Regulation of central circadian rhythms by dopamine

项目摘要/摘要：我们的生物钟已经进化到同步行为和生理 在一天中的特定时间进行活动，以优化生存。尽管达尔文主义的压力已经下降 对人类来说，现代社会的许多新出现的压力给我们的古老电路带来了负担 昼夜节律同步。因此，新的病理正在出现，包括精神、心血管、代谢 疾病和癌症。生物节律的同步过程，称为夹带，需要 能够重置分子时钟机制的环境线索(计时器)。对于哺乳动物来说，最 占主导地位的每日时代潮流是清淡的。在光携带期间，由检测到的环境光水平 光感受器被传递到位于视交叉上核(SCN)的中央昼夜节律钟 下丘脑允许与昼夜周期同步。然而，其他线索，如食物的可用性， 社会互动或体育锻炼也会影响SCN的阶段。为什么有多种模式的 夹带进化了吗？也许对这些电路进化最简明的解释是它们 向中央生物钟通知显著的事件，如在临时的 独特的利基市场。这些类型的行为被认为是由与 多巴胺(DA)。与DA进一步突出密切相关的SCN独立振荡器的存在 这种神经递质在建立一个完整和信息充分的生物计时过程中的重要性 进程。在这个方案中，我们假设SCN中增加的DA信令允许中央振荡器 进入一种更容易被夹带的状态，在这种状态下，新的线索能够更多地调整生物钟 很容易。为了解决这一想法，我们提供了初步证据，并提出了两个具体目标。在目标1中，我们 检查在选定的一组DA产生细胞和 这些连接的受体位于SCN，表达DA受体DRD1。为此，我们建议 用药理学方法测量DA释放和SCN神经元活动的后续变化 提高或抑制一组遗传上定义的DA神经元的活动的致动器系统。功能界别 在本目标中概述的映射策略提供了描述先前未定义的神经的框架 昼夜节律卷吸中的回路。在目标2中，我们试图定义DA如何诱导的分子机制(S SCN中DRD1表达的神经元的激活调节了昼夜节律的牵引力。为了实现这一目标，我们将 首先，确认表达DRD1的SCN神经元活性的升高或降低调节了夹带作用。 随后，我们确定了SCN中DA的释放是否加速了昼夜节律时钟的携带，以及 SCN中的DRD1表达对于这种反应是必要的和/或充分的。调查结果和建议 这里概述的实验具有超越昼夜节律夹带的影响，并可能提供新的 描述整个中枢神经系统信息处理的原则。

Project Summary/Abstract: Our circadian clocks have evolved to synchronize behavioral and physiological activities to a specific time of the day in order to optimize survival. Although Darwinian pressures have declined for humans, many of the emergent stresses of modern society burdens our ancient circuitry governing circadian synchrony. As such, new pathologies are emerging including mental, cardiovascular, metabolic disorders and cancer. The synchronization process of biological rhythms, termed entrainment, requires environmental cues (zeitgebers) that are able to reset the molecular clock machinery. For mammals, the most dominant daily zeitgeber is light. During photoentrainment, the ambient light levels that are detected by photoreceptors are conveyed to the central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus to permit synchrony to day/night cycles. However, other cues such as availability of food, social interactions or physical exercise also influence the phase of the SCN. Why have multiple modes of entrainment evolved? Perhaps the most parsimonious explanation for the evolution of these circuits is that they inform the central circadian clock of salient events such as availability of food or a mate during a temporally distinct niche. These types of behaviors are thought to be regulated by neural circuits associated with dopamine (DA). Existence of SCN independent oscillators that are closely associated with DA further highlights the importance of this neurotransmitter in establishment of an integrated and well informed biological timing process. In this proposal, we hypothesize that increased DA signaling in the SCN allows the central oscillator to enter a more “entrainment susceptible” state where new cues are able to adjust the circadian clock more readily. To address this idea we provide preliminary evidence and propose two specific aims. In Aim 1, we examine the existence of a functional connection between a select group of DA producing cells and the recipients of these connections in the SCN, which express the DA receptor Drd1. To this end, we propose to measure DA release and ensuing changes in SCN-neuron activity by using pharmacological methods and actuator systems that elevate or inhibit the activity of a genetically defined group of DA-neurons. The functional mapping strategy outlined in this aim provides the framework to delineate this previously undefined neural circuit in circadian entrainment. In Aim 2, we seek to define the molecular mechanism(s) of how DA-induced activation of Drd1-expressing neurons in the SCN modulates circadian entrainment. To accomplish this, we will first confirm that elevated or reduced activity of Drd1-expressing SCN neurons modulates entrainment. Subsequently, we determine whether DA release in the SCN hastens circadian clock entrainment and whether Drd1 expression in the SCN is necessary and/or sufficient for this response. The findings and proposed experiments outlined here have implications beyond the circadian entrainment and could provide new principles in delineating information processing in the central nervous system at large.