Role of the ipRGC Circadian Clock in Visual Perception

项目摘要 昼夜节律是一种生物学变化，它在一天的24小时内起作用，使动物能够 预测环境的日常变化。这些节律控制着动物生理的许多方面 以及对生存至关重要的行为，包括睡眠/觉醒周期，食物摄入时间，体温， 激素释放，它们的中断导致各种负面的健康结果。昼夜节律是 由包含在身体几乎每个组织中的单细胞内的分子“时钟”设定， 通过SCN内的中央起搏器来协调一天中生理和行为的时间。 尽管有大量的生物过程受到昼夜节律的控制，而且人们对昼夜节律的认识也在不断提高， 生物钟紊乱对人类健康的负面影响，人们对分子钟的作用知之甚少 在整个身体的单个细胞内控制它们在一天中的功能。 最可预测的日常环境变化之一是光/暗周期，它在几个月内发生变化。 从中午到午夜的数量级。视网膜神经元，必须预测和编码视觉刺激 在这个范围内，包含自己的分子钟，并且已知多种视觉行为在 昼夜节律控制这个项目的目标是用视网膜作为模型来理解分子钟是如何 控制细胞功能，最终影响行为。 对比敏感度和瞳孔对光反射（PLR）是受昼夜节律控制的两种行为。 表达黑视素的固有光敏视网膜神经节细胞（ipRGC）是视网膜神经节细胞凋亡的主要贡献者。 这两种行为都包含了全天振荡的分子钟。此外，这些细胞 可以用多种遗传工具操纵，使ipRGC成为研究 单细胞的分子钟到细胞信号和行为。在目标1中，我们将确定 ipRGC的分子钟对于适当的PLR和对比敏感度是必需的。在目标2中，我们将确定 ipRGC中分子时钟的破坏如何影响ipRGC细胞功能。统称 结果将提供深入了解单细胞内分子钟对细胞信号传导的影响， 行为

PROJECT SUMMARY Circadian rhythms are biological changes that act over the course of the 24 hour day to allow animals to anticipate daily changes to their environment. These rhythms control many aspects of an animal’s physiology and behavior crucial for survival, including sleep/wake cycles, timing of food intake, body temperature, and hormone release, and their disruption leads to a variety of negative health outcomes. Circadian rhythms are set by molecular “clocks” contained within single cells in nearly every tissue of the body and are synchronized by the central pacemaker within the SCN to coordinate the timing of physiology and behavior across the day. Despite the huge number of biological processes under circadian control and increased awareness of the negative impacts of circadian disruption on human health, little is understood about how molecular clocks act within single cells throughout the body to control their function over the course of the day. One of the most predictable daily environmental changes is the light/dark cycle, which changes over several orders of magnitude from midday to midnight. Retinal neurons, which must anticipate and encode visual stimuli over this range, contain their own molecular clocks, and multiple visual behaviors are known to be under circadian control. The goal of this project is to use the retina as a model to understand how molecular clocks control cellular function to ultimately influence behavior. Contrast sensitivity and the pupillary light reflex (PLR) are two behaviors that are under circadian control. Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are major contributors to both of these behaviors and contain molecular clocks that oscillate throughout the day. Moreover, these cells can be manipulated with multiple genetic tools, making ipRGCs an excellent model for studying the impact of the molecular clocks of single cells to cell signaling and behavior. In Aim 1 we will determine whether the molecular clock of ipRGCs is necessary for proper PLR and contrast sensitivity. In Aim 2 we will determine how ipRGC cellular function is impacted by disruption of the molecular clock in ipRGCs. Collectively these results will provide insight into the impact of molecular clocks within single cells on cellular signaling and behavior.