{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:13:15Z","timestamp":1790295195207,"version":"4.1.0"},"reference-count":87,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"the Ningxia Hui Autonomous Region Natural Science Foundation","award":["2024AAC03727"],"award-info":[{"award-number":["2024AAC03727"]}]},{"name":"the Ningxia Hui Autonomous Region health system research project","award":["2024-NWZC-A010"],"award-info":[{"award-number":["2024-NWZC-A010"]}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82174251"],"award-info":[{"award-number":["82174251"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-27535-3","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T18:55:26Z","timestamp":1765479326000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The double-edged sword effect of adverse childhood experiences forging adult stress into depression and anxiety"],"prefix":"10.1038","volume":"15","author":[{"given":"Zihan","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqing","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaohan","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxin","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"27535_CR1","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/S2215-0366(21)00251-0","volume":"8","author":"J Lu","year":"2021","unstructured":"Lu, J. et al. Prevalence of depressive disorders and treatment in china: a cross-sectional epidemiological study. Lancet Psychiatry. 8, 981\u2013990 (2021).","journal-title":"Lancet Psychiatry"},{"key":"27535_CR2","doi-asserted-by":"publisher","first-page":"4460","DOI":"10.1007\/s12325-023-02622-x","volume":"40","author":"P Greenberg","year":"2023","unstructured":"Greenberg, P. et al. The economic burden of adults with major depressive disorder in the united States (2019). Adv. Ther. 40, 4460\u20134479 (2023).","journal-title":"Adv. Ther."},{"key":"27535_CR3","doi-asserted-by":"publisher","first-page":"e140","DOI":"10.1017\/S0033291725001102","volume":"55","author":"JD O\u2019Shields","year":"2025","unstructured":"O\u2019Shields, J. D., Slavich, G. M. & Mowbray, O. Adverse childhood experiences, inflammation, and depression: evidence of sex- and stressor specific effects in a nationally representative longitudinal sample of U.S. adolescents. Psychol. Med. 55, e140 (2025).","journal-title":"Psychol. Med."},{"key":"27535_CR4","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.tins.2020.02.004","volume":"43","author":"KG Bath","year":"2020","unstructured":"Bath, K. G. Synthesizing views to understand sex differences in response to early life adversity. Trends Neurosci. 43, 300\u2013310 (2020).","journal-title":"Trends Neurosci."},{"key":"27535_CR5","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/S0749-3797(98)00017-8","volume":"14","author":"VJ Felitti","year":"1998","unstructured":"Felitti, V. J. 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. 14, 245\u2013258 (1998).","journal-title":"Am. J. Prev. Med."},{"key":"27535_CR6","doi-asserted-by":"publisher","first-page":"e232","DOI":"10.1542\/peds.2011-2663","volume":"129","author":"JP Shonkoff","year":"2012","unstructured":"Shonkoff, J. P. et al. The lifelong effects of early childhood adversity and toxic stress. Pediatrics129 129, e232-246 (2012).","journal-title":"Pediatrics129"},{"key":"27535_CR7","doi-asserted-by":"publisher","first-page":"106062","DOI":"10.1016\/j.neubiorev.2025.106062","volume":"171","author":"LH Dosanjh","year":"2025","unstructured":"Dosanjh, L. H. et al. Five hypothesized biological mechanisms linking adverse childhood experiences with anxiety, depression, and PTSD: a scoping review. Neurosci. Biobehav Rev. 171, 106062 (2025).","journal-title":"Neurosci. Biobehav Rev."},{"key":"27535_CR8","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jad.2024.11.082","volume":"372","author":"X Li","year":"2025","unstructured":"Li, X. et al. Association between adverse experiences and longitudinal allostatic load changes with depression symptom trajectories in middle-aged and older adults in China. J. Affect. Disord. 