A systematic review. Psychoneuroendocrinology 181, 107607, 2025.
- Jin Y, Song D, Yan Y, Quan Z, Qing H. The role of oxytocin in early-life-stress-related neuropsychiatric disorders. Int J Mol Sci 24, 10430, 2023.
- Jorgensen CC, Thone-Reineke C, Moscovice LR, Gimsa U. Critical biological systems linking early-life stress to later-life outcomes: A systematic review of animal models. Neurosci Biobehav Rev 179, 106425, 2025.
- Jurek B, Neumann ID. The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev 98, 1805–1908, 2018.
- Kar F, Hacioglu C, Kar E, Donmez DB, Kanbak G. Probiotics ameliorates LPS induced neuroinflammation injury on Aβ 1-42, APP, γ-β secretase and BDNF levels in maternal gut microbiota and fetal neurodevelopment processes. Metab Brain Dis 37, 1387–1399, 2022.
- Koss KJ, Gunnar MR. Annual Research Review: Early adversity, the hypothalamic-pituitary-adrenocortical axis, and child psychopathology. J Child Psychol Psychiatry 59, 327–346, 2018.
- Kuhlman KR, Horn SR, Chiang JJ, Bower JE. Early life adversity exposure and circulating markers of inflammation in children and adolescents: A systematic review and meta-analysis. Brain Behav Immun 86, 30–42, 2020.
- Lajud N, Roque A, Cajero M, Gutierrez-Ospina G, Torner L. Periodic maternal separation decreases hippocampal neurogenesis without affecting basal corticosterone during the stress hyporesponsive period, but alters HPA axis and coping behavior in adulthood. Psychoneuroendocrinology 37, 410–420, 2012.
- Levine S. Primary social relationships influence the development of the hypothalamic--pituitary--adrenal axis in the rat. Physiol Behav 73, 255–260, 2001.
- Li H, Li Y, Wang T, Li S, Liu H, Ning S, Shen W, Zhao Z, Wu H. Spatiotemporal mapping of the oxytocin receptor at single-cell resolution in the postnatally developing mouse brain. Neurosci Bull 41, 224–242, 2025.
- Li Y, Li T, Zhang Y, Wang Y, Wu G, Tan Y. Microbial metabolites in the gut-brain axis: their impact on depression pathophysiology and treatment. Neuroscience 593, 1–7, 2026.
- Liao XM, Yang XD, Jia J, Li JT, Xie XM, Su YA, Schmidt MV, Si TM, Wang XD. Blockade of corticotropin-releasing hormone receptor 1 attenuates early-life stress-induced synaptic abnormalities in the neonatal hippocampus. Hippocampus 24, 528–540, 2014.
- Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659–1662, 1997.
- Lukas M, Bredewold R, Neumann ID, Veenema AH. Maternal separation interferes with developmental changes in brain vasopressin and oxytocin receptor binding in male rats. Neuropharmacology 58,78–87, 2010.
- Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10, 434–445, 2009.
- Marlin BJ, Froemke RC. Oxytocin modulation of neural circuits for social behavior. Dev Neurobiol 77, 169–189, 2017. Meaney MJ, Szyf M. Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci 7, 103–123, 2005.
- Morais LH, Schreiber HL 4th, Mazmanian SK. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol 19, 241–255, 2021.
- Municchi D, Mancini C, Nutarelli S, Tiberi M, D’Addario SL, Chila G, Passeri A, Massa G, Di Segni M, Babicola L, Canterini S, Lo Iacono L, Cifani C, Cabib S, Renzi M, Chiurchiu V, Viscomi MT, Ventura R. The oxytocin system mediates behavioral and neurobiological alterations associated with early adversity. Mol Psychiatry 2025 Dec 28, Epub ahead of print.
- Nelson CA, Sullivan EF, Valdes V. Early adversity alters brain architecture and increases susceptibility to mental health disorders. Nat Rev Neurosci 26, 642–656, 2025.
- Onaka T, Takayanagi Y. The oxytocin system and early-life experience-dependent plastic changes. J Neuroendocrinol 33, e13049, 2021.
- O’Neill OS, Terstege DJ, Gill AK, Edge-Partington M, Ramkumar R, Epp JR, Sargin D. An open-source and highly adaptable rodent limited bedding and nesting apparatus for chronic early life stress. eNeuro 12, ENEURO.0081–25.2025, 2025.
- Pati D, Harden SW, Sheng W, Kelly KB, de Kloet AD, Krause EG, Frazier CJ. Endogenous oxytocin inhibits hypothalamic corticotrophin-releasing hormone neurones following acute hypernatraemia. J Neuroendocrinol 32, e12839, 2020.
- Quagliato LA, Nardi AE. Cytokine profile in drug-naive panic disorder patients. Transl Psychiatry 12, 75, 2022.
- Rokicki J, Kaufmann T, de Lange AG, van der Meer D, Bahrami S, Sartorius AM, Haukvik UK, Steen NE, Schwarz E, Stein DJ, Nærland T, Andreassen OA, Westlye LT, Quintana DS. Oxytocin receptor expression patterns in the human brain across development. Neuropsychopharmacology 47, 1550–1560, 2022.
