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

项目摘要/摘要 纹状体是基底神经节的主要输入核，是联想学习的中枢媒介。 评估、激励和指导对外界刺激作出反应的适当行动。行为研究 都表明纹状体的不同亚区对适应性学习有独特的贡献，并且 这种功能障碍，特别是皮质纹状体环路，可以解释学习和动机缺陷的范围 在基底节疾病中观察到，如帕金森氏症和成瘾。了解中的相关更改 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 不同群体的直接和间接通路输出神经元。这项提案将调查 纹状体不同子网络上的尺度、细胞型特定神经动力学进化为评估 外部提示，选择适当的动作，并在感官-运动学习过程中激活运动。 我们将使用我们开发的一种新的光学方法来监控和处理来自两个不同的 类型性头部固定行为小鼠纹状体在大三维空间的输出通路 已知的学习依赖于不同的纹状体亚回路。我们将调查这一事件的原因 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 纹状体体积内区域特异性多巴胺释放的测量和操作模式 学习。最后，我们将使用双光子钙成像技术来跟踪数百个个体纹状体的活动。 并确定纹状体集合中大规模学习相关变化的结果 单蜂窝和网络级别的日复一日的变化。拟议研究的结果将提供 关于细胞型特定纹状体输出的时空变化如何调节中枢方面的新见解 适应性学习和行动选择，最终，学习和动机的神经性障碍 可能是由于不同纹状体网络的局部功能障碍所致。

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.