372, 377\u2013385 (2025).","journal-title":"J. Affect. Disord"},{"key":"27535_CR9","doi-asserted-by":"publisher","first-page":"104605","DOI":"10.1016\/j.neubiorev.2022.104605","volume":"136","author":"S Finlay","year":"2022","unstructured":"Finlay, S. et al. Adverse childhood experiences and allostatic load: a systematic review. Neurosci. Biobehav Rev. 136, 104605 (2022).","journal-title":"Neurosci. Biobehav Rev."},{"key":"27535_CR10","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/s41398-023-02464-9","volume":"13","author":"SM Szymkowicz","year":"2023","unstructured":"Szymkowicz, S. M. et al. Biological factors influencing depression in later life: role of aging processes and treatment implications. Transl Psychiatry13 13, 160 (2023).","journal-title":"Transl Psychiatry13"},{"key":"27535_CR11","doi-asserted-by":"publisher","first-page":"101071","DOI":"10.1016\/j.ssmph.2022.101071","volume":"17","author":"ET Klopack","year":"2022","unstructured":"Klopack, E. T. et al. Accelerated epigenetic aging mediates link between adverse childhood experiences and depressive symptoms in older adults: results from the Health and Retirement Study. SSM Popul. Health17 17, 101071 (2022).","journal-title":"SSM Popul. Health17"},{"key":"27535_CR12","doi-asserted-by":"crossref","unstructured":"Birnie, M. T. & Baram, T. Z. The Evolving Neurobiology of early-life Stress,\u00a0Neuron,\u00a0Vol. 113, 1474\u20131490 (2025).","DOI":"10.1016\/j.neuron.2025.02.016"},{"key":"27535_CR13","doi-asserted-by":"publisher","first-page":"102","DOI":"10.3389\/fphar.2020.00102","volume":"11","author":"Y Cui","year":"2020","unstructured":"Cui, Y. et al. Early-life stress induces depression-like behavior and synaptic-plasticity changes in a maternal separation rat model: gender difference and metabolomics study. Front. Pharmacol. 11, 102 (2020).","journal-title":"Front. Pharmacol."},{"key":"27535_CR14","doi-asserted-by":"crossref","unstructured":"Cao, P. et al. Early-life Inflammation Promotes Depressive Symptoms in Adolescence Via Microglial Engulfment of Dendritic Spines,\u00a0Neuron,\u00a0Vol. 109, 2573\u20132589 (2021).","DOI":"10.1016\/j.neuron.2021.06.012"},{"key":"27535_CR15","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1002\/hipo.22302","volume":"24","author":"RA Hill","year":"2014","unstructured":"Hill, R. A. et al. Sex-specific disruptions in spatial memory and anhedonia in a \u2018two hit\u2019 rat model correspond with alterations in hippocampal brain-derived neurotrophic factor expression and signaling. Hippocampus 24, 1197\u20131211 (2014).","journal-title":"Hippocampus"},{"key":"27535_CR16","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1007\/s00213-025-06811-0","volume":"242","author":"Y Chen","year":"2025","unstructured":"Chen, Y. et al. Early maternal separation potentiates the impact of later social isolation in inducing depressive-like behavior via oxidative stress in adult rats. Psychopharmacology 242, 2503 (2025).","journal-title":"Psychopharmacology"},{"key":"27535_CR17","doi-asserted-by":"publisher","first-page":"135381","DOI":"10.1016\/j.neulet.2020.135381","volume":"738","author":"KR Gildawie","year":"2020","unstructured":"Gildawie, K. R. et al. Sex differences in prefrontal cortex microglia morphology: impact of a two-hit model of adversity throughout development. Neurosci. Lett. 738, 135381 (2020).","journal-title":"Neurosci. Lett."},{"key":"27535_CR18","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1093\/ilar\/ilu030","volume":"55","author":"JM Worlein","year":"2014","unstructured":"Worlein, J. M. Nonhuman primate models of depression: effects of early experience and stress. ILAR J. 55, 259\u2013273 (2014).","journal-title":"ILAR J."},{"key":"27535_CR19","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1038\/mp.2016.118","volume":"22","author":"JS Seo","year":"2017","unstructured":"Seo, J. S. et al. Cellular and molecular basis for stress-induced depression. Mol. Psychiatry. 22, 1440\u20131447 (2017).","journal-title":"Mol. Psychiatry"},{"key":"27535_CR20","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1007\/s00213-016-4218-9","volume":"233","author":"MA Calcia","year":"2016","unstructured":"Calcia, M. A. et al. