The roles of NK3RMnPO and KNDy neurons in vasomotor symptoms, sleep, and cognition in E2 depleted mice.

Brigham And Women'S Hospital, Boston MA

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Abstract

Vasomotor symptoms (VMS), a major source of distress for menopausal women, are often accompanied by sleep fragmentation and other neurocognitive changes (including stress response, memory, and mood problems), potentially accelerating cognitive aging and increasing the risk of dementia. While low estradiol (E2) levels trigger these symptoms and they can be modified by stress, the underlying neural mechanisms by which this occurs remain unclear. Project C of the Brigham/Harvard Reproductive Outcomes of Stress and Aging (ROSA) SCORE aims to characterize the roles of KNDy neurons in the arcuate nucleus and NK3R-expressing neurons in the median preoptic area in regulating VMS, sleep, and cognitive processes in a mouse model of menopause. We first will characterize the role of NK3R neurons in VMS onset and their interaction with stress, by evaluating expression of stress hormone (glucocorticoid [GC] and CRH) receptors in these neurons and their involvement in stress-induced changes in VMS. Next, we will investigate how KNDy and NK3R neurons contribute to sleep fragmentation and cognitive deficits after E2 depletion, using chemogenetic approaches to selectively activate or inhibit these neurons and then measuring effects on sleep patterns, cognitive performance, and memory. Finally, we will analyze the temporal activity patterns of KNDy and NK3R neurons during sleep, wake, and VMS episodes after E2 withdrawal as well as in response to stress, using in vivo calcium imaging. This work will elucidate the neural circuits underlying VMS, sleep disruption, and cognitive and memory performance (including the role of stress), with the potential to identify new therapeutic targets. By integrating analysis of thermoregulation, sleep, and cognition, we aim to develop a comprehensive understanding of how loss of estrogen and stress exposure impact multiple interrelated systems in a mouse model of estrogen depletion and VMS. These objectives build on our work in the first ROSA SCORE funding period, investigating the role of GC signaling in Kiss1 vs GABA neurons in stress effects on puberty, estrous cyclicity, and VMS. Project C uses a mouse model of menopause to investigate cognitive outcomes that mirror the human condition, enabling deeper exploration of potential shared mechanisms underlying these menopause-related cognitive symptoms and the neuronal networks through which stress is transmitted to influence these health conditions. Project C complements Project A (population level study) and Project B (clinical trial) by providing mechanistic insights into menopause-relevant hypothalamic neuronal networks that influence sleep, mood, and cognition in midlife women and how these networks are modulated by stress. Project C will continue to work with the ROSA SCORE Sleep and Light Resource Core to measure polysomnographic sleep and temperature changes reflecting VMS events in mice, as well as with the Career Enhancement Core to support the advancement of early-career investigators studying the neuroendocrine foundations of menopausal cognitive symptoms that drive risk for dementia in aging women.