Abstract：
The master circadian clock, located in the suprachiasmatic nuclei (SCN), organizes the daily rhythm in minute ventilation (V̇e). However, the extent that the daily rhythm in V̇e is secondary to SCN-imposed O2 and CO2 cycles (i.e., metabolic rate) or driven by other clock mechanisms remains unknown. Here, we experimentally shifted metabolic rate using time-restricted feeding (without affecting light-induced synchronization of the SCN) to determine the influence of metabolic rate in orchestrating the daily V̇e rhythm. Mice eating predominantly at night exhibited robust daily rhythms in O2 consumption (V̇o2), CO2 production (V̇co2), and V̇e with similar peak times (approximately ZT18) that were consistent with SCN organization. However, feeding mice exclusively during the day separated the relative timing of metabolic and ventilatory rhythms, resulting in an approximately 8.5-h advance in V̇co2 and a disruption of the V̇e rhythm, suggesting opposing circadian and metabolic influences on V̇e. To determine if the molecular clock of cells involved in the neural control of breathing contributes to the daily V̇e rhythm, we examined V̇e in mice lacking BMAL1 in Phox2b-expressing respiratory cells (i.e., BKOP mice). The ventilatory and metabolic rhythms of predominantly night-fed BKOP mice did not differ from wild-type mice. However, in contrast to wild-type mice, exclusive day feeding of BKOP mice led to an unfettered daily V̇e rhythm with a peak time aligning closely with the daily V̇co2 rhythm. Taken together, these results indicate that both daily V̇co2 changes and intrinsic circadian time-keeping within Phox2b respiratory cells are predominant orchestrators of the daily rhythm in ventilation.NEW & NOTEWORTHY The master circadian clock organizes the daily rhythm in ventilation; however, the extent that this rhythm is driven by SCN regulation of metabolic rate versus other clock mechanisms remains unknown. We report that metabolic rate alone is insufficient to explain the daily oscillation in ventilation and that neural respiratory clocks within Phox2b-expressing cells additionally optimize breathing. Collectively, these findings advance our mechanistic understanding of the circadian rhythm in ventilatory control.
摘要：
主昼夜节律时钟，位于视交叉上核（SCN），在分钟通气（VE）中组织每日节奏。然而,VE中的每日节律是SCN施加的O2和CO2循环的次要程度(即，代谢率)，或由其他时钟机制驱动，仍然未知。这里,我们使用限时进食(不影响光诱导的SCN同步)实验改变了代谢率,以确定代谢率对协调每日VE节律的影响.主要在夜间进食的小鼠在O2消耗（VO2）方面表现出强劲的每日节律，二氧化碳产量(VCO2)，和VE具有相似的峰值时间(~ZT18)，与SCN组织一致。然而,只在白天喂养小鼠，将代谢和通气节律的相对时间分开，导致VCO2提前~8.5小时，VE节律中断，提示相反的昼夜节律和代谢对VE的影响。为了确定参与呼吸神经控制的细胞的分子时钟是否有助于日常VE节律，我们检查了在表达Phox2b的呼吸细胞中缺乏BMAL1的小鼠中的VE(即，BKOP小鼠）。主要是夜间喂养的BKOP小鼠的通气和代谢节律与野生型小鼠没有差异。然而,与野生型小鼠相反，BKOP小鼠的独家日饲喂导致不受约束的每日VE节律，其峰值时间与每日VCO2节律密切相关。一起来看,这些结果表明，Phox2b呼吸细胞内的每日VCO2变化和固有的昼夜节律时间保持是通气每日节律的主要协调者。
