Cellular analysis of mammalian circadian rhythms

这个实验室的主要工作重点是研究日常行为和生理节奏是如何产生的。这包括对下丘脑、视交叉上核的中央时钟的生物学研究，以及如何通过中央时钟或直接通过感觉输入控制全身的时钟等级。因此，拟议的研究遵循两种相互关联的方法。第一个目标是了解中央时钟如何产生昼夜节律。当我们打开老鼠生物钟内的一个基因（酪蛋白激酶-1-epsilon）时，动物的行为节律周期就会缩短。我们现在将制造出只在特定细胞中开启基因的老鼠，看看这些细胞是如何参与节律产生的。第二种方法旨在了解动物如何通过学习一天中重大事件发生的时间来调整它们的日常节奏。这将通过教导动物在一天的特定时间期待食欲或厌恶的情况来实现，然后检查大脑中负责记忆时间的细胞活动是如何以及在哪里发生的。最后，我们将问在没有重要事件的情况下，中央时钟如何能够同步时间学习系统。这项工作将有助于我们理解身体中的多种定时机制是如何协调的。每天的时间调节被认为是成瘾中出现的渴望节奏的基础，而体内许多时钟的内部紊乱已被证明会导致身体和精神问题，如心血管疾病和抑郁症，以及认知障碍。

The primary focus of work in this laboratory is on how daily rhythms of behavior and physiology are generated. This includes research into the biology of the central clock in the hypothalamus, the suprachiasmatic nucleus, as well as how a hierarchy of clocks throughout the body are controlled either by the central clock or directly by sensory input. The proposed research therefore follows two interrelated approaches. The first is aimed at an understanding of how the central clock produces circadian rhythms. When we switch on a gene (casein kinase-1-epsilon) within this clock in a mouse, the period of the animal's behavioral rhythm shortens. We will now produce mice where the gene is switched on only in specific cells, to see how these cells are involved in rhythm generation. The second approach is aimed at understanding how animals adjust their daily rhythms by learning the time of day that significant events occur. This will be accomplished by teaching animals to expect appetitive or aversive conditions at defined times of day, then examining how and where the cellular activity responsible for the time of day memory occurs in the brain. Finally, we will ask how the central clock is able to synchronize the time learning system in the absence of significant event. The work will contribute to our understanding of how multiple timing mechanisms in the body are coordinated. Time of day conditioning is thought to underlie the rhythms of craving seen in addiction, and internal disorganization of the many clocks throughout the body has been shown to lead to physical and mental issues such as cardiovascular disease and depressive disorders, as well as cognitive impairment.