Molecular dissection of glia-neuron interactions

项目总结 我们的长期目标是从分子细节上了解神经胶质在神经系统健康、衰老和疾病中的作用。 人类神经系统有大约相同数量的神经胶质细胞和神经元，并且 这两种细胞类型对神经功能至关重要。神经胶质细胞和神经元接触的一个重要部位是 神经元终末，神经元接受来自其他神经元(神经元间树突棘)或 环境(感官接受--结束)。神经元末端的形状决定了适当的神经元连接性和 功能，包括感官知觉、学习和记忆。虽然可以理解神经胶质细胞可以调节 神经末梢的形态和功能，其背后的分子机制仍然不清楚。的确， 胶质细胞-神经元相互作用的许多基本原理仍不清楚，例如是否所有的胶质细胞-神经元对 使用相同的分子机制相互作用。然而，重要的是要解决我们在 对神经胶质功能的了解，因为神经胶质细胞-神经元相互作用受损与许多神经病学有关 阿尔茨海默氏症、自闭症、癫痫等疾病可能会导致神经功能随着年龄的增长而衰退。 我们建议在活体内从分子细节上剖析胶质细胞与神经元的相互作用，使用线虫作为一种强大的 基因顺从的实验平台。线虫的胶质细胞类似于脊椎动物的胶质细胞，我们最近的研究 已经验证了这是一个快速探测神经胶质细胞-神经元分子相互作用的强大设置。我们之前 确定了胶质细胞与神经元相互作用以调节其形状的两种新的分子机制， 功能和相关的动物行为。我们拥有的这些机制的所有分子成分 到目前为止尚未发现的是广泛表达的，这表明神经胶质细胞与神经元相互作用的各个方面在进化上是 在不同物种之间保存。重要的是，线虫胶质细胞可获得快速和可复制的遗传和 活体内的细胞操作。可以在多个级别的询问中调查这种操纵的效果， 来自分子(遗传、基因组、蛋白质生物化学)、细胞生物学(细胞形状、细胞间接触)和电路 (功能成像，图谱连接组)到动物行为和衰老研究，以及疾病模型 (阿尔茨海默氏症、帕金森氏症)。在这里，我们建议剖析神经胶质细胞-神经元相互作用的分子机制。 整个动物时代的细节。为此，我们将结合我们建立的实验平台，以及 上述技术，以及我们最近发现的多个基因突变，以(1)确定如何 多个分子通路一起使单个胶质细胞-神经元对之间能够相互作用；(2)在 机制详细说明单个神经胶质细胞如何分化相关神经元以不同的方式调节它们，以及(3) 剖析不同的神经胶质细胞-神经元对相互作用以随年龄调节神经元功能的机制。 总之，这些研究将建立一个全面的分子框架，研究神经胶质细胞如何调节 相关神经元在动物整个生命周期中的功能.

PROJECT SUMMARY Our long-term aim is to understand glial roles in nervous system health, aging and disease in molecular detail. The human nervous system has about equal numbers of glia cells and neurons, and interactions between these two cell types is critical for neural functions. An important site of contact between glia and neurons is the neuron-ending, where neurons receive input from other neurons (interneuron dendritic spine) or the environment (sensory receptive-endings). Neuron-ending shape dictates appropriate neuron connectivity and functions, including sensory perception and learning and memory. While it is appreciated that glia modulate neuron-ending shapes and functions, molecular mechanisms underlying this remain poorly defined. Indeed, many fundamental principles of glia-neuron interactions remain unclear, such as whether all glia-neuron pairs interact using identical molecular mechanisms. It is however important to address this gap in our understanding of glial functions, because impaired glia-neuron interactions are implicated in many neurological diseases such as Alzheimer’s disease, Autism, epilepsy and may contribute to neural decline with age. We propose to dissect glia-neuron interactions in molecular detail in vivo, using C. elegans as a powerful and genetically amenable experimental platform. C. elegans glia resemble vertebrate glia, and our recent studies have validated this as a powerful setting to rapidly probe glia-neuron molecular interactions. We previously identified two novel molecular mechanisms by which glia interact with neurons to regulate their shape, functions and associated animal behaviors. All molecular components of these mechanisms that we have uncovered so far are broadly expressed, suggesting that aspects of glia-neuron interactions are evolutionarily conserved across species. Importantly, C. elegans glia are accessible for rapid and reproducible genetic and cellular manipulations in vivo. Effects of such manipulation can be investigated at multiple levels of inquiry, from molecular (genetic, genomic, protein biochemistry), cell-biology (cell shape, cell-cell contacts) and circuits (functional imaging, mapped connectome) to animal behavior and aging studies, and disease models (Alzheimer’s, Parkinson’s). Here, we propose to dissect molecular mechanisms of glia-neuron interactions throughout animal age in detail. For this, we will couple the experimental platform we established, and techniques described above, with the multiple genetic mutants we recently identified to (1) determine how multiple molecular pathways together enable interactions between a single glia-neuron pair; (2) investigate in mechanistic detail how a single glia can differentiate associated neurons to regulate them differently, and (3) dissect mechanisms by which different glia-neuron pairs interact to regulate neuron functions with age. Together, these studies will build a comprehensive molecular framework of how a glia cell modulates the functions of associated neurons throughout animal an animal’s lifespan.