Coding and processing of error signals in inferior olivary-cerebellar networks

下橄榄小脑网络中误差信号的编码和处理

• 批准号: 9432553
• 负责人: JAVIER F MEDINA
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-02 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9432553
• 关键词: Animals; Area; Ataxia; Attention deficit hyperactivity disorder; Autistic Disorder; Automobile Driving; Behavior; Behavioral; Biological Models; Blinking; Brain; Calcium; Cells; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Code; Cognition Disorders; Cognitive; Complex; Cues; Disease; Dystonia; Educational process of instructing; Electrophysiology (science); Event; Extinction (Psychology); Eyelid structure; Fiber; Fire - disasters; Future; Goals; Grant; Habits; Head; Heterogeneity; Image; Impairment; Inferior; Instruction; Lead; Learning; Light; Link; Molecular Target; Monitor; Motor; Movement; Mus; Neurologic; Neuronal Plasticity; Occupations; Olives - dietary; Outcome; Performance; Phase; Play; Process; Purkinje Cells; Research; Role; Schizophrenia; Signal Transduction; Source; Specificity; Stimulus; Symptoms; Synapses; System; Testing; Time; Update; Work; conditioning; design; expectation; experience; experimental study; improved; motor control; motor disorder; motor learning; nervous system disorder; neural circuit; neuromechanism; neuropsychiatric disorder; neuropsychiatry; neurotransmission; new technology; novel; novel therapeutic intervention; novel therapeutics; optogenetics; predicting response; relating to nervous system; response; teacher; theories; tool; treadmill; two-photon

PROJECT SUMMARY The cerebellum plays a key role in motor control, particularly in motor learning. More recently, the cerebellum has also been implicated in cognitive processing. Indeed, cerebellar damage is associated with a wide range of neurological and neuropsychatric disorders, including ataxia, dystonia, schizophrenia and autism. Despite this apparent functional heterogeneity, the cerebellar microcircuit is remarkably homogeneous, both across its different regions and across different animal species. Thus, it has been suggested that the cerebellum may accomplish its job by performing one universal computation, and then sending out the results of the computation to other brain areas, both motor and non-motor. Previous work indicates that the universal computation performed by the cerebellum involves using past experience to predict future events, including those that are caused by our own movements. The long-term objective of this project is to achieve a full mechanistic understanding of how the cerebellum learns to make these predictions. The focus will be on the error signals that are critical for alerting the cerebellum that a prediction was wrong and needs to be updated. In the three aims of this proposal, we examine: 1) positive prediction errors (when something unexpected happens), 2) negative prediction errors (when something expected doesn't happen), and 3) temporal- difference prediction errors (when a stimulus predicts that something is about to happen). All experiments are done on a newly developed treadmill apparatus for eyeblink conditioning in head-fixed mice. Eyeblink conditioning was chosen as the model system because it offers a number of advantages for the project: 1) The behaviorally-relevant error signals are under experimental control and can be easily manipulated, 2) The basic conditioning task can be modified to ask questions about the role of error signals in driving both motor learning and higher-order associations, and 3) The olivo-cerebellar regions that are critical for processing error signals have been identified. By combining the elegant simplicity of eyeblink conditioning with new technologies for optogenetics, electrophysiology, and two-photon calcium imaging, the proposed experiments will record and manipulate the error-related neural signals present during the learning process with an unprecedented level of temporal and cellular specificity. This research could help develop new therapeutic approaches to treat motor and cognitive disorders associated with cerebellar dysfunction, not by targeting molecular mechanisms of neural plasticity, but the instructive error-related signals that drive them. In this regard, the specific aims of the application are designed to ask not only “what is the neural code for error signals in the cerebellum”, but also “how can we manipulate the code to enhance learning?”.

项目概要 小脑在运动控制中发挥着关键作用，特别是在运动学习中。 事实上，小脑损伤与多种疾病有关。 尽管如此，神经和神经精神疾病，包括共济失调、肌张力障碍、精神分裂症和自闭症。 尽管存在明显的功能异质性，但小脑微电路却异常均匀，无论是 因此，有人认为小脑可能存在于不同的区域和不同的动物物种中。 通过执行一项通用计算来完成其工作，然后发送结果 对其他大脑区域（包括运动区域和非运动区域）的计算表明，这是普遍存在的。 小脑执行的计算涉及使用过去的经验来预测未来的事件，包括 这些是由我们自己的运动引起的。该项目的长期目标是实现全面的目标。 对小脑如何学习做出这些预测的机械理解重点将放在 错误信号对于提醒小脑预测是错误的并且需要更新至关重要。 在该提案的三个目标中，我们检查：1）积极的预测错误（当出现意外情况时） 发生），2）负预测错误（当预期的事情没有发生时），3）时间- 差异预测错误（当刺激预测某事即将发生时）。 在新开发的跑步机上完成，用于对头部固定的小鼠进行眨眼调节。 选择空调作为模型系统是因为它为该项目提供了许多优势：1） 行为相关的错误信号处于实验控制之下并且可以轻松操纵，2）基本 可以修改调节任务以询问有关误差信号在驱动运动学习中的作用的问题 和高阶关联，以及 3) 对于处理误差信号至关重要的橄榄小脑区域 已确定通过将眨眼调节的优雅简单与新技术相结合。 光遗传学、电生理学和双光子钙成像，拟议的实验将记录和 以前所未有的水平操纵学习过程中出现的与错误相关的神经信号 这项研究可以帮助开发新的治疗方法来治疗运动。 和与小脑功能障碍相关的认知障碍，而不是通过针对小脑功能障碍的分子机制 神经可塑性，但驱动它们的指导性错误相关信号在这方面是具体目标。 应用程序的设计不仅要问“小脑中错误信号的神经编码是什么”，还要问 “我们如何操纵代码来增强学习？”。