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology 233, 1637\u20131650 (2016).","journal-title":"Psychopharmacology"},{"key":"27535_CR21","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1007\/s12031-016-0746-3","volume":"59","author":"C Monpays","year":"2016","unstructured":"Monpays, C. et al. Mitochondrial dysfunction in schizophrenia: determination of mitochondrial respiratory activity in a two-hit mouse model. J. Mol. Neurosci. 59, 440\u2013451 (2016).","journal-title":"J. Mol. Neurosci."},{"key":"27535_CR22","doi-asserted-by":"publisher","first-page":"114563","DOI":"10.1016\/j.bbr.2023.114563","volume":"452","author":"S Deng","year":"2023","unstructured":"Deng, S. et al. Early-life stress contributes to depression-like behaviors in a two-hit mouse model. Behav. Brain Res. 452, 114563 (2023).","journal-title":"Behav. Brain Res."},{"key":"27535_CR23","doi-asserted-by":"publisher","first-page":"e3000411","DOI":"10.1371\/journal.pbio.3000411","volume":"18","author":"Percie du Sert","year":"2020","unstructured":"Percie du Sert. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 18, e3000411 (2020).","journal-title":"PLoS Biol."},{"key":"27535_CR24","unstructured":"National Research Council. Guide for the Care and Use of Laboratory (Animals National Academies, 1996)."},{"key":"27535_CR25","doi-asserted-by":"publisher","first-page":"3903","DOI":"10.3748\/wjg.v28.i29.3903","volume":"28","author":"G Mallaret","year":"2022","unstructured":"Mallaret, G. et al. Involvement of toll-like receptor 5 in mouse model of colonic hypersensitivity induced by neonatal maternal separation. World J. Gastroenterol. 28, 3903\u20133916 (2022).","journal-title":"World J. Gastroenterol."},{"key":"27535_CR26","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1080\/10253890.2017.1389883","volume":"21","author":"R Orso","year":"2018","unstructured":"Orso, R. et al. Maternal behavior of the mouse dam toward pups: implications for maternal separation model of early life stress. Stress 21, 19\u201327 (2018).","journal-title":"Stress"},{"key":"27535_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19490976.2020.1869501","volume":"13","author":"Y Deng","year":"2021","unstructured":"Deng, Y. et al. Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain. Gut Microbes. 13, 1\u201316 (2021).","journal-title":"Gut Microbes"},{"key":"27535_CR28","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1038\/s41596-018-0011-z","volume":"13","author":"MY Liu","year":"2018","unstructured":"Liu, M. Y. et al. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat. Protoc. 13, 1686\u20131698 (2018).","journal-title":"Nat. Protoc."},{"key":"27535_CR29","doi-asserted-by":"publisher","first-page":"105666","DOI":"10.1016\/j.yrtph.2024.105666","volume":"151","author":"ER Trunnell","year":"2024","unstructured":"Trunnell, E. R. et al. The need for guidance in antidepressant drug development: revisiting the role of the forced swim test and tail suspension test. Regul. Toxicol. Pharmacol. 151, 105666 (2024).","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"27535_CR30","doi-asserted-by":"publisher","first-page":"4827","DOI":"10.3390\/ijms20194827","volume":"20","author":"Y Hao","year":"2019","unstructured":"Hao, Y., Ge, H., Sun, M. & Gao, Y. Selecting an appropriate animal model of depression. Int. J. Mol. Sci. 20, 4827 (2019).","journal-title":"Int. J. Mol. Sci."},{"key":"27535_CR31","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fnbeh.2017.00013","volume":"11","author":"LB Tucker","year":"2017","unstructured":"Tucker, L. B. & McCabe, J. T. Behavior of male and female C57BL\/6J mice is more consistent with repeated trials in the elevated zero maze than in the elevated plus maze. Front. Behav. Neurosci. 11, 13 (2017).","journal-title":"Front. Behav. Neurosci."},{"key":"27535_CR32","unstructured":"Leary, S. et al. AVMA Guidelines for the Euthanasia of Animals: 2020 (Edition American Veterinary Medical Association, 2020)."},{"key":"27535_CR33","doi-asserted-by":"publisher","first-page":"116288","DOI":"10.1016\/j.jep.2023.116288","volume":"308","author":"YX Guo","year":"2023","unstructured":"Guo, Y. X. et al. Loganin improves chronic unpredictable mild stress-induced depressive-like behaviors and neurochemical dysfunction. J. Ethnopharmacol. 