{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T19:51:31Z","timestamp":1793821891571,"version":"4.6.1"},"reference-count":86,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T00:00:00Z","timestamp":1719273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Early life adversity (ELA) increases the likelihood of later-life neuropsychiatric disorders and cognitive dysfunction. Importantly, ELA, neuropsychiatric disorders, and cognitive deficits all involve aberrant immune signaling. Microglia are the primary neuroimmune cells and regulate brain development. Microglia are particularly sensitive to early life insults, which can program their responses to future challenges. ELA in the form of maternal separation (MS) in rats alters later-life microglial morphology and the inflammatory profile of the prefrontal cortex, a region important for cognition. However, the role of microglial responses <jats:italic>during<\/jats:italic> MS in the development of later cognition is not known. Therefore, here we aimed to determine whether the presence of microglia during MS mediates long-term impacts on adult working memory. Clodronate liposomes were used to transiently deplete microglia from the brain, while empty liposomes were used as a control. We hypothesized that if microglia mediate the long-term impacts of ELA on working memory in adulthood, then depleting microglia during MS would prevent these deficits. Importantly, microglial function shifts throughout the neonatal period, so an exploratory investigation assessed whether depletion during the early versus late neonatal period had different effects on adult working memory. Surprisingly, empty liposome treatment during the early, but not late, postnatal period induced microglial activity changes that compounded with MS to impair working memory in females. In contrast, microglial depletion later in infancy impaired later life working memory in females, suggesting that microglial function during late infancy plays an important role in the development of cognitive function. Together, these findings suggest that microglia shift their sensitivity to early life insults across development. Our findings also highlight the potential for MS to impact some developmental processes only when compounded with additional neuroimmune challenges in a sex-dependent manner.<\/jats:p>","DOI":"10.1371\/journal.pone.0306022","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T18:33:22Z","timestamp":1719340402000},"page":"e0306022","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Impacts of age and environment on postnatal microglial activity: Consequences for cognitive function following early life adversity"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6979-7375","authenticated-orcid":true,"given":"Michaela","family":"Fanikos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skylar 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emotional reactivity to stress, and mood and anxiety disorders across the life course","volume":"27","author":"KA McLaughlin","year":"2010","journal-title":"Depress Anxiety"},{"key":"pone.0306022.ref003","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.drugalcdep.2016.09.021","article-title":"The relationships of childhood trauma and adulthood prescription pain reliever misuse and injection drug use","volume":"169","author":"K Quinn","year":"2016","journal-title":"Drug Alcohol Depend"},{"key":"pone.0306022.ref004","doi-asserted-by":"crossref","first-page":"531","DOI":"10.2147\/nedt.2006.2.4.531","article-title":"Cognitive deficits and functional outcome in schizophrenia","volume":"2","author":"CR Bowie","year":"2006","journal-title":"Neuropsychiatr Dis Treat"},{"key":"pone.0306022.ref005","doi-asserted-by":"crossref","DOI":"10.1001\/archpediatrics.2009.214","article-title":"Adverse Childhood Experiences and Adult Risk Factors for Age-Related Disease: Depression, Inflammation, and Clustering of Metabolic Risk Markers","volume":"163","author":"A Danese","year":"2009","journal-title":"Arch Pediatr Adolesc Med"},{"key":"pone.0306022.ref006","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1177\/070674371405901206","article-title":"Cognitive Dysfunction in Major Depressive Disorder: Effects on Psychosocial Functioning and Implications for Treatment","volume":"59","author":"RW Lam","year":"2014","journal-title":"Can J Psychiatry"},{"key":"pone.0306022.ref007","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1186\/s12888-021-03618-z","article-title":"Anxiety severity and cognitive function in primary care patients