Regulation of instructive signaling in the cerebellum

小脑指导信号的调节

基本信息

批准号：
10237314
负责人：
Jason M Christie
金额：
$ 33.79万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237314
关键词：
Acute Adaptive Behaviors Affect Animal Behavior Animals Ataxia Automobile Driving Behavior Behavior monitoring Behavioral Brain Calcium Spikes Cells Cerebellar Diseases Cerebellum Color Complex Cues Dendrites Development Disease Dystonia Ensure Fiber Functional disorder Goals Instruction Interneurons Knowledge Learning Link Measurement Measures Mediating Methods Modeling Motor Movement Movement Disorders Neurons Outcome Output Pathology Performance Physiological Play Preparation Process Purkinje Cells Regulation Research Role Signal Transduction Site Slice Stimulus Structure of molecular layer of cerebellar cortex Synapses Synaptic plasticity System Time Work adaptive learning awake base conditioning experimental study flexibility in vivo insight learned behavior learning outcome motor control motor disorder motor learning neural circuit neuronal cell body neurophysiology novel novel therapeutics operation optogenetics postsynaptic prevent relating to nervous system response vestibulo-ocular reflex

项目摘要

Project Summary/Abstract My long-term goal is to understand how neural circuits in the cerebellum ensure accurate movement through the acquisition of motor learning. When cued by performance errors, climbing fiber excitation triggers a response in postsynaptic Purkinje cells that involves both a complex spike in their somata and calcium spikes in their dendrites. While climbing fibers are highly reliable at driving complex spikes in Purkinje cells, they are not always effective at inducing learning. This indicates that there are specific processes during behavior that regulate the conversion of climbing fiber activity into adaptive information for the circuit. By regulating climbing fiber-mediated learning, inappropriate motor associations may be rejected and/or allow for other instructive signals to engage mechanistically-distinct types of plasticity. Ultimately, these mechanisms could underlie a range of adaptive responses that vary in time, amplitude, and direction. In this proposal, we explore the possible role of molecular layer interneurons (MLIs) in regulating Purkinje cell excitation in response to climbing fiber activation, with special focus on dendritic Ca2+ spikes that are particularly relevant to known mechanisms of plasticity at coactive parallel fiber synapses. We will use quantitative measurements afforded by ex-vivo brain slice preparations to mechanistically dissect the interplay of climbing fiber excitation and ML inhibition at Purkinje cell dendrites, and the influence of these interactions on the climbing fiber’s ability to generate synaptic plasticity. In conjunction, we will use in vivo methods to measure and manipulate neural activity during the acquisition of adaptive motor responses in vestibulo-ocular system to gauge how learning is affected by MLI inhibition. Our study intersects cellular and systems approaches to link the cell-level signaling mechanisms to synaptic plasticity and the circuit processes that encode adaptive behavior. Because cerebellar pathology may manifest as inappropriate learning rather than the inability to learn, completion of these aims will provide novel insight into the development of new therapies to treat cerebellar disorders that affect motor control.

项目摘要/摘要我的长期目标是了解小脑中的神经回路如何确保通过获得运动学习。当通过性能错误提示时，攀登光纤兴奋会触发反应突触后purkinje细胞涉及其somata中的复杂尖峰和钙峰值树突。虽然攀爬纤维在驱动浦肯野细胞的复杂尖峰方面非常可靠，但它们并不总是有效地诱导学习。这表明行为过程中存在特定过程来调节将攀岩活性转换为电路的自适应信息。通过调节攀岩纤维介导的学习，不适当的运动协会可能会被拒绝和/或允许其他启发性的信号参与机械固定的可塑性类型。最终，这些机制可能是一系列自适应的基础随时间变化的响应，放大器和方向。在此提案中，我们探讨了分子的可能作用响应于攀爬纤维激活的调节Purkinje细胞兴奋中的层中间神经元（MLI），特殊专注于与已知的可塑性机制特别相关的树突状Ca2+尖峰纤维突触。我们将使用前视体脑切片制剂提供的定量测量值在机械上剖析purkinje细胞树突上攀爬纤维兴奋和ML抑制的相互作用，以及这些相互作用对攀岩纤维产生突触可塑性能力的影响。结合我们将使用体内方法来测量和操纵自适应电动机的神经活动前庭 - 眼部系统中的反应，以衡量学习如何受到MLI抑制的影响。我们的研究相交细胞和系统方法将细胞级信号传导机制与突触可塑性和电路联系起来编码自适应行为的过程。因为小脑病理可能表现为不适当的学习这些目标的完成不是无法学习的，而是为新的发展提供新颖的见解治疗影响运动控制的小脑疾病的疗法。