{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:49Z","timestamp":1792790329613,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,11]]},"group-title":"Neuroscience","reference-count":95,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"S\u00e3o Paulo Research Fundation","award":["2024\/06071-1"],"award-info":[{"award-number":["2024\/06071-1"]}],"id":[{"id":"https:\/\/ror.org\/02ddkpn78","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Brazilian National Institute of Science and Technology of DOHaD-INCT","award":["409165\/2024-7"],"award-info":[{"award-number":["409165\/2024-7"]}]},{"name":"National Council for Scientific and Technological Development","award":["[308043\/2022-7]"],"award-info":[{"award-number":["[308043\/2022-7]"]}],"id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Prenatal stress influences brain development; however, its long-term, region-specific effects on brain aging in males and females remain insufficiently characterized. This study examined the impact of unpredictable mild prenatal stress on behavior, cognition, and maternal care in C57BL\/6J mice at middle (12 months) and old (18 months) ages.Stressed dams showed fragmented, unpredictable maternal behaviors, creating a stressful postnatal environment without impairing caregiving capacity. Both male and female offspring were born with lower birth weights and showed rapid postnatal growth, a trajectory associated with central insulin resistance and hippocampal signaling deficits. Sex-specific behavioral differences emerged with age. Middle-aged stressed males exhibited anhedonia, which progressed to hyperactivity, stereotypy, and persistent spatial memory deficits in old age. These outcomes corresponded with accelerated fronto-striatal decline, likely mediated by insulin resistance and increased rigidity of medial prefrontal cortex structures due to diminished local estrogenic activity. In contrast, middle-aged stressed females displayed hypoactivity and reduced anxiety, later developing anhedonia in old age while maintaining hippocampus-dependent memory. In females, this pattern supports a model in which a neuroestrogen - and growth factor-dependent feedback loop transiently preserves hippocampal plasticity but compromises dopaminergic function in reward circuits. This balance may deteriorate with reproductive senescence. Both sexes retained cognitive flexibility, indicating domain-specific rather than global cognitive impairment. These findings demonstrate that excessive prenatal glucocorticoid exposure and unpredictable postnatal care produce a combined hormonal and metabolic insult, resulting in sexually divergent trajectories of brain aging. The results underscore the necessity of incorporating sex as a biological variable in fetal programming research across the lifespan.<\/jats:p>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Prenatal stress and fragmented care drive sexually dimorphic brain aging.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Low birth weight and rapid growth associate with supposed central insulin resistance.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Stressed males exhibit accelerated fronto-striatal decline and memory loss.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Females show allostatic reallocation, transiently preserving hippocampal memory.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.10.09.757621","type":"posted-content","created":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T11:35:12Z","timestamp":1791718512000},"source":"Crossref","is-referenced-by-count":0,"title":["EARLY-LIFE STRESS INDUCES SEXUALLY DIMORPHIC BRAIN AGING VIA MESOLIMBIC ALTERATIONS AND FRONTO-STRIATAL DYSFUNCTION"],"prefix":"10.64898","author":[{"given":"Amanda Cristina","family":"de Souza","sequence":"first","affiliation":[{"name":"Fetal Programming and Hydroelectrolyte Metabolism Laboratory, Department of Internal Medicine, School of Medical Sciences, Campinas State University (UNICAMP), Campinas, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinicius Schiavinatto","family":"Mariano","sequence":"additional","affiliation":[{"name":"Fetal Programming and Hydroelectrolyte Metabolism Laboratory, Department of Internal Medicine, School of Medical Sciences, Campinas State University (UNICAMP), Campinas, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabele Cristina Gobo","family":"Tibiri\u00e7a","sequence":"additional","affiliation":[{"name":"Fetal Programming and Hydroelectrolyte Metabolism Laboratory, Department of Internal Medicine, School of Medical Sciences, Campinas State University (UNICAMP), Campinas, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Boer","family":"Grigoletti-Lima","sequence":"additional","affiliation":[{"name":"Fetal Programming and Hydroelectrolyte Metabolism Laboratory, Department of Internal Medicine, School of Medical Sciences, Campinas State University (UNICAMP), Campinas, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Antonio Rocha","family":"Gontijo","sequence":"additional","affiliation":[{"name":"Fetal Programming and Hydroelectrolyte Metabolism Laboratory, Department of Internal Medicine, School of Medical Sciences, Campinas State University (UNICAMP), Campinas, SP, Brazil"},{"name":"National Institute of Science and Technology in Developmental Origins of Health and Disease (INCT-DOHaD Brasil)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia Aline","family":"Boer","sequence":"additional","affiliation":[{"name":"Fetal Programming and Hydroelectrolyte Metabolism Laboratory, Department of Internal Medicine, School of Medical Sciences, Campinas State University (UNICAMP), Campinas, SP, Brazil"},{"name":"National Institute of Science and Technology in Developmental Origins of Health and Disease (INCT-DOHaD Brasil)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026101506001576000_2026.10.09.757621v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s10339-011-0430-z"},{"key":"2026101506001576000_2026.10.09.757621v1.2","doi-asserted-by":"publisher","DOI":"10.3109\/10253890.2014.905534"},{"key":"2026101506001576000_2026.10.09.757621v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2009.12.008"},{"key":"2026101506001576000_2026.10.09.757621v1.4","doi-asserted-by":"publisher","DOI":"10.31887\/dcns.2016.18.4\/tbale"},{"key":"2026101506001576000_2026.10.09.757621v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4112"},{"key":"2026101506001576000_2026.10.09.757621v1.6","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2012.11091347"},{"key":"2026101506001576000_2026.10.09.757621v1.7","doi-asserted-by":"crossref","unstructured":"Barker, D. 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