Role of the ipRGC Circadian Clock in Visual Perception

项目总结 昼夜节律是一种生物变化，它在一天的24小时内发生作用，使动物能够 预计他们的环境每天都会发生变化。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/清醒周期、进食时间、体温和 荷尔蒙的释放，以及荷尔蒙的干扰会导致各种负面的健康后果。昼夜节律是 由体内几乎每一个组织的单个细胞内的分子“时钟”设置，并且是同步的 由SCN内的中央起搏器协调一天中生理和行为的时间安排。 尽管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 在体内的单个细胞内控制它们在一天中的功能。 最可预测的每日环境变化之一是光/暗周期，它会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，它必须预测和编码视觉刺激 在这个范围内，包含它们自己的分子时钟，并且已知多种视觉行为在 昼夜节律控制。这个项目的目标是使用视网膜作为模型来理解分子时钟是如何 控制细胞功能，最终影响行为。 对比敏感度和瞳孔光反射(PLR)是受昼夜节律控制的两种行为。 表达黑色素的固有的光敏性视网膜神经节细胞(IpRGCs)是 这两种行为都包含了全天振荡的分子时钟。此外，这些细胞 可以用多种遗传工具操纵，使ipRGC成为研究 单细胞对细胞信号和行为的分子时钟。在目标1中，我们将确定是否 IpRGCs的分子时钟是获得合适的PLR和对比度灵敏度所必需的。在目标2中，我们将确定 IpRGC中分子时钟的中断如何影响ipRGC细胞的功能。总的来说，这些 结果将深入了解单个细胞内的分子时钟对细胞信号和 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.