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: 10656273
• 负责人: Silas Edward Busch
• 金额: $ 4.76万
• 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/10656273
• 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; 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; segregation; 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 预测错误与输入中继频谱的多感官和上下文信息。这些输入 由下橄榄核的攀爬纤维轴突（CF）和下橄榄核的平行纤维轴突（PF）携带的路径 小脑颗粒细胞，分别聚集在浦肯野细胞（PC）的精心树突状乔木， 小脑皮质的主要细胞类型和唯一输出。小脑功能的理论主要围绕 PC介导的整合和依赖的原则，每个PC：1）是一个结构和功能冗余 单位在小脑皮质，2）接收橄榄'教学'信号输入，从只有一个CF，和3）展览 在整个树突树上都有相同的信号。 这项建议的具体目的是对这些原则的普遍性提出质疑， 揭示了一个“超级整合者”PC亚群，其特征在于来自多个CF的输入和非同质性 通过树突传递信号这些PC在形态学上由分离的树突区室定义 从它们的初级树突的早期分叉（“分裂”）或从它们的初级树突的多个分支中出现的多个初级树突， 索马（Poly）。“超级整合者”PC在功能上被定义为非同质树突状细胞的存在。 信号传导由对每个隔室的独立输入产生，例如来自多CF神经支配。 本研究将探讨CF→PC的解剖学联系，描述PC树突的信号异质性， 隔间，并研究这些功能元素如何影响多感觉处理过程中的整合。 为了全面评估PC的这些解剖和功能特征，实验将平衡 在严格控制的体外制剂和生理相关的体内条件之间，并将联合收割机 电生理学、Ca2+成像和示踪免疫标记方法。本建议的一个中心培训目标是 学习和应用一系列技术，特别是通过配对钙离子成像和电生理学，和数据 分析方法对我的发展作为一个独立的研究人员。 这项工作的最终结果将为我们目前对基本原理的理解提供重要的更新。 小脑的解剖和功能本次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以及信息流动时的扩展和压缩 通过小脑回路，以及疾病中功能障碍的来源作为治疗的假定靶点。一些 野生型动物中“超级整合者”PC的特征（例如，异常CF输入和多隔室 形态学）与在自闭症谱系障碍的小鼠模型中过表达的特征重叠。是 除了赋予正常的小脑功能外，过量的“超级整合者”PC可能 可能是自闭症小脑功能障碍的一些特征的基础。