Network Properties of Circadian Clock Modulation and Entrainment

描述（由申请人提供）：我们对大脑昼夜节律计时的理解的突破对于改善伴随人类昼夜节律失调的代谢和心理病理是必要的。本提案的目标是严格测试和扩展果蝇时钟神经元网络调制和携带的当前模型。这种苍蝇的神经系统有几个显著的特征，使它成为一个有价值的昼夜节律模型。我们最近开发了一套新的实时成像工具，用于调查成年果蝇大脑中的中枢神经元网络。这些方法使得测量Ca2+和cAMP在中枢神经网络中的动态与基因定义的神经元亚群的急性刺激相一致成为可能。利用这些新技术，结合成熟的遗传、解剖学和行为学方法，我们将研究昼夜节律调节和夹带的神经生理学基础，这两个密切相关的过程是伴随现代生活的与昼夜节律失调相关的病理的核心。在我们的第一个目标中，我们将确定关键腹侧时钟神经元的胆碱能和gaba能调节在睡眠/活动节律和光周期的干扰中所起的作用。在我们的第二个目标中，我们将识别并从生理上表征调节生物钟神经元网络的神经光输入通路，并从基因上确定这些通路在光夹带中发挥的作用。在我们的第三个也是最后一个目标中，我们将采用新的电路询问方法来确定腹侧和背侧时钟神经元之间的调节连接的生理性质，这些连接是如何日常和季节性调节的，并将使用遗传方法来确定两个腹侧到背侧的肽能连接在维持和调节昼夜节律时所起的具体作用。这项提议的目标是推进我们对大脑中昼夜节律计时和娱乐的理解。我们相信，这项工作的成果将最终有助于开发和实施干预措施，以减轻昼夜节律功能障碍对代谢和心理的显著不利影响。

DESCRIPTION (provided by applicant): Breakthroughs in our understanding of circadian timekeeping in the brain will be necessary to ameliorate the metabolic and psychological pathologies that accompany human circadian misalignment. The goal of this proposal is to critically test and extend current models of clock neuron network modulation and entrainment in Drosophila. The nervous system of this fly has several remarkable features that make it a valuable model for circadian timekeeping. We have recently developed a new set of live-imaging tools for the interrogation of central neuron networks in the adult Drosophila brain. These methods have made it possible to measure Ca2+ and cAMP dynamics in central neuronal networks in concert with the acute stimulation of genetically defined neuronal subsets. Using these new techniques, coupled with well-established genetic, anatomical, and behavioral methods, we will investigate the neurophysiological basis of circadian modulation and entrainment, two closely related processes that are central to the pathologies associated with the circadian misalignment that accompanies modern life. In our first aim we will determine the roles that cholinergic and GABAergic modulation of critical ventral clock neurons plays in the entrainment of sleep/activity rhythms to light cycles. In our second aim, we will identify and physiologically characterize the neural light input pathways that modulate the circadian clock neuron network and genetically determine the roles these pathways play in light entrainment. In our third and final aim, we will employ new methods of circuit interrogation to determine the physiological nature of the modulatory connections between the ventral and dorsal clock neuron classes, how these connections are daily and seasonally adjusted, and will use genetic methods to identify the specific roles that two ventral-to-dorsal peptidergic connections play in the maintenance and adjustment of circadian timekeeping. The goal of this proposal is to advance our understanding of circadian timekeeping and entrainment in the brain. We believe that the fruits of this work will ultimately aid the development and implementation of interventions designed to alleviate the significantly adverse metabolic and psychological effects of circadian dysfunction.