308, 116288 (2023).","journal-title":"J. Ethnopharmacol."},{"key":"27535_CR34","doi-asserted-by":"publisher","first-page":"S95","DOI":"10.1093\/schbul\/sbad130","volume":"51","author":"N Barrantes-Vidal","year":"2025","unstructured":"Barrantes-Vidal, N. et al. Genetic susceptibility to the environment moderates the impact of childhood experiences on psychotic, depressive, and anxiety dimensions. Schizophr Bull. 51, S95\u2013S106 (2025).","journal-title":"Schizophr Bull."},{"key":"27535_CR35","doi-asserted-by":"publisher","first-page":"114530","DOI":"10.1016\/j.physbeh.2024.114530","volume":"279","author":"Y Zhang","year":"2024","unstructured":"Zhang, Y. et al. Maternal separation regulates sensitivity of stress-induced depression in mice by affecting hippocampal metabolism. Physiol. Behav. 279, 114530 (2024).","journal-title":"Physiol. Behav."},{"key":"27535_CR36","doi-asserted-by":"publisher","first-page":"3000","DOI":"10.1073\/pnas.0506571103","volume":"103","author":"KJ Parker","year":"2006","unstructured":"Parker, K. J., Buckmaster, C. L., Sundlass, K., Schatzberg, A. F. & Lyons, D. M. Maternal mediation, stress inoculation, and the development of neuroendocrine stress resistance in primates. Proc. Natl. Acad. Sci. U.S.A 103, 3000\u20133005 (2006).","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"27535_CR37","doi-asserted-by":"publisher","first-page":"825522","DOI":"10.3389\/fphar.2022.825522","volume":"13","author":"C Calpe-L\u00f3pez","year":"2022","unstructured":"Calpe-L\u00f3pez, C. et al. Brief maternal separation inoculates against the effects of social stress on depression-like behavior and cocaine reward in mice. Front. Pharmacol. 13, 825522 (2022).","journal-title":"Front. Pharmacol."},{"key":"27535_CR38","doi-asserted-by":"publisher","first-page":"114280","DOI":"10.1016\/j.bbr.2022.114280","volume":"441","author":"OS Cevik","year":"2023","unstructured":"Cevik, O. S. et al. Maternal separation increased memory function and anxiety without effects of environmental enrichment in male rats. Behav. Brain Res. 441, 114280 (2023).","journal-title":"Behav. Brain Res."},{"key":"27535_CR39","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.bbi.2024.08.009","volume":"122","author":"R Ding","year":"2024","unstructured":"Ding, R. et al. Lateral Habenula IL\u201310 controls GABAA receptor trafficking and modulates depression susceptibility after maternal separation. Brain Behav. Immun. 122, 122\u2013136 (2024).","journal-title":"Brain Behav. Immun."},{"key":"27535_CR40","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1146\/annurev.clinpsy.1.102803.144141","volume":"1","author":"N Schneiderman","year":"2005","unstructured":"Schneiderman, N., Ironson, G. & Siegel, S. D. Stress and health: psychological, behavioral, and biological determinants. Annu. Rev. Clin. Psychol. 1, 607\u2013628 (2005).","journal-title":"Annu. Rev. Clin. Psychol."},{"key":"27535_CR41","doi-asserted-by":"publisher","first-page":"7296","DOI":"10.1038\/s41380-021-01293-w","volume":"26","author":"DD Shi","year":"2021","unstructured":"Shi, D. D. et al. Predictable maternal separation confers adult stress resilience via the medial prefrontal cortex Oxytocin signaling pathway in rats. Mol. Psychiatry. 26, 7296\u20137307 (2021).","journal-title":"Mol. Psychiatry"},{"key":"27535_CR42","doi-asserted-by":"publisher","first-page":"848251","DOI":"10.3389\/fphar.2022.848251","volume":"13","author":"P Meng","year":"2022","unstructured":"Meng, P. et al. Epigenetic mechanism of 5-HT\/NE\/DA triple reuptake inhibitor on adult depression susceptibility in early stress mice. Front. Pharmacol. 13, 848251 (2022).","journal-title":"Front. Pharmacol."},{"key":"27535_CR43","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.3390\/ph15101203","volume":"15","author":"Y Jiang","year":"2022","unstructured":"Jiang, Y. et al. Monoamine neurotransmitters control basic emotions and affect major depressive disorders. Pharmaceuticals 15, 1203 (2022).","journal-title":"Pharmaceuticals"},{"key":"27535_CR44","doi-asserted-by":"publisher","first-page":"117891","DOI":"10.1016\/j.jep.2024.117891","volume":"325","author":"N Jiang","year":"2024","unstructured":"Jiang, N. et al. Antidepressant effects of parishin C in chronic social defeat stress-induced depressive mice. J. Ethnopharmacol. 