with anxiety disorder: a cross-sectional study","volume":"21","author":"J Nyberg","year":"2021","journal-title":"BMC Psychiatry"},{"key":"pone.0306022.ref008","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1017\/S0033291718003203","article-title":"The roles of early-life adversity and rumination in neural response to emotional faces amongst anxious and depressed adults","volume":"49","author":"AT Peters","year":"2019","journal-title":"Psychol Med"},{"key":"pone.0306022.ref009","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.schres.2007.02.004","article-title":"Response inhibition and cognitive flexibility in schizophrenia with and without comorbid substance use disorder","volume":"92","author":"P Thoma","year":"2007","journal-title":"Schizophr Res"},{"key":"pone.0306022.ref010","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s41983-021-00441-x","article-title":"Prevalence and clinical implication of adverse childhood experiences and their association with substance use disorder among patients with schizophrenia","volume":"58","author":"AM Yousef","year":"2022","journal-title":"Egypt J Neurol Psychiatry Neurosurg"},{"key":"pone.0306022.ref011","doi-asserted-by":"crossref","first-page":"7917","DOI":"10.1523\/JNEUROSCI.0307-12.2012","article-title":"Structural variations in prefrontal cortex mediate the relationship between early childhood stress and spatial working memory","volume":"32","author":"JL Hanson","year":"2012","journal-title":"J Neurosci Off J Soc Neurosci"},{"key":"pone.0306022.ref012","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1002\/hipo.22661","article-title":"MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early-life adversity","volume":"26","author":"J Molet","year":"2016","journal-title":"Hippocampus"},{"key":"pone.0306022.ref013","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1016\/j.neuropsychologia.2010.06.013","article-title":"Early-life stress is associated with impairment in cognitive control in adolescence: An fMRI study","volume":"48","author":"SC Mueller","year":"2010","journal-title":"Neuropsychologia"},{"key":"pone.0306022.ref014","doi-asserted-by":"crossref","first-page":"6635","DOI":"10.1523\/JNEUROSCI.0247-10.2010","article-title":"Severe early life stress hampers spatial learning and neurogenesis but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood","volume":"30","author":"CA Oomen","year":"2010","journal-title":"J Neurosci Off J Soc Neurosci"},{"key":"pone.0306022.ref015","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.neurobiolaging.2012.12.012","article-title":"Cognitive ability and decline after early life stress exposure","volume":"34","author":"A-K Pesonen","year":"2013","journal-title":"Neurobiol Aging"},{"key":"pone.0306022.ref016","doi-asserted-by":"crossref","first-page":"e35744","DOI":"10.1371\/journal.pone.0035744","article-title":"The impact of social disparity on prefrontal function in childhood","volume":"7","author":"MA Sheridan","year":"2012","journal-title":"PloS One"},{"key":"pone.0306022.ref017","doi-asserted-by":"crossref","first-page":"863734","DOI":"10.3389\/fpsyt.2022.863734","article-title":"Inflammatory Markers in Substance Use and Mood Disorders: A Neuroimaging Perspective","volume":"13","author":"K Agarwal","year":"2022","journal-title":"Front Psychiatry"},{"key":"pone.0306022.ref018","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s00702-017-1730-y","article-title":"A molecular pathway analysis stresses the role of inflammation and oxidative stress towards cognition in schizophrenia","volume":"124","author":"EK Fischer","year":"2017","journal-title":"J Neural Transm"},{"key":"pone.0306022.ref019","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000201116","article-title":"Association of Midlife Inflammatory Markers with Cognitive Performance at 10-Year Follow-up","volume":"99","author":"T Kipinoinen","year":"2022","journal-title":"Neurology"},{"key":"pone.0306022.ref020","doi-asserted-by":"crossref","first-page":"7393","DOI":"10.1038\/s41380-021-01188-w","article-title":"Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts","volume":"26","author":"Y Milaneschi","year":"2021","journal-title":"Mol Psychiatry"},{"key":"pone.0306022.ref021","doi-asserted-by":"crossref","first-page":"5790","DOI":"10.1038\/s41598-019-42286-8","article-title":"Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice","volume":"9","author":"J Zhao","year":"2019","journal-title":"Sci Rep"},{"key":"pone.0306022.ref022","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.stem.2010.08.014","article-title":"Microglia