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bioRxiv · 10.64898/2026.10.09.757621

EARLY-LIFE STRESS INDUCES SEXUALLY DIMORPHIC BRAIN AGING VIA MESOLIMBIC ALTERATIONS AND FRONTO-STRIATAL DYSFUNCTION

Souza, A. C.·Tibirica, I. C. G.·Mariano, V. S.·Grigoletti-Lima, G. B.·Gontijo, J. A. R.·BOER, P. A.
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Abstract

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.

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Souza, A. C., Tibirica, I. C. G., Mariano, V. S., Grigoletti-Lima, G. B., Gontijo, J. A. R., BOER, P. A.. 2026-10-11. EARLY-LIFE STRESS INDUCES SEXUALLY DIMORPHIC BRAIN AGING VIA MESOLIMBIC ALTERATIONS AND FRONTO-STRIATAL DYSFUNCTION. https://doi.org/10.64898/2026.10.09.757621

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