Finding time for dinner: neural and molecular mechanisms of food-entrainable circadian clocks

哺乳动物的行为和生理由大脑和外周器官和组织中的内源性昼夜节律(24小时)时钟调节。这些时钟产生每天的睡眠-唤醒、食欲和体温的节奏，并协调所有器官系统的功能，使之与每天的明暗循环和用餐时间相协调。位于下丘脑的主生物钟对于将日常节律同步到明暗周期至关重要，但与进餐时间的同步是由未知位置的一个或多个其他生物钟调节的。我们的研究旨在了解食物调节日常节律的大脑机制。在昼夜节律的分子生物学方面的最新进展已经确定了一些基因，这些基因表现出昼夜节律的表达，并形成产生自我维持的细胞自主节律性的连锁反馈环。我们将使用免疫细胞化学和光度学技术来测量时钟基因，并识别与每天一到两次进餐时间同步振荡的大脑区域。我们将使用损毁技术，探索特定节律脑区在控制进食同步节律中的作用。我们将利用时钟基因突变小鼠来探索特定时钟基因在进食同步节律中的作用。最后，我们将描述进餐时间和食物匮乏对行为和生理节律在明暗周期相变后重新同步的速度的影响，模拟东移或西移或轮班工作。这些研究的结果将阐明食物调节日常节律的神经和分子机制，并可能提出将旅行或轮换后的昼夜节律中断降至最低的技术。

The behaviour and physiology of mammals is regulated by endogenous circadian (24 h) clocks in the brain and in peripheral organs and tissues. These clocks generate daily rhythms of sleep-wake, appetite and body temperature and coordinate the functions of all organ systems with daily cycles of light-dark and mealtimes. A master circadian clock located in the hypothalamus is critical for synchronizing daily rhythms to light-dark cycles, but synchrony to mealtimes is mediated by one or more other circadian clocks at an unknown location. Our research aims to understand the brain mechanisms by which food regulates daily rhythms. Recent advances in the molecular biology of circadian timekeeping have identified a number of genes that exhibit circadian rhythms of expression, and that form interlocking feedback loops that produce self-sustaining, cell autonomous rhythmicity. We will use immunocytochemical and photometric techniques to measure clock genes and identify brain regions that oscillate in synchrony with one or two daily mealtimes. We will explore the role of specific rhythmic brain regions in the control of meal synchronized rhythms, using lesion techniques. We will explore the role of specific clock genes for meal synchronized rhythms using clock gene mutant mice. Finally, we will characterize the effects of meal timing and food deprivation on the rate at which behavioural and physiological rhythms re-synchronize following phase shifts of the light-dark cycle, simulating east or west travel or shift work rotations. The results of these studies will clarify neural and molecular mechanisms by which food regulates daily rhythms and may suggest techniques for minimizing disruption of circadian rhythms following travel or shift rotation.