Age at menopause onset shapes cognitive and inflammatory outcomes in female mice

Menopause is a major endocrinological shift occurring at mid-life that leaves women vulnerable to neuroinflammation, cognitive decline and an increased risk for dementia. However, the effects of endocrine vs. chronological aging in this progression are poorly understood. In our current investigation we assessed whether the age at menopause onset in mice would influence these outcomes. Using young-adult (2.5-month-old) and middle-aged (8-month-old) C57BL/6 J female mice, we modeled menopause via injections of 4-vinylcyclohexene diepoxide (VCD), which accelerates ovarian failure inducing a gradual transition to a peri-menopausal state followed by a menopausal state. Behavioral testing was performed once mice had become acyclic (menopausal). We found that age or menopause each independently reduced distinct estrogen receptors in the brain. Age and menopause status both worsened cognition, with recognition memory impairment being driven by both chronological age and VCD treatment. Spatial recognition memory in the object place test was impacted by age, whereas spatial memory in the Barnes maze was influenced by menopausal status. Markers of neuroinflammation increased primarily with age, while menopause at middle-age exacerbated hippocampal microglia activation. In contrast, peripheral pro-inflammatory cytokines were only influenced by menopause. Overall, we found that menopause onset at middle-age leads to a wider array of behavioral and inflammatory impairments. These findings highlight the need to consider chronological aging as a key biological variable in menopause research, especially when considering critical windows to initiate interventions to prevent cognitive decline through the menopausal transition.