Computation of negative prediction error in the inferior olive and its role in cerebellar motor learning

下橄榄负预测误差的计算及其在小脑运动学习中的作用

• 批准号: 9396792
• 负责人: Olivia Ann Kim
• 金额: $ 4.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396792
• 关键词: Address; Air; Alpha Cell; Animals; Ataxia; Automobile Driving; Behavior; Behavioral; Blinking; CRH gene; Cells; Cerebellar Diseases; Cerebellum; Cornea; Data Set; Dystonia; Electrophysiology (science); Extinction (Psychology); Eye; Future; Generations; Goals; Heart; Inferior; Intervention; Investigation; Knowledge; Learning; Lighting; Link; LoxP-flanked allele; Measures; Memory; Modeling; Monitor; Motor; Movement; Mus; Neurons; Olives - dietary; Opsin; Optics; Pathologic; Pathway interactions; Play; Population; Process; Research; Role; Sensory; Signal Transduction; Stimulus; Symptoms; System; Techniques; Testing; Time; Training; Transgenic Mice; Viral Vector; Work; awake; base; cell type; classical conditioning; conditioning; expectation; experience; experimental study; in vivo; learning extinction; motor impairment; motor learning; motor symptom; nervous system disorder; new technology; new therapeutic target; optogenetics; relating to nervous system; response; symptom management; theories; tool

PROJECT SUMMARY/ABSTRACT Neurological diseases of the olivo-cerebellum result in crippling motor impairments associated with ataxia and dystonia, reflecting this system’s critical role in the generation and coordination of movement. The proposed research focuses on the mechanisms by which the olivo-cerebellum learns to suppress, or extinguish, behaviors that are no longer adaptive. To understand the mechanisms of extinction during cerebellar learning, I will measure and manipulate the activity of neurons in the olivo-cerebellum of mice, while they are being trained in delay eyeblink conditioning (dEC). During this cerebellum-dependent task, mice receive repeated trials on which a neutral stimulus like an LED precedes a periocular airpuff. Over time, the mice learn to blink during the LED presentation and protect their eyes from the puff. After this learning occurs, it is possible to extinguish the blink by repeatedly presenting the LED without the puff, removing the blink’s adaptive value. According to long- standing theories of cerebellar function, blink extinction is caused by activation of the GABAergic nucleo-olivary (NO) projection, which results in inhibition of the inferior olive (IO). Due to technological limitations, no studies to date have established causal links between NO activity, IO inhibition, and extinction. To resolve this issue, I will leverage recently developed techniques allowing for simultaneous dEC and optogenetic manipulation in mice. By using transgenic mouse lines and viral vectors, I will express opsins in IO or NO cells, enabling me to manipulate these populations’ firing in a cell-type-specific manner on behaviorally relevant timescales in vivo. In the first aim of the proposed project, I will test the hypothesis that IO inhibition is sufficient for extinction, by optogenetically suppressing IO activity during paired LED-puff trials in well-trained mice and examining if the photostimulation causes extinction. In my second aim, I will test the hypothesis that NO activity is both sufficient and necessary for extinction, by using optogenetic tools to selectively stimulate or suppress the firing of NO neurons in well-trained mice, while measuring their blink responses to the LED stimulus. Together, the results of aims 1 and 2 will demonstrate whether there are causal links between NO activation, IO inhibition, and extinction. My experiments will be the first to directly test the prevailing theory of cerebellar-dependent extinction. In addition, my results could help identify new therapeutic targets for treating maladaptive cerebellar motor symptoms, by taking advantage of the extinction principles revealed in my work.

项目概要/摘要 橄榄小脑的神经系统疾病会导致与共济失调相关的严重运动障碍 肌张力障碍，反映了该系统在运动的产生和协调中的关键作用。 研究重点是橄榄小脑学习抑制或消除行为的机制 为了理解小脑学习过程中的消退机制，我将 在小鼠接受训练时，测量和操纵小鼠橄榄小脑神经元的活动 延迟眨眼调节（dEC） 在这项依赖小脑的任务中，小鼠接受了重复的试验。 在眼周吹气之前先施加中性刺激（例如 LED），随着时间的推移，小鼠学会在 LED 照射期间眨眼。 学习完成后，就可以熄灭眨眼。 通过在不吹气的情况下重复显示 LED，消除闪烁的自适应值。 根据小脑功能的现行理论，眨眼消退是由 GABA 核橄榄激活引起的 (NO) 投影，导致下橄榄 (IO) 的抑制，由于技术限制，尚无研究。 迄今为止已经建立了 NO 活性、IO 抑制和灭绝之间的因果关系。 利用最近开发的技术，允许在小鼠中同时进行 dEC 和光遗传学操作。 通过使用转基因小鼠系和病毒载体，我将在 IO 或 NO 细胞中表达视蛋白，使我能够 在体内行为相关的时间尺度上以细胞类型特异性的方式操纵这些群体的放电。 该项目的第一个目标是，我将测试 IO 抑制足以导致灭绝的假设，方法是 在训练有素的小鼠中进行配对 LED-puff 试验期间，通过光遗传学抑制 IO 活性，并检查是否 在我的第二个目标中，我将检验 NO 活动就足够的假设。 通过使用光遗传学工具选择性地刺激或抑制 NO 的发射，这是灭绝所必需的 训练有素的老鼠的神经元，同时测量它们对 LED 刺激的眨眼反应，结果。 目标 1 和 2 将证明 NO 激活、IO 抑制和消退之间是否存在因果关系。 我的实验将是第一个直接检验流行的小脑依赖性灭绝理论的实验。 我的结果可以帮助确定治疗适应不良小脑运动症状的新治疗目标 利用我的作品中揭示的灭绝原理。