Regulation of Synchrony and Input Layer Excitability by Purkinje Cell Collaterals

浦肯野细胞络脉对同步性和输入层兴奋性的调节

• 批准号: 9027638
• 负责人: WADE G REGEHR
• 金额: $ 41.69万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-22 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027638
• 关键词: Address; Adolescent; Adult; Anatomy; Animals; Ataxia; Autistic Disorder; Axon; Behavior; Brain; Brush Cell; Cells; Cerebellar Diseases; Cerebellar Nuclei; Cerebellar cortex structure; Cerebellum; Cytoplasmic Granules; Electron Microscopy; Electrophysiology (science); Exhibits; Feedback; Fire - disasters; Functional disorder; Goals; Golgi Apparatus; Impaired cognition; Impairment; Interneurons; Investigation; Lead; Learning; Lobule; Mediating; Morphology; Motor; Mus; Neurons; Newborn Infant; Output; Phase; Play; Process; Property; Purkinje Cells; Regulation; Rest; Role; Site; Slice; Social Behavior; Source; Stratum Granulosum; Synapses; Techniques; Testing; Travel; Work; autism spectrum disorder; cell type; cellular targeting; granule cell; human TFRC protein; in vivo; insight; interest; juvenile animal; light microscopy; motor disorder; motor learning; nervous system disorder; neuronal cell body; oculomotor; optogenetics; public health relevance; ranpirnase

 DESCRIPTION (provided by applicant): The cerebellum is involved in behaviors ranging from motor learning to social behaviors. It is therefore important to understand the cerebellar circuit and how it's dysfunction can lead to neurological disorders, such as ataxia and autism. To accomplish this it is necessary to clarify the function and connectivity of Purkinje cells (PCs), te sole output cells of the cerebellar cortex. Much is known about the intrinsic firing properties, synaptic integration and plasticity of PC inputs. However, it is unclear how PC collaterals allow PCs to influence cells within the cerebellar cortex. Our primary goal is to elucidate the propertie and functional roles of PC collaterals in juveniles and adults by answering several fundamental questions. First, what are the properties of PC collaterals in juveniles and adults and what are their targets? It is known that in newborn mice PC collaterals are prominent. They provide the primary source of inhibition to PCs, and they can mediate widespread travelling waves of activity. This is not the case in older animals where it is not clear if PC collaterals are extensie and what their targets are. Our initial studies indicate that all PCs have extensive collaterals confined to a parasagittal plane. A variety of light and electron microscopy techniques will be used in combination with electrophysiological investigations to identify cellular targets. Second, do PC collaterals allow PCs to regulate the excitability of the input layer of the cerebellum? Optogenetic approaches will be combined with slice and in vivo electrophysiology to determine the targets of PC collaterals within the granular layer and to test the hypothesis that a primary function of the collateral is to allow the output of the cerebellar cortex to feedback and regulate the input layer. Third, do PC collaterals promote synchronous PC firing and do synchronously firing PCs converge on cells in the deep cerebellar nuclei (DCN) to control their spiking? It has been proposed that synchrony allows PCs to control the spiking of cells in the DCN: If PCs fire asynchronously they suppress DCN neuron firing, and if they fire synchronously they promote phase-locked DCN firing. Our initial slice studies suggest that PC collaterals inhibit neighboring PCs and can promote synchronous activity. We will test the hypothesis that the spatial extent of PC collaterals determines the range of synchronous firing in vivo. We will also test the hypothesis that synaptically-connected PCs converge onto the same DCN neuron and regulate its firing. These studies will extend our understanding of cerebellar processing and will provide important insights into neurological disorders that arise from cerebellar dysfunction.

 描述（由申请人提供）：小脑参与从运动学习到社会行为的行为。因此，了解小脑回路及其功能障碍如何导致神经系统疾病，如共济失调和自闭症，是很重要的。要做到这一点，有必要澄清浦肯野细胞（PC），小脑皮质的唯一输出细胞的功能和连接。关于PC输入的内在放电特性、突触整合和可塑性，我们已经知道很多。然而，目前还不清楚PC侧支如何允许PC影响小脑皮质内的细胞。我们的主要目标是通过回答几个基本问题来阐明青少年和成人PC侧支的性质和功能作用。首先，青少年和成年人的PC侧支的性质是什么，它们的靶点是什么？已知在新生小鼠中PC侧支是突出的。它们提供了抑制PC的主要来源，并且它们可以介导广泛的活动行波。在年龄较大的动物中，情况并非如此，因为不清楚PC侧支是否广泛以及它们的靶点是什么。我们的初步研究表明，所有的PC有广泛的侧支局限于一个parastrophic平面。各种光学和电子显微镜技术将与电生理学研究相结合，以确定细胞靶点。第二，PC侧支是否允许PC调节小脑输入层的兴奋性？光遗传学方法将与切片和体内电生理学相结合，以确定颗粒层内PC侧支的靶点，并验证侧支的主要功能是允许小脑皮质的输出反馈和调节的假设 输入层。第三，PC侧支是否促进同步PC放电，以及同步放电的PC是否聚集在小脑深核（DCN）的细胞上以控制它们的尖峰放电？有人提出，同步允许PC控制DCN中细胞的尖峰：如果PC异步激发，它们会抑制DCN神经元的放电，如果它们同步激发，它们会促进锁相DCN放电。我们最初的切片研究表明，PC侧支抑制相邻的PC，可以促进同步活动。我们将测试的假设，PC侧支的空间范围决定了在体内同步放电的范围。我们还将测试突触连接的PC会聚到同一个DCN神经元并调节其放电的假设。这些研究将扩展我们对小脑处理的理解，并将为小脑功能障碍引起的神经系统疾病提供重要的见解。