The role of direct and indirect pathway activity in striatal learning

描述(申请人提供)：基底节是一套大脑结构，有助于许多功能，包括联想和奖励学习。不幸的是，这种大脑系统易患多种疾病。帕金森氏症(PD)就是一个例子，其特征是使人虚弱的运动和认知功能障碍。这种疾病影响了大约150万美国人，随着老年人口的增长，这个数字预计还会增加。尽管进行了几十年的研究，但对于基底节的这些主要疾病中的任何一种，都没有有效的长期治疗或治愈方法。此外，许多旨在改善运动障碍的治疗方法并没有解决所谓的“执行功能”方面的缺陷：多任务处理困难、依赖经验的决策和行为灵活性。为了治疗与帕金森病相关的广泛症状，了解基底节回路在学习和行为灵活性中的作用是重要的。我们建议 将新的光遗传学工具与慢性电生理学相结合，以前所未有的通路和控制力询问清醒小鼠的基底节回路。我们的首要目标是更好地了解基底神经节及其在学习和行为灵活性中的作用。虽然基底节由许多大脑结构组成，但这一建议侧重于纹状体，纹状体是基底节的主要输入核团。纹状体有两类主要的输出神经元：“直接”和“间接”通路神经元。直接通路神经元促进运动，而间接通路神经元抑制运动。此外，新的研究表明，直接通路参与奖励性联想的形成，而间接通路参与厌恶联想的形成。尽管知道这两个神经细胞群的功能，但这些不同的细胞群在联想学习和奖赏学习中的作用还不是很清楚。在这项提议中，我们将使用新的技术来记录清醒小鼠的纹状体神经元，表征每个群体在联想和奖赏学习期间的活动，并操纵这些神经元的放电，以研究神经元活动在学习中的作用。有了这些知识，我们希望更好地理解回路功能障碍如何导致与基底节疾病相关的认知问题。

DESCRIPTION (provided by applicant): The basal ganglia are a set of brain structures that contribute to many functions, including associative and reward learning. Unfortunately, this brain system is susceptible to many diseases. One example is Parkinson's Disease (PD), characterized by debilitating motor and cognitive dysfunction. This disease affects approximately 1.5 million Americans, and this number is projected to increase as our elderly population grows. Despite decades of research, there are no effective long term treatments or cures for any of these major diseases of the basal ganglia. In addition, many treatments targeted at improving motor deficits do not address the deficits in what are called "executive function": difficulties with multitasking, experience-dependent decision-making and behavioral flexibility. In order to treat the broad spectrum of symptoms associated with PD, understanding the role of basal ganglia circuitry in learning and behavioral flexibility is important. We propose to combine novel optogenetic tools with chronic electrophysiology to interrogate basal ganglia circuitry in awake mice with unprecedented access and control. Our overarching goal is to better understand the basal ganglia and its role in learning and behavioral flexibility. Although the basal ganglia consist of many brain structures, this proposal focuses on the striatum, the major input nuclei of the basal ganglia. The striatum has two major populations of output neurons: the "direct" and "indirect" pathway neurons. The direct pathway neurons facilitate movement, while the indirect pathway neurons inhibit movement. In addition, new research indicates that the direct pathway is involved in the formation of rewarding associations, while the indirect pathway is involved in aversive associations. Despite knowledge of the function of these two neural populations, the role of these separate populations of cells in associative and reward learning is not well understood. In this proposal, we will use novel techniques to record from striatal neurons in awake mice, characterize the activity of each population during associative and reward learning, and manipulate the firing of these neurons to study the role of neuronal activity in learning. With this knowledge, we hope to better understand how dysfunction of the circuit can lead to cognitive problems associated with diseases of the basal ganglia.