Abstract
Disclosure: E. Torres Jimenez: None. M. Voliotis: None. E.G. Wall: None. I. Lopez: None. S.T. Zdon: None. J. Zhuo: None. V.M. Navarro: None.
Vasomotor symptoms (VMS), characterized by hot flashes and night sweats, significantly impair quality of life during menopause. Estrogen deficiency and subsequent hyperactivity of arcuate KNDy neurons (expressing kisspeptin, neurokinin B, and dynorphin) are implicated in VMS, but the absence of appropriate animal models has limited direct mechanistic studies. Here, we characterized circadian and ultradian changes in core (Tc) and skin (Ts) temperatures as physiological indicators of VMS in ovariectomized (OVX) mice, examining their direct relationship with KNDy neuron activity. Continuous monitoring revealed distinct circadian rhythms that were disrupted after OVX. Specifically, one week after OVX, increased Tc and Ts during the resting (light) phase correlated with elevated cold-seeking behavior, whereas two weeks post-OVX showed a reversed pattern, with decreased Ts and preference for warmer environments, closely mirroring nocturnal VMS experienced by menopausal women. Wavelet analysis revealed notable changes in frequency content and coherence of ultradian oscillations between Ts and Tc following OVX, predominantly during the light phase. Using fiber photometry in Kiss1Cre mice, we observed that KNDy neurons exhibited a higher frequency of synchronous event (SE) activity post-OVX, with a strong correlation between SEs and acute temperature fluctuations characterized by rapid Ts elevations and simultaneous Tc reductions, that resemble VMS. These results establish an effective mouse model capturing critical menopause-related temperature rhythms and provide the first direct evidence linking KNDy neuron activity to VMS. Thus, we present a preclinical model with high translational value for dissecting neuroendocrine mechanisms and evaluating potential therapeutic interventions for menopause-associated VMS.
Presentation: Sunday, July 13, 2025