Circadian output mechanisms in nocturnal and diurnal animals

项目摘要 动物已经进化出昼夜节律（近24小时）来预测和调整它们的行为，以适应日常生活。 机会和挑战，如交配，食物供应和捕食。这些行为节奏 通过中央昼夜节律起搏器，视交叉上核（SCN）与太阳日同步。SCN 神经元在放电率和时钟基因表达方面表现出每日节律，这些基因表达将昼夜节律时间传达给神经元。 大脑和身体的其余部分。然而，关键的是，我们不知道SCN信号如何与分子和细胞相互作用。 下游神经元中的神经元时钟以产生昼夜节律输出。因此，我们实验室的首要目标是 了解来自SCN的昼夜节律输入如何被目标神经元编码，以最终产生不同的 在一天中不同时间达到高峰的行为节奏。为了解决这个问题，在未来五年，我们的研究 该计划将重点关注几个相互关联但独立的主题，包括定义“传递函数”， 昼夜输出电路，确定目标神经元中的分子钟如何有助于行为 节律性，以及理解目标神经元如何整合不同的输入以产生行为节律。 我们认为，下游神经元的内源性节律性和SCN神经元的每日输入都是 需要驱动适当定时的昼夜节律行为输出。在这里，我们将使用多层次分析， 分子、电路和行为水平，包括体内和体外时钟基因的靶向基因组编辑 节律神经元的成像，以及行为的机器学习分析，以剖析 两个互补的物种，夜间活动的实验室小鼠和白天活动的非洲条纹小鼠。奇怪的是， 在日间和夜间动物中，SCN中的分子和神经元活动节律在相似的时间达到峰值。如何 表面上相同的SCN节律决定了这些截然不同的时间生态位吗？我们 这种方法将使我们能够解决这个问题和其他长期存在的问题，在时间生物学，通过确定这两个 暂时组织行为的机制以及分子和神经功能的差异， 决定动物的时间生态位偏好。确定基因，神经元，和电路，调节 实验室小鼠和条纹小鼠的行为时间也将提供一个新的框架， 了解人类生理时钟类型的生物学基础和昼夜节律睡眠的病因学 紊乱通过我们的研究计划，我们将发现的发现可以超越昼夜节律 生物学揭示了基因和电路与行为之间的基本机制。

Project Summary Animals have evolved circadian (near-24 h) rhythms to anticipate and adjust their behavior to daily opportunities and challenges such as mating, food availability, and predation. These behavioral rhythms are synchronized to the solar day by the central circadian pacemaker, the suprachiasmatic nucleus (SCN). SCN neurons exhibit daily rhythms in firing rate and clock gene expression that communicate circadian time to the rest of the brain and body. However, critically, we do not know how SCN signals interact with molecular and neuronal clocks in downstream neurons to generate circadian outputs. Our lab’s overarching goal is thus to understand how circadian input from the SCN is encoded by target neurons to ultimately generate diverse behavioral rhythms that peak at different times of day. To address this, over the next five years, our research program will focus on several interrelated but independent themes, including defining the “transfer function” for circadian output circuits, determining how molecular clocks in target neurons contribute to behavioral rhythmicity, and understanding how target neurons integrate diverse inputs to generate behavioral rhythms. We propose that endogenous rhythmicity in downstream neurons and daily input from SCN neurons are each required to drive appropriately timed circadian behavioral outputs. Here, we will use multi-level analysis at the molecular, circuit, and behavioral levels including targeted genomic editing of clock genes, in vivo and ex vivo imaging of rhythmic neurons, and machine learning analysis of behavior to dissect circadian output circuitry in two complementary species, the nocturnal laboratory mouse and the diurnal African striped mouse. Curiously, molecular and neuronal activity rhythms in the SCN peak at similar times in diurnal and nocturnal animals. How does an ostensibly identical SCN rhythm determine these dramatically different temporal niches? Our approach will allow us to address this and other long-standing questions in chronobiology by identifying both the mechanisms that temporally organize behaviors and the differences in molecular and neural function that decide an animal’s temporal niche preference. Identifying the genes, neurons, and circuits that regulate the timing of behavior in both laboratory mice and striped mice will also provide a novel framework for understanding the biological basis of chronotype in humans and the etiology of circadian rhythm sleep disorders. The discoveries we will make through our research program can generalize beyond circadian biology to reveal fundamental mechanisms linking genes and circuits to behavior.