Glial control of neuronal receptive ending morphology

神经胶质细胞对神经元接受末梢形态的控制

• 批准号: 8015937
• 负责人: Shai Shaham
• 金额: $ 42.25万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015937
• 关键词: Accounting; Affect; Anatomy; Animal Behavior; Autistic Disorder; Behavior; Behavioral; Brain; Caenorhabditis elegans; Cell Shape; Cognitive; Complex; Cues; Defect; Dendritic Spines; Disease; Drosophila genus; Human; Learning; Learning Disabilities; Memory; Methods; Molecular; Morphology; Mutation; Nematoda; Nervous system structure; Neuroglia; Neurons; Neurosciences; Output; Pathway interactions; Play; Proteins; Role; Sensory; Shapes; Structure; System; Time; cell type; experience; genetic analysis; in vivo; nervous system disorder; novel; postsynaptic; presynaptic; public health relevance; response; synaptic function

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.

描述（由申请人提供）：我们的长期目的是了解经验改变神经元接受形状的机制。在神经系统中，细胞形状是可延展的。神经元的接受末端，例如树突状刺和感觉突起，在结构上是通过经验重塑的，细胞神经科学的新出现的假设是这些形状的变化适应神经元输出的变化。因此，接收到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。接受结构如何获得和改变形状尚不清楚；但是，已经假定突触后神经元对突触前活性的直接反应解释了现象的大多数方面。在这里，我们挑战了这一观点，表明与接受末端相关的神经胶质细胞在确定接受形状，因此与突触前提示一起起作用。 神经胶质是人脑中最丰富的细胞类型，而神经胶质有助于神经系统疾病。但是，神经胶质在神经系统中扮演的角色仍然很神秘。几种观察结果表明，神经胶质可能会影响神经元接受结束的形状：它们在正确的时间位于正确的位置，它们可以感觉到突触后环境，它们的形状动态地相关，与神经元的接受性细胞形状相关，与某些神经胶质蛋白中的突变会影响接收到的结束形状。我们先前证明了线虫秀丽隐杆线虫提供了一个独特的舞台，可以在其中探索神经系统中的神经胶质功能，从而使对神经胶质功能的体内研究以在脊椎动物环境甚至果蝇中均不适合的方式进行固定。我们建议在秀丽隐杆线虫中使用强大的遗传分析方法来揭示1）胶质影响神经元形状的分子机制，以及2）重塑如何影响神经元的功能和动物行为。从长远来看，我们计划探索对秀丽隐杆线虫以外的途径的保护。 对赋予神经系统具有解剖学和行为可塑性的机制的全面理解对于理解大脑至关重要。这种理解最终应该使我们能够应对人类疾病，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而导致的。 公共卫生相关性：对赋予神经系统具有改变经验的能力的机制进行全面的理解对于理解学习，记忆和大脑的其他方面至关重要。这样的理解最终应该使我们能够解决人类疾病，包括学习障碍和自闭症，这可能是由于这种缺陷而导致的。我们的研究描述了一种新型的系统，即线虫秀丽隐杆线虫，有可能解锁导致经验依赖行为变化的某些机制。