Circadian output mechanisms in nocturnal and diurnal animals

夜间和白天动物的昼夜节律输出机制

基本信息

批准号：
10713602
负责人：
JEFFREY R JONES
金额：
$ 37.55万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

项目摘要

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.

项目摘要动物已经进化了昼夜节律（接近24 h）的节奏，以预测并调整其行为每天机会和挑战，例如交配，粮食可用性和掠夺。这些行为节奏是由中央昼夜节奏起搏器（SCN）同步到太阳日。 SCN 神经元暴露于发射速率和时钟基因表达中的节奏，这些节奏将昼夜节律传达给大脑和身体的其余部分。但是，至关重要的是，我们不知道SCN信号如何与分子和下游神经元中的神经元时钟可产生昼夜节律输出。因此，我们实验室的总体目标是了解目标神经元如何编码SCN的昼夜节律输入，以最终产生潜水员在一天中的不同时间达到顶峰的行为节奏。为了解决这个问题，在接下来的五年中，我们的研究计划将重点关注几个相互关联但独立的主题，包括定义“转移功能” 昼夜节律电路，确定目标神经元中的分子钟如何促进行为节奏性，并了解靶向神经元如何整合潜水员的输入以产生行为节奏。我们建议下游神经元中的内源性节奏和SCN神经元的每日输入是需要适当定时的昼夜节律行为输出。在这里，我们将在分子，电路和行为水平，包括时钟基因的靶向基因组编辑，体内和ex vivo 节奏神经元的成像以及行为的机器学习分析，以剖析昼夜节律电路两个完整的物种，夜间实验室小鼠和昼夜非洲条纹小鼠。奇怪的是在昼夜和夜间动物中，SCN峰的分子和神经元活性节奏。如何表面上是否相同的SCN节奏决定了这些截然不同的临时壁ni？我们的方法将使我们能够通过识别这两者来解决时间生物学和其他长期存在的问题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临时利基偏好。识别调节的基因，神经元和圆圈实验室小鼠和条纹小鼠的行为时机还将为了解人类时型的生物学基础和昼夜节律睡眠的病因疾病。我们将通过研究计划进行的发现可以推广到昼夜节律之外生物学揭示将基因和电路与行为联系起来的基本机制。