325, 117891 (2024).","journal-title":"J. Ethnopharmacol."},{"key":"27535_CR45","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1177\/0269881115609072","volume":"30","author":"S K\u00f6hler","year":"2016","unstructured":"K\u00f6hler, S. et al. The serotonergic system in the neurobiology of depression: relevance for novel antidepressants. J. Psychopharmacol. 30, 13\u201322 (2016).","journal-title":"J. Psychopharmacol."},{"key":"27535_CR46","doi-asserted-by":"publisher","first-page":"2201","DOI":"10.3389\/fpsyg.2018.02201","volume":"9","author":"Y Liu","year":"2018","unstructured":"Liu, Y., Zhao, J. & Guo, W. Emotional roles of monoaminergic neurotransmitters in major depressive disorder and anxiety disorders. Front. Psychol. 9, 2201 (2018).","journal-title":"Front. Psychol."},{"key":"27535_CR47","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1002\/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2-4","volume":"Anxiety12","author":"KJ Ressler","year":"2000","unstructured":"Ressler, K. J. & Nemeroff, C. B. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety12, 2\u201319 (2000).","journal-title":"Depress"},{"key":"27535_CR48","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1111\/nyas.13140","volume":"1394","author":"S Kim","year":"2017","unstructured":"Kim, S. et al. Early adverse experience and substance addiction: dopamine, oxytocin, and glucocorticoid pathways. Ann. N Y Acad. Sci. 1394, 74\u201391 (2017).","journal-title":"Ann. N Y Acad. Sci."},{"key":"27535_CR49","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41398-022-02092-9","volume":"12","author":"L Malave","year":"2022","unstructured":"Malave, L., van Dijk, M. T. & Anacker, C. Early life adversity shapes neural circuit function during sensitive postnatal developmental periods. Transl. Psychiatry 12, 306 (2022).","journal-title":"Transl. Psychiatry"},{"key":"27535_CR50","doi-asserted-by":"publisher","first-page":"105832","DOI":"10.1016\/j.neubiorev.2024.105832","volume":"164","author":"M Sheppard","year":"2024","unstructured":"Sheppard, M. et al. Noradrenergic alterations associated with early life stress. Neurosci. Biobehav Rev. 164, 105832 (2024).","journal-title":"Neurosci. Biobehav Rev."},{"key":"27535_CR51","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/nrn2632","volume":"10","author":"M Jo\u00ebls","year":"2009","unstructured":"Jo\u00ebls, M. & Baram, T. Z. The neuro-symphony of stress. Nat. Rev. Neurosci. 10, 459\u2013466 (2009).","journal-title":"Nat. Rev. Neurosci."},{"key":"27535_CR52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00441-003-0807-0","volume":"315","author":"G Fl\u00fcgge","year":"2004","unstructured":"Fl\u00fcgge, G., Van Kampen, M. & Mijnster, M. J. Perturbations in brain monoamine systems during stress. Cell. Tissue Res. 315, 1\u201314 (2004).","journal-title":"Cell. Tissue Res."},{"key":"27535_CR53","doi-asserted-by":"publisher","first-page":"104858","DOI":"10.1016\/j.neuint.2020.104858","volume":"141","author":"SJ Tripathi","year":"2020","unstructured":"Tripathi, S. J., Chakraborty, S. & Rao, B. S. S. Remediation of chronic immobilization stress-induced negative affective behaviors and altered metabolism of monoamines in the prefrontal cortex by inactivation of basolateral amygdala. Neurochem Int. 141, 104858 (2020).","journal-title":"Neurochem Int."},{"key":"27535_CR54","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/7854_2016_42","volume":"38","author":"MR VanTieghem","year":"2018","unstructured":"VanTieghem, M. R. & Tottenham, N. Neurobiological programming of early life stress: functional development of amygdala-prefrontal circuitry and vulnerability for stress-related psychopathology. Curr. Top. Behav. Neurosci. 38, 117\u2013136 (2018).","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"27535_CR55","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s00401-013-1223-5","volume":"127","author":"PJ Lucassen","year":"2024","unstructured":"Lucassen, P. J. et al. Neuropathology of stress. Acta Neuropathol. 127, 109\u2013135 (2024).","journal-title":"Acta Neuropathol."