Shape Adult Hippocampal Neurogenesis through Apoptosis-Coupled Phagocytosis","volume":"7","author":"A Sierra","year":"2010","journal-title":"Cell Stem Cell"},{"key":"pone.0306022.ref023","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.1202529","article-title":"Synaptic Pruning by Microglia Is Necessary for Normal Brain Development","volume":"333","author":"RC Paolicelli","year":"2011","journal-title":"Science"},{"key":"pone.0306022.ref024","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1038\/s41467-018-03566-5","article-title":"Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction","volume":"9","author":"L Weinhard","year":"2018","journal-title":"Nat Commun"},{"key":"pone.0306022.ref025","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1523\/JNEUROSCI.1268-12.2013","article-title":"Microglia Are Essential to Masculinization of Brain and Behavior","volume":"33","author":"KM Lenz","year":"2013","journal-title":"J Neurosci"},{"key":"pone.0306022.ref026","doi-asserted-by":"crossref","first-page":"698","DOI":"10.3389\/fimmu.2018.00698","article-title":"Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function","volume":"9","author":"KM Lenz","year":"2018","journal-title":"Front Immunol"},{"key":"pone.0306022.ref027","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41380-019-0609-8","article-title":"Microglial regional heterogeneity and its role in the brain","volume":"25","author":"Y-L Tan","year":"2020","journal-title":"Mol Psychiatry"},{"key":"pone.0306022.ref028","doi-asserted-by":"crossref","DOI":"10.1523\/ENEURO.0036-15.2015","article-title":"Morphological and Phagocytic Profile of Microglia in the Developing Rat Cerebellum","volume":"2","author":"M Perez-Pouchoulen","year":"2015","journal-title":"eneuro"},{"key":"pone.0306022.ref029","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0306-4522(85)90215-5","article-title":"Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain","volume":"15","author":"VH Perry","year":"1985","journal-title":"Neuroscience"},{"key":"pone.0306022.ref030","doi-asserted-by":"crossref","first-page":"111161","DOI":"10.1016\/j.celrep.2022.111161","article-title":"Prenatal environmental stressors impair postnatal microglia function and adult behavior in males","volume":"40","author":"CL Block","year":"2022","journal-title":"Cell Rep"},{"key":"pone.0306022.ref031","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1126\/science.1194637","article-title":"Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages","volume":"330","author":"F Ginhoux","year":"2010","journal-title":"Science"},{"key":"pone.0306022.ref032","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.cellimm.2018.01.001","article-title":"Fetal monocytes and the origins of tissue-resident macrophages","volume":"330","author":"G Hoeffel","year":"2018","journal-title":"Cell Immunol"},{"key":"pone.0306022.ref033","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.celrep.2017.07.004","article-title":"The Lifespan and Turnover of Microglia in the Human Brain","volume":"20","author":"P R\u00e9u","year":"2017","journal-title":"Cell Rep"},{"key":"pone.0306022.ref034","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bbr.2005.12.002","article-title":"A behavioural characterization of neonatal infection-facilitated memory impairment in adult rats","volume":"169","author":"SD Bilbo","year":"2006","journal-title":"Behav Brain Res"},{"key":"pone.0306022.ref035","doi-asserted-by":"crossref","first-page":"8000","DOI":"10.1523\/JNEUROSCI.1748-05.2005","article-title":"Neonatal Infection-Induced Memory Impairment after Lipopolysaccharide in Adulthood Is Prevented via Caspase-1","volume":"25","author":"SD Bilbo","year":"2005","journal-title":"Inhibition. J Neurosci"},{"key":"pone.0306022.ref036","doi-asserted-by":"crossref","first-page":"15511","DOI":"10.1523\/JNEUROSCI.3688-11.2011","article-title":"Microglia and Memory: Modulation by Early-Life Infection","volume":"31","author":"LL Williamson","year":"2011","journal-title":"J Neurosci"},{"key":"pone.0306022.ref037","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.semcdb.2019.01.001","article-title":"Microglia: Neuroimmune-sensors of stress","volume":"94","author":"MG Frank","year":"2019","journal-title":"Semin Cell Dev Biol"},{"key":"pone.0306022.ref038","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/mp.2013.155","article-title":"Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis","volume":"19","author":"T Kreisel","year":"2014","journal-title":"Mol