Dynamics of pulsatile activities of arcuate kisspeptin neurons in aging female mice.

Abstract

Reproductive senescence is broadly observed across mammalian females, including humans, eventually leading to a loss of fertility. The pulsatile secretion of gonadotropin-releasing hormone (GnRH), which is essential for gonad function, is primarily controlled by kisspeptin neurons in the hypothalamic arcuate nucleus (ARC^kiss), the pulse generator of GnRH. The pulsatility of GnRH release, as assessed by the amount of circulating gonadotropin, is markedly reduced in aged animals, suggesting that the malfunctions of ARC^kiss may be responsible for reproductive aging and menopause-related disorders. However, the activity dynamics of ARC^kiss during the natural transition to reproductive senescence remain unclear. Herein, we introduce chronic in vivo Ca²⁺ imaging of ARC^kiss in female mice by fiber photometry to monitor the synchronous episodes of ARC^kiss (SEs^kiss), a known hallmark of GnRH pulse generator activity, from the fully reproductive to acyclic phase over 1 year. During the reproductive phase, we find that not only the frequency, but also the intensities and waveforms of individual SEs^kiss, vary depending on the stage of the estrus cycle. During the transition to reproductive senescence, the integrity of SEs^kiss patterns, including the frequency and waveforms, remains mostly unchanged, whereas the intensities tend to decline. These data illuminate the temporal dynamics of ARC^kiss activities in aging female mice. More generally, our findings demonstrate the utility of fiber-photometry-based chronic imaging of neuroendocrine regulators in the brain to characterize aging-associated malfunction.