Glial control of neuronal receptive ending morphology

描述（由申请人提供）：我们的长期目标是了解神经元感受器末端形状因经验而改变的机制。在神经系统中，细胞的形状是可塑的。神经元的感受性末梢，如树突棘和感觉突起，在结构上被经验重塑，细胞神经科学中的一个新兴假设是，这些形状变化适应并定义了神经元输出的变化。因此，感受器末梢结构的改变可能是神经系统可塑性的基础，并可能有助于复杂的认知能力，包括学习和记忆。感受性末梢结构如何获得和改变形状还没有很好的理解;然而，人们认为突触后神经元对突触前活动的直接反应解释了这种现象的大部分方面。在这里，我们挑战这一观点，认为神经胶质细胞与感受性末梢起着重要作用，在确定感受性末梢的形状，因此功能，与突触前的线索。 胶质细胞是人脑中最丰富的细胞类型，并且胶质细胞广泛地促进神经系统疾病。然而，神经胶质细胞在神经系统中扮演的角色在很大程度上仍然是个谜。一些观察结果表明，胶质细胞可以影响神经元受体末端的形状：它们在正确的时间出现在正确的位置，它们可以感知突触后环境，它们的形状与神经元受体末端细胞的形状动态相关，一些胶质蛋白的突变会影响受体末端的形状。我们以前证明，线虫C。elegans提供了一个独特的竞技场，在其中探索神经系统中的胶质功能，允许以目前在脊椎动物环境中甚至在果蝇中不可能的方式进行胶质功能的体内研究。我们建议使用强大的遗传分析方法在C。elegans揭示1）胶质细胞影响神经元形状的分子机制，以及2）重塑如何影响神经元功能和动物行为。从长远来看，我们计划探索我们确定的C以外的途径的保护。优雅 全面理解赋予神经系统解剖和行为可塑性的机制对理解大脑至关重要。这样的理解最终将使我们能够解决人类疾病，包括学习障碍和自闭症，这可能是由于突触功能和可塑性的改变造成的。 公共卫生相关性：全面理解赋予神经系统响应经验的能力的机制对于理解学习，记忆和大脑的其他方面至关重要。这样的理解最终将使我们能够解决人类疾病，包括学习障碍和自闭症，这可能是由于这些缺陷造成的。我们的研究描述了一个新的系统，线虫C。elegans，有可能解开一些导致行为经验依赖性变化的机制。

DESCRIPTION (provided by applicant): Our long-term aim is to understand the mechanism by which neuronal receptive-ending shape is altered by experience. In the nervous system, cell shape is malleable. Neuronal receptive endings, such as dendritic spines and sensory protrusions, are structurally remodelled by experience, and an emerging hypothesis in cellular neuroscience is that these shape changes accommodate and define changes in neuron output. Alterations in receptive-ending structures may, therefore, underlie nervous system plasticity, and may contribute to complex cognitive capacities including learning and memory. How receptive-ending structures acquire and change shape is not well understood; however, it has been assumed that a direct response of postsynaptic neurons to presynaptic activity accounts for most aspects of the phenomenon. Here we challenge this view, suggesting that glial cells associated with receptive endings play major roles in determining receptive-ending shape, and therefore function, together with presynaptic cues. Glia are the most abundant cell type in the human brain, and glia contribute extensively to nervous system disease. However, the roles played by glia in the nervous system remain largely mysterious. Several observations suggest that glia could influence the shapes of neuronal receptive-endings: they are in the right place at the right time, they can sense the postsynaptic milieu, their shapes correlate dynamically with neuronal receptive-ending cell shapes, and mutations in some glial proteins affect receptive ending shape. We previously demonstrated that the nematode C. elegans offers a unique arena in which to explore glial functions in the nervous system, allowing in vivo studies of glial function to be adresed in ways curently not posible in vertebrate settings or even in Drosophila. We propose to use the powerful methods of genetic analysis in C. elegans to uncover 1) the molecular mechanisms by which glia affect neuronal shape, and 2) how remodeling afects neurons function and animal behavior. In the longer term, we plan to explore conservation of the pathways we identify beyond C. elegans. Achieving a comprehensive understanding of the mechanisms that endow nervous systems with anatomic and behavioural plasticity is of paramount importance in understanding the brain. Such an understanding should, eventually, allow us to tackle human disorders, including learning disabilities and autism, which may result from alterations in synaptic function and plasticity. PUBLIC HEALTH RELEVANCE: Achieving a comprehensive understanding of the mechanisms that endow nervous systems with the ability to change in response to experience is of paramount importance in understanding learning, memory and other aspects of the brain. Such an understanding should ultimately allow us to tackle human disorders, including learning disabilities and autism, which may result from defects in such. Our studies describe a novel system, the nematode C. elegans, with the potential to unlock some of the mechanisms leading to experience-dependent changes in behavior.