Psychiatry"},{"key":"pone.0306022.ref039","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jneuroim.2005.09.012","article-title":"Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation","volume":"171","author":"A Nair","year":"2006","journal-title":"J Neuroimmunol"},{"key":"pone.0306022.ref040","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.neuroscience.2007.02.043","article-title":"Stress induced morphological microglial activation in the rodent brain: Involvement of interleukin-18","volume":"146","author":"S Sugama","year":"2007","journal-title":"Neuroscience"},{"key":"pone.0306022.ref041","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/j.bbi.2010.02.001","article-title":"Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions","volume":"24","author":"RJ Tynan","year":"2010","journal-title":"Brain Behav Immun"},{"key":"pone.0306022.ref042","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1097\/WNR.0000000000001544","article-title":"Repeated and single maternal separation specifically alter microglial morphology in the prefrontal cortex and neurogenesis in the hippocampus of 15-day-old male mice","volume":"31","author":"V Reshetnikov","year":"2020","journal-title":"NeuroReport"},{"key":"pone.0306022.ref043","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jpsychires.2019.05.001","article-title":"Maternal deprivation increases microglial activation and neuroinflammatory markers in the prefrontal cortex and hippocampus of infant rats","volume":"115","author":"VV Giridharan","year":"2019","journal-title":"J Psychiatr Res"},{"key":"pone.0306022.ref044","doi-asserted-by":"crossref","first-page":"135381","DOI":"10.1016\/j.neulet.2020.135381","article-title":"Sex differences in prefrontal cortex microglia morphology: Impact of a two-hit model of adversity throughout development","volume":"738","author":"KR Gildawie","year":"2020","journal-title":"Neurosci Lett"},{"key":"pone.0306022.ref045","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.bbi.2019.01.006","article-title":"Effects of early life stress on cocaine conditioning and AMPA receptor composition are sex-specific and driven by TNF","volume":"78","author":"P Ganguly","year":"2019","journal-title":"Brain Behav Immun"},{"key":"pone.0306022.ref046","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/dev.21390","article-title":"Effects of early adolescent environmental enrichment on cognitive dysfunction, prefrontal cortex development, and inflammatory cytokines after early life stress","volume":"58","author":"CH Do Prado","year":"2016","journal-title":"Dev Psychobiol"},{"key":"pone.0306022.ref047","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.psyneuen.2016.04.016","article-title":"Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: Impacts of sex, experience, and cytokines","volume":"71","author":"R Grassi-Oliveira","year":"2016","journal-title":"Psychoneuroendocrinology"},{"key":"pone.0306022.ref048","doi-asserted-by":"crossref","DOI":"10.1523\/ENEURO.0026-21.2021","article-title":"Generation of an Iba1-EGFP Transgenic Rat for the Study of Microglia in an Outbred Rodent Strain","volume":"8","author":"JW VanRyzin","year":"2021","journal-title":"eneuro"},{"key":"pone.0306022.ref049","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1002\/glia.23007","article-title":"Critical data\u2010based re\u2010evaluation of minocycline as a putative specific microglia inhibitor","volume":"64","author":"T M\u00f6ller","year":"2016","journal-title":"Glia"},{"key":"pone.0306022.ref050","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.neuron.2014.02.040","article-title":"Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain","volume":"82","author":"MRP Elmore","year":"2014","journal-title":"Neuron"},{"key":"pone.0306022.ref051","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.immuni.2015.06.012","article-title":"Genetic Cell Ablation Reveals Clusters of Local Self-Renewing Microglia in the Mammalian Central Nervous System","volume":"43","author":"J Bruttger","year":"2015","journal-title":"Immunity"},{"key":"pone.0306022.ref052","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/s41593-018-0090-8","article-title":"Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion","volume":"21","author":"Y Huang","year":"2018","journal-title":"Nat Neurosci"},{"key":"pone.0306022.ref053","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.bbr.2016.09.006","article-title":"Microglia depletion in early life programs persistent changes in social, mood-related, and locomotor behavior in male and female rats","volume":"316","author":"LH