PHYSIOLOGICAL AND PATHOLOGICAL AGING DRIVE SEX-DEPENDENT STRUCTURAL REMODELING OF OXYTOCINERGIC CIRCUITS IN THE MOUSE BRAIN

Oxytocinergic (OXT) circuits are critical regulators of social behavior, yet how their structural organization is reshaped by aging and whether these changes differ between sexes, remains poorly understood. Here, we investigated sex-dependent structural remodeling of the oxytocinergic system across physiological and pathological aging in the mouse brain. Using whole-brain iDISCO+ clearing combined with light-sheet fluorescence microscopy, we generated high-resolution 3D reconstructions of OXT circuits in models of natural aging and Alzheimer’s disease (AD), in particular the APP/PS1 mice. Natural aging induced pronounced, sex-specific remodeling of OXT populations. Females exhibited reductions in OXT-positive neurons within the PVN and bed nucleus of the stria terminalis (BNST), whereas males showed a selective vulnerability of the anterodorsal preoptic nucleus (ADPN). Across these regions, aging was associated with a decreased representation of magnocellular OXT neurons, indicating subtype-specific susceptibility. Pathological aging further amplified sex-dependent divergence. In APP/PS1 mice, the most prominent alterations emerged at 18 months of age, with males displaying a trend toward increased OXT expression that drove a significant sexual dimorphism in the ADPN relative to AD females. Preliminary analyses additionally suggest disease-associated changes in the intracellular abundance of OXT-containing vesicles, pointing to altered peptide handling at the cellular level. Together, these findings reveal that oxytocinergic circuits undergo extensive, sex-dependent structural remodeling across both physiological and pathological aging. Importantly, pathological aging engages mechanisms that are distinct from those observed during natural aging, potentially contributing to sex-specific vulnerabilities in social dysfunction during neurodegeneration.