藉由觀察活體視交叉上核解析近日週期相反應曲線神經網路之研究

Abstract

地球上的生物必須適應和預測日夜週期性變化，以促進它們的生存和適應性，因此能夠受環境光變化調控的內源性生理時鐘至關重要。這些生理時鐘能夠通過根據接收的時鐘刺激來調整其時鐘相位延遲或提前，以與環境協調。這種時鐘相位延遲或提前依賴於時鐘時間接收刺激的特性，被描述為相位響應曲線（phase response curve, PRC）。在哺乳動物中，位於下視丘底部的視交叉上核（suprachiasmatic nucleus, SCN）負責主要的生理時鐘，並整合經視下丘胞束傳遞的環境光信號，觸發生理時鐘的光節律。然而，SCN如何計算PRC仍然不清楚。為了闡明這一問題，我們使用通過梯度折射光纖內窺鏡中繼的螢光基因編碼的鈣指示劑，在未麻醉的小鼠中觀察SCN的急性光響應，這使得可以在不同條件下重複觀察SCN中的相同一組神經元。結果顯示，不同的時鐘時區具有不同的神經元活動模式，包括相位延遲區、相位提前區和行為無反應區。此外，神經元活動與光敏感神經元的組成之間的相關性在不同的時鐘時區之間也發生了變化。與傳統的SCN信息流的簡單階層模型不同，我們的研究結果表明，SCN在早期和晚期主觀夜晚分別處理光信號的雙模式網絡。

Creatures on the earth have to adapt and predict the periodic changes of day and night to facilitate their survival and fitness, which endogenous circadian clocks that can be entrained by the environmental light changes are critical. The clocks can harmonize with the environment by shifting their circadian phase delay or advance dependent on the circadian time receiving stimuli. The circadian time-dependent response function is described as the phase response curve (PRC). In mammals, the suprachiasmatic nucleus (SCN) located in the bottom of the hypothalamus is in charge of the master circadian oscillator and integrating environmental light signals transmitted through the retinohypothalamic tract that trigger photoentrainment of circadian rhythms. However, how the SCN computes PRC remains unclear. To elucidate it, we observe acute light responses of SCN in unanesthetized mice using fluorescent genetically encoded calcium indicators relayed through gradient-index endoscopes, enabling repeated observation of the same set of neurons in the SCN under various conditions. The results showed distinct neuron activity patterns at different circadian time zones, including phase delay zone, phase advance zone, and the behaviorally irresponsive dead zone. Moreover, the correlation between neuron activities and the composition of light-responsive neurons is changed between circadian time zones. Instead of conventional simple hierarchical models of SCN information flow, our findings suggest that SCN employed a bimodal network to process light signals separately in the early and late subjective night.