Aging and Sex Shape the Intrinsic and Synaptic Properties of Mitral Cells in the Mouse Olfactory Bulb

Aging is accompanied by a progressive decline in olfactory function, which affects a large proportion of older adults and has substantial consequences for nutrition, safety, and overall quality of life. Increasing evidence indicates that sex-dependent differences in olfactory processing become more pronounced with advancing age, particularly in late life. However, the cellular basis beyond the peripheral level by which aging and sex interact to influence neuronal and synaptic functions in central structures remains poorly understood. To bridge this gap, we compared behavioral outcomes, intrinsic and synaptic properties of the olfactory bulb (OB) output neurons mitral cells (MCs) that receive direct sensory input from odor receptor neurons and integrate olfactory information to most higher order brain regions, in male and female C57BL/6J mice of three ages spanning the natural lifespan. Consistent with human studies and the key role of mitral cells in transforming input to output in the OB, our behavioral tests showed that both aging and sex significantly influenced odor detection performance, which declined with age, particularly in females while locomotor activity remained preserved. At the cellular level, our whole-cell patch-clamp recordings in OB slices demonstrated that MCs in male mice across the lifespan exhibit a gradual decline in excitability and synaptic strength with age, while female mice maintain stable function until advanced age, when marked alterations emerge. This study provides the first physiological evidence of the joint influence of aging and sex on the functional operation of the OB at the cellular and synaptic levels. Considering olfactory impairment as the earliest and most sensitive indicator of the age-dependent and sex-biased neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, our findings provide functional insights not only into normal aging-induced olfactory deficits but also into the future development of early biomarkers and intervention strategies for these neurodegenerative disorders.