Neural circuit basis of age-related changes in female social behavior

Menopause is a major neuroendocrine transition experienced by nearly two million individuals in the United States each year. It is associated with increased rates of depression, social withdrawal, and loss of sexual motivation, posing significant challenges to mental health, interpersonal relationships, and public health. While hormonal decline has been implicated, the neural circuit mechanisms underlying these behavioral symptoms remain poorly understood. This proposal seeks to define how hormonal decline during reproductive aging disrupts a specific hormone-sensitive neural circuit and impairs female sexual behavior. Our work focuses on a projection from Cckar-expressing neurons in the ventromedial hypothalamus (VMHvlCckar) to the anteroventral periventricular nucleus (AVPV), a pathway that is essential for female sexual behavior and highly sensitive to ovarian hormones. Using a physiologically relevant menopause model induced by 4-vinylcyclohexene diepoxide (VCD), which gradually depletes ovarian follicles without surgery, we will determine how hormonal decline alters both the structural connectivity and functional activity of this projection. Specific Aim 1 will test whether structural atrophy of the VMHvlCckar to AVPV projection occurs with hormonal decline and whether it is reversible by hormone supplementation. Specific Aim 2 will examine how hormonal decline affects activity along this circuit, revealing where circuit dysfunction arises. Specific Aim 3 will use optogenetics to test whether activating this pathway restores sexual behavior and whether AVPV activity is necessary for hormone-induced behavioral rescue. By linking hormone-sensitive circuit remodeling to behavioral impairments, this study will identify new neurobiological targets for intervention. The findings may guide the development of circuit-based therapies to support mental health and social functioning during aging. Project Number: 1R01AG100231-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Sayaka Inoue | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $326,550 | Activity Code: R01 | Study Section: Behavioral Neuroendocrinology, Neuroimmunology, Rhythms, and Sleep Study Section [BNRS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11341071