Adaptive Cerebellar Processing at Cellular Resolution in Flexible Behavior

项目总结/摘要 小脑整合感觉、运动和内部信息，以快速引导和微调动作。这 在运动控制中，小脑的作用最为广泛，但小脑也参与了运动控制。 内部状态的更新，如奖励和工作记忆。这个实验室以前的工作表明， 小脑区E1是证据积累和决策所必需的。这些发现， 沿着初步的数据，导致了一个假设，小脑处理感觉和内部信息 在学习过程中不断发展，以发挥即时的预测影响力，并形成灵活的 行为拟议的实验将确定，与定量的严谨性，如何认知区域的 小脑有助于神经编码、预测学习和前脑靶活动。过去的研究 小脑对认知的贡献被神经元活动的粗糙程度所阻碍， 被监控和干扰，跟踪路径，并测量行为。该提案将克服这些 使用先进的工具，包括双光子钙成像，全脑跨突触病毒 示踪、高密度硅探针记录和光遗传学扰动。目标1将决定预测 小脑活动中的信息影响工作记忆。在一项证据积累决策任务中， 区分与证据积累，信息保留和决策有关的神经活动，初步 数据显示，光遗传学失活的CDFI消除了决策对先前证据的依赖性， 表明在证据整合中的必要作用。这一目标将检查主要的小脑通路， 光遗传学、双光子成像和多电极记录来探测小脑对学习的贡献。 感觉处理、工作记忆、决策和运动输出，具有亚秒级时间分辨率。目标2将 表征与工作记忆相关的神经动力学的学习和转移。这一目标将研究如何任务 在浦肯野细胞和深核神经元的学习过程中， 参与运动准备的小脑信号为学习神经反应提供了基础， 随着时间的推移积累感官证据。目标3将评估参与认知形成的小脑区域 连接的前脑区域的活动。这个目标将使用跨突触病毒追踪来识别从神经胶质瘤的途径。 我通过中脑和丘脑到达它们的目标新皮层，然后有针对性地进行扰动和监控 这些途径，以确定其对任务绩效的贡献。该项目的长期目标是建立一个 复杂行为中小脑功能的定量解释框架。结果预计 为预测和解释详细的小脑-前脑相互作用的影响的计算模型提供信息。 总之，这些研究将大大推进小脑的基础神经科学，并有助于 理解以小脑功能障碍为标志的综合征，包括注意力缺陷多动障碍 和自闭症谱系障碍

PROJECT SUMMARY/ABSTRACT The cerebellum integrates sensory, motor, and internal information to rapidly guide and fine-tune action. This process has been investigated most extensively for movement control, but the cerebellum is also involved in the updating of internal states such as reward and working memory. Previous work from this laboratory shows that the cerebellar region crus I is required for evidence accumulation and decision-making. These findings, along with preliminary data, led to the hypothesis that cerebellar processing of sensory and internal information evolves over the course of learning to exert moment-to-moment predictive influence and shape flexible behavior. The proposed experiments will determine, with quantitative rigor, how cognitive regions of the cerebellum contribute to neural coding, predictive learning, and forebrain target activity. Past studies of cerebellar contributions to cognition have been hampered by the coarseness with which neuronal activity could be monitored and perturbed, pathways traced, and behavior measured. This proposal will overcome these limitations by using advanced tools, including two-photon calcium imaging, whole-brain transsynaptic viral tracing, high-density silicon probe recording, and optogenetic perturbation. Aim 1 will determine how predictive information in cerebellar activity influences working memory. In an evidence-accumulation decision task that distinguishes neural activity related to evidence accumulation, information retention, and decisions, preliminary data show that optogenetic inactivation of crus I removes the dependence of decisions on previous evidence, indicating a necessary role in evidence integration. This aim will examine the main cerebellar pathway with optogenetics, two-photon imaging, and many-electrode recording to probe learned cerebellar contributions to sensory processing, working memory, decisions, and motor output with subsecond time resolution. Aim 2 will characterize learning and transfer of working memory-related neural dynamics. This aim will examine how task representations evolve during learning in Purkinje cells and deep-nuclear neurons to test the idea that intrinsic cerebellar signals involved in movement preparation provide a foundation for learning neural responses that accumulate sensory evidence over time. Aim 3 will evaluate how cerebellar areas involved in cognition shape activity in connected forebrain areas. This aim will use transsynaptic viral tracing to identify pathways from crus I through midbrain and thalamus to their targets in the neocortex, and then specifically perturb and monitor these pathways to identify their contribution to task performance. The long-term goal of this project is to build a quantitative explanatory framework for cerebellar function in complex behavior. The results are expected to inform computational models that predict and explain the impact of detailed cerebellum-forebrain interactions. Together, these studies will significantly advance basic neuroscience of the cerebellum and contribute to understanding of syndromes marked by cerebellar dysfunction, including attention-deficit hyperactivity disorder and autism spectrum disorder.