Nelson","year":"2017","journal-title":"Behav Brain Res"},{"key":"pone.0306022.ref054","doi-asserted-by":"crossref","DOI":"10.1523\/ENEURO.0297-16.2016","article-title":"Temporary Depletion of Microglia during the Early Postnatal Period Induces Lasting Sex-Dependent and Sex-Independent Effects on Behavior in Rats","volume":"3","author":"JW VanRyzin","year":"2016","journal-title":"eneuro"},{"key":"pone.0306022.ref055","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0022-1759(96)00056-7","article-title":"Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine","volume":"193","author":"N Van Rooijen","year":"1996","journal-title":"J Immunol Methods"},{"key":"pone.0306022.ref056","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-1-60327-360-2_13","volume-title":"Liposomes","author":"N Van Rooijen","year":"2010"},{"key":"pone.0306022.ref057","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.bbr.2016.09.006","article-title":"Microglia depletion in early life programs persistent changes in social, mood-related, and locomotor behavior in male and female rats","volume":"316","author":"LH Nelson","year":"2017","journal-title":"Behav Brain Res"},{"key":"pone.0306022.ref058","doi-asserted-by":"crossref","DOI":"10.3389\/fnana.2015.00161","article-title":"Atlas of the Postnatal Rat Brain in Stereotaxic Coordinates","volume":"9","author":"R Khazipov","year":"2015","journal-title":"Front Neuroanat"},{"key":"pone.0306022.ref059","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0149-7634(01)00041-0","article-title":"The neurobiological basis of spontaneous alternation","volume":"26","author":"R. Lalonde","year":"2002","journal-title":"Neurosci Biobehav Rev"},{"key":"pone.0306022.ref060","article-title":"3DMorph Automatic Analysis of Microglial Morphology in Three Dimensions from Ex Vivo and In Vivo Imaging","volume":"5","author":"EM York","year":"2018","journal-title":"eneuro"},{"key":"pone.0306022.ref061","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"CA Schneider","year":"2012","journal-title":"Nat Methods"},{"key":"pone.0306022.ref062","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1525528113","article-title":"New tools for studying microglia in the mouse and human CNS","volume":"113","author":"ML Bennett","year":"2016","journal-title":"Proc Natl Acad Sci"},{"key":"pone.0306022.ref063","article-title":"A postnatal peak in microglial development in the mouse hippocampus is correlated with heightened sensitivity to seizure triggers","volume":"5","author":"I Kim","year":"2015","journal-title":"Brain Behav"},{"key":"pone.0306022.ref064","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jneuroim.2014.11.018","article-title":"Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week","volume":"278","author":"M Nikodemova","year":"2015","journal-title":"J Neuroimmunol"},{"key":"pone.0306022.ref065","article-title":"Sex differences in microglial colonization of the developing rat brain: Sex differences in microglial colonization","author":"JM Schwarz","year":"2012","journal-title":"J Neurochem"},{"key":"pone.0306022.ref066","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.neubiorev.2014.04.009","article-title":"Developmental studies of the hippocampus and hippocampal-dependent behaviors: Insights from interdisciplinary studies and tips for new investigators","volume":"43","author":"SH Albani","year":"2014","journal-title":"Neurosci Biobehav Rev"},{"key":"pone.0306022.ref067","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.neuroscience.2020.10.009","article-title":"Microglia Regulate Cell Genesis in a Sex-dependent Manner in the Neonatal Hippocampus","volume":"453","author":"LH Nelson","year":"2021","journal-title":"Neuroscience"},{"key":"pone.0306022.ref068","doi-asserted-by":"crossref","first-page":"104485","DOI":"10.1016\/j.chiabu.2020.104485","article-title":"Adverse Childhood Experiences and Executive Function Difficulties in Children: A Systematic Review","volume":"106","author":"JI Lund","year":"2020","journal-title":"Child Abuse Negl"},{"key":"pone.0306022.ref069","doi-asserted-by":"crossref","first-page":"21177","DOI":"10.1038\/s41598-021-00402-7","article-title":"Apparatus design and behavioural testing protocol for the evaluation of spatial working memory in mice through the spontaneous alternation T-maze","volume":"11","author":"R d\u2019Isa","year":"2021","journal-title":"Sci Rep"},{"key":"pone.0306022.ref070","doi-asserted-by":"crossref","first-page":"100924","DOI":"10.1016\/j.dcn.2021.100924","article-title":"A two-hit adversity model in developing rats reveals