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

基本信息

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
项目类别：
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

项目摘要

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编码输入信号来优化电机和非运动性能预测错误，输入继电器多感官和上下文信息。这些输入通过从下橄榄和平行纤维轴突（PFS）攀爬纤维轴突（CFS）的路径小脑颗粒细胞，分别在宾夕法尼亚细胞的精细树突植物（PC），converge gonverge（PCS）上小脑皮层的主要细胞类型和唯一输出。小脑功能的理论集中 PC介导的集成并依赖每个PC的原理：1）在结构和功能上是冗余小脑皮层中的单位，2）仅收到一个CF的橄榄度“教学”信号输入，3）展示整个树突树的同质信号传导。该提案的具体目的旨在挑战这些原则的宇宙揭示了一个“超级积分器” PC亚群，其特征是来自多个CF和非共生的输入跨树枝状的信号传导。这些PC是通过隔离的树突室在形态上定义的从其主要树突的早期分叉（“拆分”）或从 soma（'poly'）。 “超级积分器” PC是通过存在非家庭树突的存在来定义的由独立输入到每个隔室产生的信号传导，例如来自多CF神经。这项研究将检查解剖学CF→PC连接，描述PC树突状的信号异质性隔室，并检查这些功能元素如何影响多感官处理过程中的整合。为了全面评估PC的这些解剖和功能功能，实验将保持平衡在严格控制的体外制剂和体内条件上具有物理相关的之间，将结合电生理学，CA2+成像和示踪剂免疫标记方法。该建议的中心培训目标是学习和应用一系列技术，尤其是通过配对Ca2+成像和电生理学以及数据分析方法是我作为独立研究人员的发展。这项工作的最终结果将为我们当前对基本的理解提供重大更新小脑解剖和功能。此更新将介绍一个新的研究问题小组，以更好地了解与任务相关的小脑计算，信息的扩展和压缩通过小脑回路，以及疾病功能障碍的来源，作为治疗的推定靶标。一些野生型动物中“超级积分器” PC的特征（例如，异常CF输入和多室形态）与自闭症谱系障碍小鼠模型中过表达的特征重叠。这是除了会议正常的小脑功能外，可能的“超级积分器” PC有过多可能是自闭症小脑功能障碍的一些特征。