Regulation of instructive signaling in the cerebellum

小脑指导信号的调节

• 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
• 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

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.

项目总结/摘要 我的长期目标是了解小脑中的神经回路是如何确保通过大脑的精确运动的。 获得运动学习。当受到表现错误的提示时，攀爬纤维的兴奋会触发一种反应， 突触后浦肯野细胞，涉及其胞体中的复杂尖峰和其胞体中的钙尖峰。 树突虽然攀缘纤维在驱动浦肯野细胞的复杂尖峰时是高度可靠的，但它们并不总是 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 将攀爬纤维活动转换为电路的自适应信息。通过调节攀爬纤维介导的 在学习中，不适当的运动关联可以被拒绝和/或允许其他指导性信号参与 不同类型的可塑性。最终，这些机制可能是一系列适应性 在时间、幅度和方向上变化的响应。在这个建议中，我们探讨了分子的可能作用， 层中间神经元（MLI）在调节浦肯野细胞兴奋响应攀缘纤维激活，与特殊的 集中于树突状Ca 2+尖峰，特别是相关的可塑性在共活性平行的已知机制 纤维突触我们将使用离体脑切片制备提供的定量测量， 机械地剖析浦肯野细胞树突处的攀爬纤维兴奋和ML抑制的相互作用，以及 这些相互作用对攀爬纤维产生突触可塑性的能力的影响。同时， 我们将使用体内方法来测量和操纵适应性运动获得过程中的神经活动 前庭眼系统的反应，以衡量学习如何受到MLI抑制。我们的研究 细胞和系统的方法来连接细胞水平的信号机制，突触可塑性和电路 编码适应性行为的过程。因为小脑的病理可能表现为不适当的学习 而不是不能学习，完成这些目标将提供新的洞察力的发展， 治疗影响运动控制的小脑疾病的疗法。