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; 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.

项目摘要/摘要 Olivo-Cerebellum的神经系统疾病导致共济和共济失调和 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。提议 研究重点是奥利沃 - 埃里贝勒学会抑制或熄灭行为的机制 不再是适应性的。要了解小脑学习过程中扩展的机制，我将 测量和操纵小鼠奥利沃脑中神经元的活性，并在接受训练时 延迟眼神调节（DEC）。在这项依赖小脑的任务中，小鼠经过反复的试验 像LED这样的中性刺激在Ai​​rpuff之前。随着时间的流逝，老鼠学会在LED期间眨眼 表现并保护他们的眼睛免受泡芙的侵害。在学习发生之后，有可能熄灭眨眼 通过反复呈现LED而没有吹气，消除了眨眼的适应性价值。根据长期 小脑功能的基准，眨眼延伸是由GABA能核叶出的激活引起的 （否）投影，导致抑制下橄榄（IO）。由于技术局限性，没有研究 日期已经建立了无活动，IO抑制和扩展之间的因果关系。为了解决这个问题，我将 最近开发的技术允许小鼠进行简单的DEC和光学遗传操作。 通过使用转基因小鼠线和病毒矢量，我将在IO或无细胞中表达Opsins，使我能够 在体内与行为相关的时间表以细胞类型的方式操纵这些人群的射击。 拟议项目的第一个目的是，我将检验以下假设：IO抑制作用足以扩展。 在训练有素的小鼠中对成对的LED-PUFF试验期间的光源抑制IO活性，并检查是否存在 光刺激会导致延伸。在我的第二个目标中，我将检验以下假设：没有任何活动足够 并且通过使用光遗传学工具有选择地刺激或抑制NO的发射，这是扩展所必需的 训练有素的小鼠中的神经元，同时测量其对LED刺激的眨眼反应。一起，结果 目标1和2将证明没有激活，IO抑制和扩展之间是否存在因果关系。 我的实验将是第一个直接测试小脑依赖性扩展理论的实验。此外， 我的结果可以帮助确定通过治疗适应不良小脑运动症状的新的治疗靶标 利用我的工作中揭示的扩展原则。