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

Prenatal stress has lasting effects on brain development, but the impact on aging in males and females is not well understood. A study in C57BL/6J mice sought to investigate the consequences of unpredictable mild prenatal stress during the middle (12 months) and old (18 months) ages. The stressed mother mice exhibited erratic maternal behaviors, creating a stressful postnatal environment without hindering their caregiving abilities.

Both male and female offspring were born with lower birth weights and experienced rapid postnatal growth, linked to central insulin resistance and deficits in hippocampal signaling. As the offspring aged, sex-specific behavioral differences became apparent. Middle-aged stressed males displayed anhedonia, which evolved into hyperactivity, stereotypy, and persistent spatial memory deficits in old age.

These symptoms were associated with accelerated fronto-striatal decline, potentially due to insulin resistance and reduced estrogenic activity in medial prefrontal cortex structures. Middle-aged stressed females, on the other hand, exhibited hypoactivity and reduced anxiety, later developing anhedonia in old age while preserving hippocampus-dependent memory.

This pattern in females suggests a neuroestrogen and growth factor-dependent feedback loop that initially preserves hippocampal plasticity but impairs dopaminergic function in reward circuits, which may deteriorate with reproductive senescence. Despite these differences, both sexes maintained cognitive flexibility, indicating domain-specific cognitive impairment rather than a global decline.

The study underscores the importance of considering sex as a biological variable in fetal programming research throughout the lifespan, as excessive prenatal glucocorticoid exposure and unpredictable postnatal care result in sexually divergent trajectories of brain aging.