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Early life stress (ELS), which includes factors such as inadequate parental care and childhood abuse, significantly increases the risk of developing neuropsychiatric disorders, including anxiety and depression. This review examines the impact of maternal separation (MS) on depression, anxiety and pain behaviour, with a particular emphasis on neuroinflammatory pathways. Experiences of ELS can adversely affect the maturation of neurotransmitter systems and associated neural circuits that are crucial for processing painful stimuli and regulating anxiety and depression. Stressful experiences trigger inflammatory processes in the brain, initiating immune responses in neural cells and stimulating the production of pro\u2010inflammatory cytokines. In mammals, MS serves as a significant stressor that activates the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis and other stress\u2010related systems, leading to increased immune challenges and heightened pain sensitivity in adulthood due to systemic inflammation. Key inflammatory mediators, such as IL\u20101\u03b2, IL\u20106 and TNF\u2010\u03b1, play critical roles in the development of pathological pain, while the activation of microglia releases inflammatory mediators that contribute to neurological dysfunction and the pathophysiology of stress, depression and anxiety. Moreover, therapeutics targeting oxidative stress and inflammation have shown promise in alleviating affective disorders following MS. This review discusses potential pathways, with a primary focus on neuroinflammatory mechanisms and the therapeutic strategies that may mitigate the adverse effects of MS. There is a pressing need for further research to elucidate the underlying pathways and identify effective interventions to improve mental health outcomes in individuals affected by MS.<\/jats:p>","DOI":"10.1002\/jdn.70002","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T09:34:12Z","timestamp":1738575252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Understanding Role of Maternal Separation in Depression, Anxiety,and Pain Behaviour: A Mini Review of Preclinical Research With Focus on Neuroinflammatory Pathways"],"prefix":"10.1002","volume":"85","author":[{"given":"Shima","family":"Mohammadi","sequence":"first","affiliation":[{"name":"Department of Neuroscience, School of Medicine Shahroud University of Medical Sciences  Shahroud Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alieh","family":"Bashghareh","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine Shahroud University of Medical Sciences  Shahroud Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Karimi\u2010Zandi","sequence":"additional","affiliation":[{"name":"School of Advanced Technologies in Medicine Golestan University of Medical Sciences  Gorgan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-7102","authenticated-orcid":false,"given":"Tahmineh","family":"Mokhtari","sequence":"additional","affiliation":[{"name":"Department of Entomology and Nematology and UCD Comprehensive Cancer Center University of California  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2016.11.005"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2015.08.025"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2018.11.037"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2017.02.022"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-013-0119-1"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.107436"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbih.2020.100142"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/10253890.2019.1604666"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2009.04.013"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cobeha.2015.11.018"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0954579424000725"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.29271\/jcpsp.2019.06.528"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00102"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-012-9304-z"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/antib4040369"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0000000000000182"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2021.06.001"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40200-021-00902-3"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2016.02.016"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0202599"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.8179"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2019.05.001"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.20259"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02591-y"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2014.01.036"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13030-022-00258-x"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389557520666200727154453"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.02.003"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci11060723"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.289.23.3095"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.repbio.2019.10.003"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","unstructured":"Khodamoradi K. 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