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各种行为，因此了解小脑回路及其功能障碍如何导致共济失调和自闭症等神经系统疾病非常重要。阐明浦肯野细胞 (PC) 的功能和连接性是必要的，浦肯野细胞是小脑皮质的唯一输出细胞，人们对 PC 的内在放电特性、突触整合和可塑性了解很多。然而，目前尚不清楚 PC 侧枝循环如何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 PC 侧枝循环的特性和功能作用。 PC 络合物在幼年和成年小鼠中的作用以及它们的目标是什么？众所周知，PC 络合物在新生小鼠中是重要的，它们是 PC 的主要抑制来源，并且它们可以介导广泛的行波活动。在老年动物中，尚不清楚 PC 侧枝是否广泛以及其目标是什么，我们的初步研究表明，所有 PC 都有广泛的侧枝，局限于矢状面，将与多种光学和电子显微镜技术结合使用。其次，PC 侧支是否可以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来确定 PC 的目标。颗粒层内的络脉，并检验络络的主要功能是允许小脑皮层的输出进行反馈和调节的假设 第三，PC 侧支是否会促进同步 PC 放电，并且同步放电 PC 是否会汇聚到小脑深部核团 (DCN) 的细胞上以控制其尖峰？有人提出，同步性允许 PC 控制小脑深部核中细胞的尖峰。 DCN：如果 PC 异步放电，它们会抑制 DCN 神经元放电，如果它们同步放电，则会促进锁相 DCN 放电。我们最初的切片研究表明，PC 侧支会抑制相邻的 PC 和 DCN 神经元放电。我们将检验 PC 侧支的空间范围决定体内同步放电范围的假设。我们还将检验突触连接的 PC 汇聚到同一 DCN 神经元并调节其放电的假设。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。