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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：
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
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/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

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.

项目总结