- Roque A, Valles Mendez KM, Ruiz R, Pineda E, Lajud N. Early life stress induces a transient increase in hippocampal corticotropin-releasing hormone in rat neonates that precedes the effects on hypothalamic neuropeptides. Eur J Neurosci 55, 2108–2121, 2022.
- Schmidt MV. From “Gig” to Genes: The enduring legacy of Seymour Levine in developmental stress neurobiology. Neurobiol Stress 40, 100772, 2025.
- Schneider E, O’Riordan KJ, Clarke G, Cryan JF. Feeding gut microbes to nourish the brain: unravelling the diet-microbiota-gut-brain axis. Nat Metab 6, 1454–1478, 2024.
- Short AK, Maras PM, Pham AL, Ivy AS, Baram TZ. Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity. Neuropsychopharmacology 45, 515–523, 2020.
- Slopen N, Kubzansky LD, McLaughlin KA, Koenen KC. Childhood adversity and inflammatory processes in youth: a prospective study. Psychoneuroendocrinology 38, 188–200, 2013.
- Smith KE, Pollak SD. Early life stress and development: potential mechanisms for adverse outcomes. J Neurodev Disord 12, 34, 2020.
- Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature 440, 1054–1059, 2006.
- Stilling RM, van de Wouw M, Clarke G, Stanton C, Dinan TG, Cryan JF. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? Neurochem Int 99, 110–132, 2016.
- Sullivan O, Sie C, Ng KM, Cotton S, Rosete C, Hamden JE, Singh AP, Lee K, Choudhary J, Kim J, Yu H, Clayton CA, Carranza Garcia NA, Voznyuk K, Deng BD, Plett N, Arora S, Ghezzi H, Huan T, Soma KK, Yu JJ, Tropini C, Ciernia AV. Early-life gut inflammation drives sex-dependent shifts in the microbiome-endocrine-brain axis. Brain Behav Immun 125, 117–139, 2025.
- Surtees P, Wainwright N, Day N, Brayne C, Luben R, Khaw KT. Adverse experience in childhood as a developmental risk factor for altered immune status in adulthood. Int J Behav Med 10, 251–268, 2003.
- Taniguchi L, Goodpaster CM, Chen Y, de Carvalho GB, Birnie MT, Paul A, Chiang A, Chen LY, Baram TZ, DeNardo LA. Sex and stress govern the function and innervation of a basolateral amygdala to nucleus accumbens corticotropin-releasing hormone/GABA-expressing projection. J Neurosci 46, e1239252025, 2026.
- Taylor MA, Kokiko-Cochran ON. Context is key: glucocorticoid receptor and corticosteroid therapeutics in outcomes after traumatic brain injury. Front Cell Neurosci 18, 1351685, 2024.
- Varian BJ, Weber KT, Erdman SE. Oxytocin and the microbiome. Compr Psychoneuroendocrinol 16, 100205, 2023. Wang XD, Rammes G, Kraev I, Wolf M, Liebl C, Scharf SH, Rice CJ, Wurst W, Holsboer F, Deussing JM, Baram TZ,
- Stewart MG, Muller MB, Schmidt MV. Forebrain CRF₁ modulates early-life stress-programmed cognitive deficits. J Neurosci 31, 13625–13634, 2011.
- Wang XD, Labermaier C, Holsboer F, Wurst W, Deussing JM, Muller MB, Schmidt MV. Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1. Eur J Neurosci 36, 2360–2367, 2012.
- Wang XD, Su YA, Wagner KV, Avrabos C, Scharf SH, Hartmann J, Wolf M, Liebl C, Kuhne C, Wurst W, Holsboer F, Eder M, Deussing JM, Muller MB, Schmidt MV. Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nat Neurosci 16, 706–713, 2013.
- Wang Q, Yang Q, Liu X. The microbiota-gut-brain axis and neurodevelopmental disorders. Protein Cell 14, 762–775, 2023a.
- Wang T, Ma YN, Zhang CC, Liu X, Sun YX, Wang HL, Wang H, Zhong YH, Su YA, Li JT, Si TM. The nucleus accumbens CRH-CRHR1 system mediates early-life stress-induced sleep disturbance and dendritic atrophy in the adult mouse. Neurosci Bull 39, 41–56, 2023b.
- Wang J, Hou Y, Mu L, Yang M, Ai X. Gut microbiota contributes to the intestinal and extraintestinal immune homeostasis by balancing Th17/Treg cells. Int Immunopharmacol 143, 113570, 2024.
- Wang C, He T, Jie Qin J, Jiao J, Ji F. The roles of immune factors in neurodevelopment. Front Cell Neurosci 19, 1451889, 2025.
- Zhang Y, Wang S, Hei M. Maternal separation as early-life stress: Mechanisms of neuropsychiatric disorders and inspiration for neonatal care. Brain Res Bull 217, 111058, 2024.
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Published on: Jun 27, 2026
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© 2026 Peter Vargovic, Jana Osacka, Lubica Horvathova, Andrej Tillinger, Denisa Mihalj, Barbora Bugar Bodorova, Lila Dziewiczova, Tomas Havranek, Zuzana Bacova, Jan Bakos, published by Slovak Academy of Sciences, Institute of Experimental Endocrinology
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