},{"key":"27535_CR56","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.brainres.2011.12.049","volume":"1476","author":"F Mora","year":"2012","unstructured":"Mora, F. et al. Stress, neurotransmitters, corticosterone and body-brain integration. Brain Res. 1476, 71\u201385 (2012).","journal-title":"Brain Res."},{"key":"27535_CR57","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1016\/j.pnpbp.2005.08.006","volume":"Psychiatry29","author":"JP Herman","year":"2005","unstructured":"Herman, J. P., Ostrander, M. M., Mueller, N. K. & Figueiredo, H. Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol. Biol. Psychiatry29, 1201\u20131213 (2005).","journal-title":"Prog Neuropsychopharmacol. Biol."},{"key":"27535_CR58","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1017\/S0954579418000512","volume":"30","author":"JC Thomas","year":"2018","unstructured":"Thomas, J. C. et al. Social buffering of the maternal and infant HPA axes: mediation and moderation in the intergenerational transmission of adverse childhood experiences. Dev. Psychopathol. 30, 921\u2013939 (2018).","journal-title":"Dev. Psychopathol."},{"key":"27535_CR59","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1017\/S0954579419001779","volume":"33","author":"ES Young","year":"2021","unstructured":"Young, E. S. et al. Life stress and cortisol reactivity: an exploratory analysis of the effects of stress exposure across life on HPA-axis functioning. Dev. Psychopathol. 33, 301\u2013312 (2021).","journal-title":"Dev. Psychopathol."},{"key":"27535_CR60","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/s41392-024-01738-y","volume":"9","author":"L Cui","year":"2024","unstructured":"Cui, L. et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal. Transduct. Target. Ther. 9, 30 (2024).","journal-title":"Signal. Transduct. Target. Ther."},{"key":"27535_CR61","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1002\/j.2040-4603.2016.tb00694.x","volume":"6","author":"JP Herman","year":"2016","unstructured":"Herman, J. P. et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr. Physiol. 6, 603\u2013621 (2016).","journal-title":"Compr. Physiol."},{"key":"27535_CR62","doi-asserted-by":"publisher","first-page":"136037","DOI":"10.1016\/j.neulet.2021.136037","volume":"759","author":"MF Juruena","year":"2021","unstructured":"Juruena, M. F., Bourne, M., Young, A. H. & Cleare, A. J. Hypothalamic\u2013pituitary\u2013adrenal axis dysfunction by early life stress. Neurosci. Lett. 759, 136037 (2021).","journal-title":"Neurosci. Lett."},{"key":"27535_CR63","doi-asserted-by":"publisher","first-page":"3807","DOI":"10.1038\/s41380-022-01540-8","volume":"27","author":"J Lu","year":"2022","unstructured":"Lu, J. et al. An entorhinal-visual cortical circuit regulates depression-like behaviors. Mol. Psychiatry. 27, 3807\u20133820 (2022).","journal-title":"Mol. Psychiatry"},{"key":"27535_CR64","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.pneurobio.2011.01.006","volume":"93","author":"MR Bennett","year":"2011","unstructured":"Bennett, M. R. The prefrontal-limbic network in depression: modulation by hypothalamus, basal ganglia and midbrain. Prog Neurobiol. 93, 468\u2013487 (2011).","journal-title":"Prog Neurobiol."},{"key":"27535_CR65","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s10548-023-00955-y","volume":"36","author":"A Kamali","year":"2023","unstructured":"Kamali, A. et al. The Cortico-Limbo-Thalamo-Cortical circuits: an update to the original Papez circuit of the human limbic system. Brain Topogr. 36, 371\u2013389 (2023).","journal-title":"Brain Topogr"},{"key":"27535_CR66","doi-asserted-by":"publisher","first-page":"136464","DOI":"10.1016\/j.neulet.2022.136464","volume":"771","author":"DRC F\u00f3scolo","year":"2022","unstructured":"F\u00f3scolo, D. R. C. et al. Early maternal separation alters the activation of stress-responsive brain areas in adulthood. Neurosci. Lett. 771, 136464 (2022).","journal-title":"Neurosci. Lett."},{"key":"27535_CR67","doi-asserted-by":"publisher","first-page":"10594","DOI":"10.1523\/JNEUROSCI.2542-04.2004","volume":"24","author":"LI Perrotti","year":"2004","unstructured":"Perrotti, L. I. et al. Induction of DeltaFosB in reward-related brain structures after chronic stress. J. Neurosci. 