The Mammalian Circadian Time-Keeping System.
The Mammalian Circadian Time-Keeping System.
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DOI：
10.3233/jhd-230571
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Hastings MH
中科院分区：
文献类型：
--
作者：
Patton AP;Hastings MH
我们的生理和行为遵循精确的日常计划，使我们能够适应白天和黑夜交替出现的机会和挑战。在实验隔离下，这些节律持续大约一天（昼夜节律），这表明它们受到内部自主时钟的控制。昼夜节律时间是在细胞水平上通过转录/翻译反馈环路 (TTFL) 创建的，其中周期和隐花色素基因的蛋白质产物抑制其自身的转录。由于蛋白质的积累缓慢且延迟，系统会自发振荡，周期约为 24 小时。这种细胞自主的 TTFL 控制着所有主要组织中的基因表达周期，这些周期支撑着我们的日常代谢程序。反过来，我们无数的细胞时钟由中央起搏器（下丘脑的视交叉上核（SCN））协调。当在切片培养物中分离时，SCN TTFL 及其依赖的神经活动周期无限期地持续存在，就像“盘子里的时钟”一样。在体内，SCN 时间通过专门的视网膜感光器的直接神经支配与太阳时同步。反过来，动作电位放电的精确昼夜节律周期向下丘脑和脑干目标发出 SCN 生成的时间信号，这些目标协调下游自主、内分泌和行为（进食）线索，以同步和维持分布式细胞时钟网络。因此，昼夜节律时间遍及生物组织的各个层面，从分子到社会。了解其机制为减轻现代社会中普遍存在的昼夜节律紊乱的后果提供了重要的机会，这种紊乱是由轮班工作、衰老和神经退行性疾病（尤其是亨廷顿病）引起的。
Our physiology and behavior follow precise daily programs that adapt us to the alternating opportunities and challenges of day and night. Under experimental isolation, these rhythms persist with a period of approximately one day (circadian), demonstrating their control by an internal autonomous clock. Circadian time is created at the cellular level by a transcriptional/translational feedback loop (TTFL) in which the protein products of the Period and Cryptochrome genes inhibit their own transcription. Because the accumulation of protein is slow and delayed, the system oscillates spontaneously with a period of ∼24 hours. This cell-autonomous TTFL controls cycles of gene expression in all major tissues and these cycles underpin our daily metabolic programs. In turn, our innumerable cellular clocks are coordinated by a central pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus. When isolated in slice culture, the SCN TTFL and its dependent cycles of neural activity persist indefinitely, operating as “a clock in a dish”. In vivo, SCN time is synchronized to solar time by direct innervation from specialized retinal photoreceptors. In turn, the precise circadian cycle of action potential firing signals SCN-generated time to hypothalamic and brain stem targets, which co-ordinate downstream autonomic, endocrine, and behavioral (feeding) cues to synchronize and sustain the distributed cellular clock network. Circadian time therefore pervades every level of biological organization, from molecules to society. Understanding its mechanisms offers important opportunities to mitigate the consequences of circadian disruption, so prevalent in modern societies, that arise from shiftwork, aging, and neurodegenerative diseases, not least Huntington’s disease.