Glial Cell Regulation of Circadian Behavior

描述（由申请人提供）：人类大脑含有超过1000亿个细胞，其中大多数是不可兴奋的胶质细胞。最近的研究，包括申请人实验室的研究，表明脊椎动物和无脊椎动物神经系统的胶质细胞在生理和行为过程的调节中具有显著的动态作用。哺乳动物的研究表明，神经元和神经胶质细胞相互交流，这就产生了“三方突触”模型，其中神经胶质细胞（星形胶质细胞）与突触前和突触后神经元元件合作，调节交流事件和行为过程（见意义）。申请人实验室最近的研究描述了果蝇星形胶质细胞在调节昼夜节律行为中的作用。其他研究也证实了果蝇胶质细胞在调节神经传递和行为方面的其他功能（见Jackson和Haydon， 2008）。在目前的应用中，我们提出了实验来阐明胶质细胞在昼夜节律计时中的功能。我们的研究将采用果蝇，以便能够利用复杂的遗传技术来研究昼夜节律系统中神经元-胶质细胞的相互作用。这项工作将利用创新的遗传、行为、成像和电生理方法，重要的是，PI和co-I在这些领域具有互补的优势。我们提出了三个具体目标，将测试关于昼夜节律系统中神经元-胶质细胞相互作用的明确假设：(1)测试胶质传递或其他胶质过程对昼夜节律行为至关重要的假设；(2)验证神经胶质调节起搏器神经元的假说；(3)验证时钟神经元调节神经胶质节律的假设。我们期望这些研究的结果将突出神经元和胶质细胞合作影响昼夜节律和其他行为的一般机制。在大多数神经系统疾病和精神状态中，神经胶质细胞基因表达谱发生改变，这很可能引发大脑中剧烈的结构/功能变化，从而导致这些疾病。神经胶质细胞生物学的改变与精神和神经退行性疾病有关，包括多发性硬化症（MS）、肌萎缩侧索硬化症（ALS）、精神分裂症、癫痫和阿尔茨海默氏症。我们提出的神经胶质和昼夜节律控制机制的研究对于理解由昼夜节律系统的环境或遗传扰动引起的时差和睡眠/觉醒障碍等病理生理状况具有重要意义。昼夜节律系统的分子组成部分在昆虫和哺乳动物（包括人类）之间是保守的，果蝇是进行昼夜节律行为遗传研究的杰出模型。预计我们提出的研究结果将为神经胶质细胞与控制行为的神经回路的相互作用提供重要的和普遍的见解，这些见解对于理解神经胶质细胞在健康和疾病中的作用至关重要。

DESCRIPTION (provided by applicant): The human brain contains more than 100 billion cells, the majority being non-excitable glial cells. Recent studies, including those from the applicant's lab, demonstrate that glial cells of vertebrate and invertebrate nervous systems have remarkably dynamic roles in the regulation of physiological and behavioral processes. Studies in mammals have demonstrated that neurons and glia communicate with one another and this has given rise to a model of the "tripartite synapse" wherein a glial cell (an astrocyte) cooperates with presynaptic and postsynaptic neuronal elements to regulate communication events and behavioral processes (see Significance). Recent studies from the applicant's lab describe a role for a defined population of Drosophila astrocytes in the regulation of circadian behavior. Other studies have documented additional functions for fly glia in the regulation of neurotransmission and behavior (reviewed in Jackson and Haydon, 2008). In the present application, we propose experiments to elucidate the functions of glia in circadian timing. Our studies will employ Drosophila so as to be able to utilize sophisticated genetic techniques to study neuron-glia interactions in the circadian system. The work will utilize innovative genetic, behavioral, imaging and electrophysiological approaches and, importantly, the PI and co-I have complementary strengths in these areas. We propose three specific aims that will test explicit hypotheses about neuron-glia interactions in the circadian system: (1) Test the hypothesis that gliotransmission or other glial processes are essential for circadian behavior; (2) Test the hypothesis that glia regulate pacemaker neurons; and (3) Test the hypothesis that clock neurons regulate glial rhythms. We expect that the results of these studies will highlight general mechanisms by which neurons and glia cooperate to influence circadian rhythmicity and other behaviors. In most neurological disorders and psychiatric states, glial cell gene expression profiles are altered, and it is likely that this initiates dramatic structural/functional changes in the brain that lead to these disorders. Alterations of glial cell biology have been implicated in mental and neurodegenerative diseases including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), schizophrenia, epilepsy, and Alzheimer's. Our proposed studies of glia and circadian control mechanisms have considerable significance for an understanding of pathophysiological conditions such as jetlag and sleep/wake disorders resulting from environmental or genetic perturbations of the circadian system. Molecular components of the circadian system are conserved between insects and mammals, including humans, and Drosophila is an outstanding model for conducting genetic investigations of circadian behavior. It is anticipated that the results of our proposed studies will provide important and general insights about the interaction of glia with the neuronal circuitry controlling behavior, insights which are critical for understanding the roles of glial cells in health and disease. PUBLIC HEALTH RELEVANCE: The human brain contains more than 100 billion cells, the majority being non-excitable glial cells; we propose studies that will utilize behavioral measures, imaging technology and other neurobiological methods to understand communication between neurons and glia of the adult nervous system. The model we propose to use for understanding neuron-glia communication is the circadian clock system as much is known about the neural circuitry responsible for circadian behavior. Our proposed studies have significance for understanding the roles of glia and neuron-glia communication in health and many different neurological diseases.