24, 10594\u201310602 (2004).","journal-title":"J. Neurosci."},{"key":"27535_CR68","doi-asserted-by":"publisher","first-page":"114277","DOI":"10.1016\/j.celrep.2024.114277","volume":"43","author":"S Peng","year":"2024","unstructured":"Peng, S. et al. Dual circuits originating from the ventral hippocampus independently facilitate affective empathy. Cell. Rep. 43, 114277 (2024).","journal-title":"Cell. Rep."},{"key":"27535_CR69","doi-asserted-by":"publisher","first-page":"3650","DOI":"10.1016\/j.neuron.2023.08.008","volume":"111","author":"K Wu","year":"2023","unstructured":"Wu, K. et al. Distinct circuits in anterior cingulate cortex encode safety assessment and mediate flexibility of fear reactions. Neuron 111, 3650\u20133667 (2023).","journal-title":"Neuron"},{"key":"27535_CR70","doi-asserted-by":"publisher","first-page":"7212","DOI":"10.3390\/ijms21197212","volume":"21","author":"M Nishi","year":"2020","unstructured":"Nishi, M. Effects of early-life stress on the brain and behaviors: implications of early maternal separation in rodents. Int. J. Mol. Sci. 21, 7212 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"27535_CR71","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.ibneur.2022.05.003","volume":"12","author":"PJ Hunt","year":"2022","unstructured":"Hunt, P. J. et al. Cotransmitting neurons in the lateral septal nucleus exhibit features of neurotransmitter switching. IBRO Neurosci. Rep. 12, 390\u2013398 (2022).","journal-title":"IBRO Neurosci. Rep."},{"key":"27535_CR72","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.biopsych.2014.07.007","volume":"79","author":"M Engeln","year":"2016","unstructured":"Engeln, M. et al. Selective inactivation of striatal FosB\/\u2206FosB-expressing neurons alleviates L-DOPA-induced dyskinesia. Biol. Psychiatry. 79, 354\u2013361 (2016).","journal-title":"Biol. Psychiatry"},{"key":"27535_CR73","doi-asserted-by":"publisher","first-page":"R1095","DOI":"10.1152\/ajpregu.2001.280.4.R1095","volume":"280","author":"E Moellenhoff","year":"2001","unstructured":"Moellenhoff, E. et al. Effect of repetitive Icv injections of ANG II on c-Fos and AT(1)-receptor expression in the rat brain. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R1095\u20131104 (2001).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"27535_CR74","doi-asserted-by":"publisher","first-page":"287","DOI":"10.21307\/ane-2018-027","volume":"78","author":"J Jaworski","year":"2018","unstructured":"Jaworski, J., Kalita, K. & Knapska, E. c-Fos and neuronal plasticity: the aftermath of kaczmarek\u2019s theory. Acta Neurobiol. Exp. 78, 287\u2013296 (2018).","journal-title":"Acta Neurobiol. Exp."},{"key":"27535_CR75","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.biopsych.2011.04.021","volume":"70","author":"YN Ohnishi","year":"2011","unstructured":"Ohnishi, Y. N. et al. FosB is essential for the enhancement of stress tolerance and antagonizes locomotor sensitization by \u2206FosB. Biol. Psychiatry. 70, 487\u2013495 (2011).","journal-title":"Biol. Psychiatry"},{"key":"27535_CR76","doi-asserted-by":"publisher","first-page":"109367","DOI":"10.1016\/j.neuropharm.2022.109367","volume":"224","author":"S Trask","year":"2023","unstructured":"Trask, S., Kuczajda, M. T. & Ferrara, N. C. The lifetime impact of stress on fear regulation and cortical function. Neuropharmacology 224, 109367 (2023).","journal-title":"Neuropharmacology"},{"key":"27535_CR77","doi-asserted-by":"publisher","first-page":"100711","DOI":"10.1016\/j.bbih.2023.100711","volume":"35","author":"KR Kuhlman","year":"2023","unstructured":"Kuhlman, K. R. Pitfalls and potential: translating the two-hit model of early life stress from preclinical nonhuman experiments to human samples. Brain Behav. Immun. Health. 35, 100711 (2023).","journal-title":"Brain Behav. Immun. Health"},{"key":"27535_CR78","doi-asserted-by":"publisher","first-page":"74","DOI":"10.3389\/fnmol.2019.00074","volume":"12","author":"I Jaric","year":"2019","unstructured":"Jaric, I. et al. Sex and estrous cycle effects on anxiety- and depression-related phenotypes in a two-hit developmental stress model. Front. Mol. Neurosci. 