Dynamics of pulsatile activities of arcuate kisspeptin neurons in aging female mice
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eLife assessment
This interesting manuscript assesses calcium dynamics in the kisspeptin neurons of the arcuate nucleus of the hypothalamus during the estrous cycle and during reproductive aging in female mice. In particular, the authors succeed in tracking arcuate kisspeptin calcium activity in the same mice over 10 months, which is quite impressive and provides novel findings that will be of interest to the field.
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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 Ca 2+ 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.
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eLife assessment
This interesting manuscript assesses calcium dynamics in the kisspeptin neurons of the arcuate nucleus of the hypothalamus during the estrous cycle and during reproductive aging in female mice. In particular, the authors succeed in tracking arcuate kisspeptin calcium activity in the same mice over 10 months, which is quite impressive and provides novel findings that will be of interest to the field.
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Reviewer #1 (Public Review):
This interesting manuscript by Goto and Miyamichi analyses calcium dynamics in the kisspeptin neurons of the arcuate nucleus of the hypothalamus during the estrous cycle and during reproductive aging in female mice. In particular, the authors succeed in tracking arcuate kisspeptin calcium activity in the same mice over 10 months, which is quite impressive and brings highly valuable information. The authors demonstrate that the frequency and the amplitude and waveforms of individual synchronous episodes of arcuate kisspeptin neuronal activation vary across the estrous cycle. Unexpectedly, however, aging does not appear to alter markedly calcium dynamics in these neurons.
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Reviewer #2 (Public Review):
Goto and Miyamachi aimed to use fiber photometry to chronically record the activity of arcuate kisspeptin neurons, widely accepted as the GnRH pulse generator responsible for reproductive potential, to determine whether changes in their activity occur during the transition to reproductive senescence in female mice. The authors report that reduced estrous cycle regularity in aging mice is accompanied by changes in the amplitude, but not the frequency, of kisspeptin events. They conclude that the reduction in kisspeptin event amplitude may explain prior results showing reduced LH pulse amplitude in aged rats, potentially due to a reduction in kisspeptin expression. The following is a description of the strengths and weaknesses of this study.
Strengths: Fiber photometry recordings of kisspeptin cells in …
Reviewer #2 (Public Review):
Goto and Miyamachi aimed to use fiber photometry to chronically record the activity of arcuate kisspeptin neurons, widely accepted as the GnRH pulse generator responsible for reproductive potential, to determine whether changes in their activity occur during the transition to reproductive senescence in female mice. The authors report that reduced estrous cycle regularity in aging mice is accompanied by changes in the amplitude, but not the frequency, of kisspeptin events. They conclude that the reduction in kisspeptin event amplitude may explain prior results showing reduced LH pulse amplitude in aged rats, potentially due to a reduction in kisspeptin expression. The following is a description of the strengths and weaknesses of this study.
Strengths: Fiber photometry recordings of kisspeptin cells in unanesthetized, freely moving mice at multiple time points over a period of months are technically impressive and a strong approach for interrogating changes in kisspeptin cell physiology that may control the reproductive lifespan of mice.
Weaknesses: Although the approach to use chronic imaging of kisspeptin cells from the same animal from 6 months to 15-18 months is impactful; this has only been conducted in two animals. The correlation between LH pulsatile secretion and kisspeptin activity has been well characterized in mice of reproductive ages in prior reports, however, no accompanying LH pulse measurements have been included in this study, and it is possible that the relationship between kisspeptin activity and LH secretion changes during the transition to acyclicity. The paper lacks a clear description of the parameters used to define acyclicity and to affirm that mice have reached reproductive senescence. Finally, the paper lacks histological analysis of the recorded kisspeptin cells, and although the viral vector used in this study has been well characterized, there is a potential for cytotoxicity from repeated imaging and long-term transfection of the vector.
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