Dendritic morphology, patterns of input, and calcium signal heterogeneity in a novel subpopulation of cerebellar Purkinje cells

小脑浦肯野细胞新亚群的树突形态、输入模式和钙信号异质性

• 批准号: 10534975
• 负责人: Silas Edward Busch
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534975
• 关键词: Affect; Anatomy; Animals; Architecture; Ataxia; Axon; Calcium; Calcium Signaling; Cell physiology; Cells; Cellular Morphology; Cerebellar Cortex; Cerebellar Diseases; Cerebellum; Characteristics; Cognitive; Complex; Data Analyses; Dendrites; Dependence; Development; Disease; Educational process of instructing; Electrophysiology (science); Elements; Emotional; Essential Tremor; Event; Exhibits; Fiber; Frequencies; Functional disorder; Goals; Heterogeneity; Image; In Vitro; Individual; Inferior; Instruction; Knowledge; Learning; Measurable; Mediating; Methods; Modality; Morphology; Motor; Mus; Neurons; Olives - dietary; Output; Pathway interactions; Pattern; Performance; Physiological; Physiology; Picrotoxin; Preparation; Presynaptic Terminals; Process; Purkinje Cells; Research; Research Personnel; Rest; Role; Running; Sensory; Severities; Signal Transduction; Source; Structure-Activity Relationship; System; Techniques; Testing; Tracer; Training; Trees; Update; Work; autism spectrum disorder; awake; cell type; confocal imaging; design; experimental study; granule cell; in vivo; insight; mouse model; multimodality; multisensory; nerve supply; network models; neural network; neuronal cell body; novel; operation; overexpression; patch clamp; response; sensory input; targeted treatment; theories; two-photon

Project Summary The cerebellum optimizes motor and non-motor performance by integrating input signals encoding prediction error with input relaying a spectrum of multisensory and contextual information. These input pathways–carried by climbing fiber axons (CFs) from the inferior olive and parallel fiber axons (PFs) of cerebellar granule cells, respectively–converge on the elaborate dendritic arbor of Purkinje cells (PCs), the primary cell type and sole output of the cerebellar cortex. Theories of cerebellar function are centered around PC-mediated integration and rely on the principles that each PC: 1) is a structurally and functionally redundant unit in the cerebellar cortex, 2) receives olivary ‘teaching’ signal input from only one CF, and 3) exhibits homogenous signaling across the entire dendritic tree. The specific aims of this proposal are designed to challenge the universality of these principles by revealing a ‘super-integrator’ PC subpopulation characterized by input from multiple CFs and non-homogenous signaling across dendrites. These PCs are defined morphologically by segregated dendritic compartments from either the early bifurcation of their primary dendrite (‘Split’) or multiple primary dendrites emerging from the soma (‘Poly’). ‘Super-integrator’ PCs are defined functionally by the presence of non-homogenous dendritic signaling produced by independent input to each compartment, such as from multi-CF innervation. This study will examine the anatomical CF→PC connection, describe signal heterogeneity in PC dendritic compartments, and examine how these functional elements affect integration during multisensory processing. To comprehensively assess these anatomical and functional features of PCs, experiments will be balanced between tightly controlled in vitro preparations and physiologically relevant in vivo conditions and will combine electrophysiology, Ca2+ imaging, and tracer immunolabeling methods. A central training goal of this proposal is to learn and apply a range of techniques, especially by pairing Ca2+ imaging and electrophysiology, and data analysis methods toward my development as an independent researcher. The final results of this work will provide a significant update to our current understanding of fundamental cerebellar anatomy and function. This update will introduce a panel of new research questions to better understand task-dependent cerebellar computations, expansion and compression of information as it flows through cerebellar circuits, and sources of dysfunction in disease as putative targets for therapy. Some features of ‘super-integrator’ PCs in wildtype animals (e.g. abnormal CF inputs and multi-compartment morphology) overlap with features that are overexpressed in mouse models of autism spectrum disorder. It is possible that, in addition to conferring normal cerebellar function, an overabundance of ‘super-integrator’ PCs may underlie some characteristics of cerebellar dysfunction in autism.

项目摘要 小脑通过整合输入信号编码来优化运动和非运动性能 输入传递一系列多感官和上下文信息时的预测误差。这些输入 途径--由来自下橄榄的攀升纤维轴突和平行的纤维轴突携带 小脑颗粒细胞分别聚集在浦肯野细胞(PC)精细的树突状突起上， 小脑皮质的初级细胞类型和唯一输出。关于小脑功能的理论围绕着 PC中介的集成，并依赖于这样的原则：每台PC：1)在结构和功能上是冗余的 小脑皮质中的单位，2)只接受来自一个CF的橄榄‘教学’信号输入，以及3)展示 在整个树状突起树上都有同质信号。 这项提案的具体目标旨在通过以下方式挑战这些原则的普遍性 揭示了一个以来自多个CF的输入为特征的非齐次的超级积分器PC子群 通过树突发出信号。这些PC在形态上是由隔离的树突隔间定义的 从它们的一次枝晶的早期分叉(‘分裂’)或从 The Soma(保利)。超整合型PC在功能上是由非均质树枝晶的存在定义的 由独立输入到每个隔室产生的信号，例如来自多个CF神经支配。 本研究将检查解剖学上的CF→PC连接，描述PC树突中的信号异质性 并研究这些功能元素在多感官处理过程中如何影响整合。 为了全面评估PC的这些解剖和功能特征，将平衡实验 在严格控制的体外制剂和生理相关的体内条件之间，将结合 电生理学、钙离子成像和示踪免疫标记方法。这项提议的一个核心培训目标是 学习和应用一系列技术，特别是通过将钙离子成像和电生理学与数据相结合 分析方法有助于我作为一名独立研究员的发展。 这项工作的最终结果将为我们目前对基本面的理解提供一个重要的更新 小脑的解剖和功能。此更新将引入一组新的研究问题，以更好地 了解与任务相关的小脑计算、信息流动时的扩展和压缩 通过小脑环路和疾病中的功能障碍来源作为假定的治疗目标。一些人 野生型动物的‘超级整合者’PC的特征(如异常的CF输入和多隔室 形态学)与自闭症谱系障碍小鼠模型中过度表达的特征重叠。它是 可能的是，除了赋予正常的小脑功能外，过多的“超级集成器”PC 可能是自闭症患者小脑功能障碍的一些特征。