Striatum Wide Dynamics and Neuromodulation of Cell-Type Specific Striatum Populations during Learning

项目总结/摘要 纹状体是基底神经节的主要输入核团，是联合学习的中枢介质， 评估、激励和指导适当的行动以应对外部刺激。行为研究 提出纹状体的不同子区域对适应性学习做出独特的贡献， 皮质纹状体回路的功能障碍可以解释学习和动机缺陷的范围 在基底神经节疾病如帕金森病和成瘾中观察到。学习相关的变化 纹状体神经元被广泛认为是由多巴胺依赖的双向突触可塑性驱动的， 直接和间接通路输出神经元的不同群体。该提案将调查 尺度，细胞类型特定的神经动力学跨越不同的子网络的纹状体演变，以评估 外部提示，选择适当的动作，并在感觉运动学习过程中激发运动。 我们将使用我们开发的一种新的光学方法来监测和操纵来自两个不同的 在头部固定行为小鼠中，在类型期间，纹状体的输出通路穿过大的3维体积 学习依赖于不同的纹状体子回路。我们将调查的因果关系的贡献 纹状体输出神经元双向学习相关变化的分布式多巴胺能信号转导 测量和操纵在纹状体体积中区域特异性多巴胺释放的模式， 学习最后，我们将采用双光子钙成像跟踪数百个个体纹状体的活动 神经元之间的关系，并确定大规模学习相关的变化，在纹状体合奏的结果 在单个小区和网络级别上每天都在变化。拟议研究的结果将提供 细胞类型特异性纹状体输出的时空变化如何介导 适应性学习和行动选择，以及最终，神经系统疾病的学习和动机， 可能是由不同纹状体网络的区域功能障碍引起的。

PROJECT SUMMARY/ABSTRACT The striatum, the principle input nucleus of the basal ganglia, is a central mediator of associative learning for evaluating, motivating, and directing appropriate actions in response to external stimuli. Behavioral studies have suggested that distinct sub-regions of the striatum make unique contributions to adaptive learning, and that dysfunction in particular corticostriatal circuits may explain the range of learning and motivational deficits observed in basal ganglia disorders such as Parkinson’s Disease and addiction. Learning related changes in striatum neurons are widely believed to be driven by dopamine dependent bi-directional synaptic plasticity in distinct populations of direct and indirect pathway output neurons. This proposal will investigate how large scale, cell-type specific neural dynamics across distinct sub-networks of the striatum evolve to evaluate external cues, select appropriate actions, and invigorate movement over the course of sensori-motor learning. We will use a new optical approach we have developed to monitor and manipulate signals from two distinct output pathways of the striatum across a large 3-dimensional volume in head-fixed behaving mice during types of learning known to depend on different striatal sub-circuits. We will investigate the causal contribution of distributed dopaminergic signaling to bi-directional learning related changes in striatum output neurons by measuring and manipulating patterns of region specific dopamine release across the striatum volume during learning. Finally, we will employ 2-photon calcium imaging to track activity in hundreds of individual striatum neurons across days and determine how large scale learning related changes in striatum ensembles result from day to day changes at the single cell and network levels. Results from the proposed studies will provide new insight into how spatiotemporal changes in cell-type specific striatum output mediate central aspects of adaptive learning and action selection, and ultimately, how neurological disorders of learning and motivation might result from regional dysfunctions in distinct striatum networks.