Longitudinal MRI reveals hormone-dependent brain remodeling supporting preserved cognition in aged females

Adaptive plasticity, the brain’s capacity to counteract structural decline and preserve performance with age, is a hallmark of successful aging, yet its biological underpinnings remain poorly understood. Here, we combined longitudinal magnetic resonance imaging (MRI) spanning the entire lifespan with electrophysiology, immunohistochemistry, and behavioral assays in female and male rats to identify key region- and systems-level mechanisms underlying this process. Resting-state functional MRI revealed a striking sex-specific pattern of connectivity reorganization in anterior brain regions, emerging in midlife and more pronounced in females. Microstructural MRI and histological analyses linked increased connectivity to prolonged white matter preservation and downstream maintenance of neuronal function in the female prefrontal cortex, while electrophysiological recordings demonstrated enhanced effective connectivity in the same region in aged females. Behaviorally, enhanced anterior connectivity was associated with superior memory performance. Ovariectomy at a critical time point for white matter maturation compromised this female-specific neuroprotection, disrupting microstructural integrity and functional reorganization, thereby highlighting the role of sex hormones in shaping these trajectories. Together, these findings identify a novel sexually dimorphic pattern of functional reorganization in anterior brain regions and point to estrogen availability during critical periods as a key modulator of brain aging.