sex-specific impacts on prefrontal cortex structure and behavior","volume":"48","author":"KR Gildawie","year":"2021","journal-title":"Dev Cogn Neurosci"},{"key":"pone.0306022.ref071","doi-asserted-by":"crossref","first-page":"100142","DOI":"10.1016\/j.bbih.2020.100142","article-title":"Maternal separation leads to regional hippocampal microglial activation and alters the behavior in the adolescence in a sex-specific manner","volume":"9","author":"S Bachiller","year":"2020","journal-title":"Brain Behav Immun\u2014Health"},{"key":"pone.0306022.ref072","doi-asserted-by":"crossref","first-page":"1147951","DOI":"10.3389\/fnmol.2023.1147951","article-title":"The impact of environmental factors during maternal separation on the behaviors of adolescent C57BL\/6 mice","volume":"16","author":"S Shin","year":"2023","journal-title":"Front Mol Neurosci"},{"key":"pone.0306022.ref073","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/npp.2014.304","article-title":"Stress during a Critical Postnatal Period Induces Region-Specific Structural Abnormalities and Dysfunction of the Prefrontal Cortex via CRF1","volume":"40","author":"X-D Yang","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"pone.0306022.ref074","doi-asserted-by":"crossref","DOI":"10.3389\/fnbeh.2011.00013","article-title":"Resistance to Early-Life Stress in Mice: Effects of Genetic Background and Stress Duration","volume":"5","author":"HM Savignac","year":"2011","journal-title":"Front Behav Neurosci"},{"key":"pone.0306022.ref075","doi-asserted-by":"crossref","first-page":"4048","DOI":"10.1016\/j.cell.2021.06.018","article-title":"GABA-receptive microglia selectively sculpt developing inhibitory circuits","volume":"184","author":"E Favuzzi","year":"2021","journal-title":"Cell"},{"key":"pone.0306022.ref076","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.neuron.2023.10.024","article-title":"Reorganization of adolescent prefrontal cortex circuitry is required for mouse cognitive maturation","volume":"112","author":"JA P\u00f6pplau","year":"2024","journal-title":"Neuron"},{"key":"pone.0306022.ref077","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/syn.21909","article-title":"Synaptic number changes in the medial prefrontal cortex across adolescence in male and female rats: A role for pubertal onset","volume":"70","author":"CM Drzewiecki","year":"2016","journal-title":"Synapse"},{"key":"pone.0306022.ref078","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1006\/hbeh.2000.1572","article-title":"Hippocampal Anatomy and Water Maze Performance Are Affected by Neonatal Cryoanesthesia in Rats of Both Sexes","volume":"37","author":"JL Nu\u00f1ez","year":"2000","journal-title":"Horm Behav"},{"key":"pone.0306022.ref079","doi-asserted-by":"crossref","first-page":"146495","DOI":"10.1016\/j.brainres.2019.146495","article-title":"Neuroinflammation induced by secretion of acetylated HMGB1 from activated microglia in hippocampi of mice following chronic cold exposure","volume":"1726","author":"B Xu","year":"2020","journal-title":"Brain Res"},{"key":"pone.0306022.ref080","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1111\/j.1469-7610.2007.01730.x","article-title":"Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights","volume":"48","author":"A Kaffman","year":"2007","journal-title":"J Child Psychol Psychiatry"},{"key":"pone.0306022.ref081","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1002\/jdn.10230","article-title":"One week of maternal separation induces more frequent, but less predictable, maternal caregiving behaviors","volume":"82","author":"L Granata","year":"2022","journal-title":"Int J Dev Neurosci"},{"key":"pone.0306022.ref082","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0031-9384(03)00149-5","article-title":"Variations in maternal care in the rat as a mediating influence for the effects of environment on development","volume":"79","author":"FA Champagne","year":"2003","journal-title":"Physiol Behav"},{"key":"pone.0306022.ref083","doi-asserted-by":"crossref","first-page":"100373","DOI":"10.1016\/j.bbih.2021.100373","article-title":"Phagocytic microglia in development: Are they what they eat?","volume":"18","author":"JW VanRyzin","year":"2021","journal-title":"Brain Behav Immun\u2014Health"},{"key":"pone.0306022.ref084","doi-asserted-by":"crossref","first-page":"506","DOI":"10.3389\/fimmu.2020.00506","article-title":"Microglial Corpse Clearance: Lessons From Macrophages","volume":"11","author":"M M\u00e1rquez-Ropero","year":"2020","journal-title":"Front 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