12, 74 (2019).","journal-title":"Front. Mol. Neurosci."},{"key":"27535_CR79","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1001\/jamapediatrics.2024.4385","volume":"179","author":"S Madigan","year":"2025","unstructured":"Madigan, S. et al. Prevalence of adverse childhood experiences in child population samples: a systematic review and meta-analysis. JAMA Pediatr. 179, 19\u201333 (2025).","journal-title":"JAMA Pediatr."},{"key":"27535_CR80","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1007\/s00787-021-01745-2","volume":"31","author":"BW Sahle","year":"2022","unstructured":"Sahle, B. W. et al. The association between adverse childhood experiences and common mental disorders and suicidality: an umbrella review of systematic reviews and meta-analyses. Eur. Child. Adolesc. Psychiatry. 31, 1489\u20131499 (2022).","journal-title":"Eur. Child. Adolesc. Psychiatry"},{"key":"27535_CR81","doi-asserted-by":"publisher","first-page":"e2130143","DOI":"10.1001\/jamanetworkopen.2021.30143","volume":"4","author":"L Lin","year":"2021","unstructured":"Lin, L. et al. Adverse childhood experiences and subsequent chronic diseases among middle-aged or older adults in China and associations with demographic and socioeconomic characteristics. JAMA Netw. 4, e2130143 (2021).","journal-title":"JAMA Netw."},{"key":"27535_CR82","doi-asserted-by":"publisher","first-page":"e2346323","DOI":"10.1001\/jamanetworkopen.2023.46323","volume":"6","author":"C Peterson","year":"2023","unstructured":"Peterson, C. et al. Economic burden of health conditions associated with adverse childhood experiences among US adults. JAMA Netw. 6, e2346323 (2023).","journal-title":"JAMA Netw."},{"key":"27535_CR83","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1038\/s41380-024-02845-6","volume":"30","author":"YN Ma","year":"2025","unstructured":"Ma, Y. N. et al. Prefrontal parvalbumin interneurons mediate CRHR1-dependent early-life stress-induced cognitive deficits in adolescent male mice. Mol. Psychiatry. 30, 2407\u20132426 (2025).","journal-title":"Mol. Psychiatry"},{"key":"27535_CR84","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.brainres.2015.11.018","volume":"1631","author":"YW Liu","year":"2016","unstructured":"Liu, Y. W. et al. Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and na\u00efve adult mice. Brain Res. 1631, 1\u201312 (2016).","journal-title":"Brain Res."},{"key":"27535_CR85","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/s41380-019-0551-9","volume":"25","author":"NE Holz","year":"2020","unstructured":"Holz, N. E., Tost, H. & Meyer-Lindenberg, A. Resilience and the brain: a key role for regulatory circuits linked to social stress and support. Mol. Psychiatry. 25, 379\u2013396 (2020).","journal-title":"Mol. Psychiatry"},{"key":"27535_CR86","doi-asserted-by":"publisher","first-page":"3245","DOI":"10.1038\/s41380-024-02556-y","volume":"29","author":"N Vaidya","year":"2024","unstructured":"Vaidya, N. et al. The impact of psychosocial adversity on brain and behavior: an overview of existing knowledge and directions for future research. Mol. Psychiatry. 29, 3245\u20133267 (2024).","journal-title":"Mol. Psychiatry"},{"key":"27535_CR87","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1038\/s41591-023-02426-0","volume":"29","author":"ZA Bhutta","year":"2023","unstructured":"Bhutta, Z. A. et al. Adverse childhood experiences and lifelong health. Nat. Med. 29, 1639\u20131648 (2023).","journal-title":"Nat. Med."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-27535-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-27535-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-27535-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T20:01:36Z","timestamp":1765483296000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-27535-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,11]]},"references-count":87,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["27535"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-27535-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,11]]},"assertion":[{"value":"29 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"43632"}}