Regulation of instructive signaling in the cerebellum

小脑指导信号的调节

• 批准号: 9977802
• 负责人: Jason M Christie
• 金额: $ 20.77万
• 依托单位: MAX PLANCK FLORIDA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977802
• 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

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 运动学习的习得。当受到性能错误的提示时，攀升光纤激发在 突触后浦肯野细胞既涉及其体细胞的复杂尖峰，也涉及其胞体的钙尖峰。 树枝状结构。虽然攀爬纤维在驱动浦肯野细胞的复杂棘波方面高度可靠，但它们并不总是如此 有效地诱导学习。这表明在行为过程中有特定的过程来调节 将攀升纤维活性转换为电路的适应性信息。通过调节攀援纤维介导的 学习，不适当的运动联想可能会被拒绝和/或允许其他指导性信号参与 机械--不同类型的可塑性。最终，这些机制可能构成一系列适应性机制的基础 在时间、幅度和方向上不同的反应。在这个提议中，我们探索了分子的可能作用 层中间神经元(MLI)在调节浦肯野细胞兴奋中的作用 重点关注树枝状钙离子尖峰，这些尖峰与共作用平行的已知可塑性机制特别相关 纤维突触。我们将使用体外脑片制剂提供的定量测量来 从力学上剖析了浦肯野细胞树突上攀升纤维的兴奋和ML抑制的相互作用。 这些相互作用对攀爬纤维产生突触可塑性的能力的影响。同时， 我们将使用活体方法来测量和操纵在获得适应性运动期间的神经活动 前庭-眼睛系统的反应，以衡量MLI抑制对学习的影响。我们的研究是交叉的 将细胞水平的信号机制与突触可塑性和回路联系起来的细胞和系统方法 编码自适应行为的进程。因为小脑病理可能表现为不适当的学习 完成这些目标将为新的发展提供新的洞察力，而不是无法学习 治疗影响运动控制的小脑疾病的疗法。