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?”.

项目摘要 小脑在运动控制中起着关键作用，特别是在运动学习中。最近，小脑 也与认知过程有关。事实上，小脑损伤与广泛的 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。尽管如此 小脑微电路具有明显的功能异质性，但在其两端都是非常均匀的。 不同的地区和不同的动物物种。因此，有人认为小脑可能 通过执行一个通用计算来完成其工作，然后将计算结果发送出去。 计算到其他大脑区域，包括运动和非运动区域。以前的工作表明，普遍的 由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 这些都是由我们自己的运动引起的。该项目的长期目标是实现一个全面的 对小脑如何学会做出这些预测的机械理解。重点是 错误信号是警告小脑预测错误并需要更新的关键信号。 在这个建议的三个目标中，我们研究：1）积极的预测误差（当意外的事情发生时， 2）负预测误差（当预期的事情没有发生时），以及3）时间- 差异预测错误（当刺激预测某事即将发生时）。所有实验均 在一种新开发的跑步机上进行，用于头部固定小鼠的眨眼条件反射。眨眼 空调被选为模型系统，因为它为项目提供了许多优点：1） 行为相关的错误信号是在实验控制下，可以很容易地操纵，2）基本 条件反射任务可以修改为询问关于错误信号在驱动运动学习中的作用的问题。 和更高阶的协会，和3）橄榄小脑区域是处理错误信号的关键 已被确认。通过将眨眼调节的优雅简单性与新技术相结合， 光遗传学，电生理学和双光子钙成像，拟议的实验将记录和 操纵错误相关的神经信号在学习过程中出现前所未有的水平， 时间和细胞特异性。这项研究可以帮助开发新的治疗方法来治疗运动 以及与小脑功能障碍相关的认知障碍，而不是通过靶向 神经可塑性，但有指导意义的错误相关的信号，驱动他们。在这方面， 应用程序的设计不仅要问“小脑中错误信号的神经代码是什么”， “我们如何操纵代码来增强学习？”。