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 活动到一天中的特定时间，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古老的控制电路带来了负担。 昼夜同步因此，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 环境线索（zeitgebers）能够重置分子时钟机制。对于哺乳动物来说， 主导的每日时代性是光。在光夹带过程中，通过 光感受器被传送到位于视交叉上核（SCN）的中央昼夜节律钟， 下丘脑使昼夜周期同步。然而，其他线索，如食物的可用性， 社会交往或体育锻炼也会影响SCN的相位。为什么有多种模式的 夹带进化？也许对这些电路进化的最简单的解释是， 通知中央生物钟的突出事件，如食物或伴侣的可用性，在时间上的 独特的利基。这些类型的行为被认为是由神经回路调节的， 多巴胺（DA）。与DA密切相关的SCN独立振子的存在进一步强调了 这种神经递质在建立一个完整的和充分知情的生物定时的重要性 过程在这个提议中，我们假设SCN中增加的DA信号允许中央振荡器 进入一个更“易受诱导”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。为了解决这个问题，我们提供了初步的证据，并提出了两个具体的目标。目标1： 检查选择的一组DA产生细胞和细胞之间的功能连接的存在， SCN中这些连接的受体，其表达DA受体Drd 1。为此，我们建议 通过使用药理学方法测量DA释放和随后SCN-神经元活性的变化， 致动器系统，其提升或抑制遗传定义的DA神经元组的活性。功能 在这个目标中概述的映射策略提供了一个框架来描绘这个以前未定义的神经元。 循环中的昼夜节律在目标2中，我们试图定义DA诱导的细胞凋亡的分子机制。 SCN中表达Drd 1的神经元的激活调节昼夜节律的夹带。为了实现这一目标，我们将 首先证实表达Drd 1的SCN神经元的活性升高或降低调节夹带。 随后，我们确定SCN中DA的释放是否加速了生物钟的夹带，以及是否 SCN中的Drd 1表达对于这种反应是必要的和/或足够的。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意义，可以提供新的 描述中枢神经系统信息处理的原理。

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.