Adaptive Cerebellar Processing at Cellular Resolution in Flexible Behavior

项目摘要/摘要 小脑整合了感觉、运动和内部信息，以快速指导和微调行动。这 对运动控制过程的研究最广泛，但小脑也参与了 奖赏和工作记忆等内部状态的更新。这个实验室之前的工作表明 小脑I区是证据积累和决策所必需的。这些发现， 与初步数据一起，导致了小脑处理感觉和内部信息的假设 在学习过程中不断演变，以施加随时可预测的影响并形成灵活性 行为。拟议中的实验将以定量的严谨方式确定大脑的认知区域 小脑参与神经编码、预测性学习和前脑靶点活动。过去的研究 小脑对认知的贡献受到神经元活动的粗糙性的阻碍 被监视和干扰，跟踪路径，测量行为。这项建议将克服这些问题 使用先进工具的局限性，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微扰。目标1将决定如何预测 小脑活动中的信息会影响工作记忆。在一个证据积累决策任务中， 区分与证据积累、信息保留和决策相关的神经活动，初步 数据显示，CRU I的光基因失活消除了决策对先前证据的依赖， 表明在证据整合中起到了必要的作用。这一目标将检查主要的小脑通路与 光遗传学、双光子成像和多电极记录来探测学习到的小脑贡献 感觉处理、工作记忆、决策和亚秒级时间分辨率的运动输出。目标2将 描述与工作记忆相关的神经动力学的学习和迁移。此目标将检查任务如何 在学习过程中，浦肯野细胞和深核神经元中的表征会进化，以测试这种内在的想法 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将评估小脑区域如何参与认知形成 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来自CRU的通路 我通过中脑和丘脑到它们的新皮质靶点，然后专门干扰和监测 通过这些途径来确定它们对任务绩效的贡献。这个项目的长期目标是建立一个 复杂行为小脑功能的定量解释框架。预计结果将是 告知预测和解释详细的小脑-前脑相互作用的影响的计算模型。 总之，这些研究将极大地推进小脑的基础神经科学，并有助于 对以小脑功能障碍为特征的综合征的认识，包括注意缺陷多动障碍 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.