The role of direct and indirect pathway activity in striatal learning

描述（由申请人提供）：基底神经节是一组大脑结构，有助于许多功能，包括联想和奖励学习。不幸的是，这个大脑系统容易受到许多疾病的影响。一个例子是帕金森病（PD），其特征在于使人衰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，随着我们老年人口的增长，这一数字预计还会增加。尽管几十年的研究，有没有有效的长期治疗或治愈任何这些主要疾病的基底神经节。此外，许多旨在改善运动缺陷的治疗方法并没有解决所谓的“执行功能”的缺陷：多任务处理，经验依赖性决策和行为灵活性的困难。为了治疗与PD相关的广泛症状，了解基底神经节回路在学习和行为灵活性中的作用是重要的。我们提出 联合收割机将新型光遗传学工具与慢性电生理学相结合，以前所未有的访问和控制来询问清醒小鼠的基底神经节电路。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。虽然基底神经节由许多脑结构组成，但本建议集中在纹状体，基底神经节的主要输入核团。纹状体有两个主要的输出神经元群体：“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性联想的形成。尽管知道这两个神经群体的功能，但这些单独的细胞群体在联想和奖励学习中的作用还没有得到很好的理解。在这个提议中，我们将使用新的技术来记录清醒小鼠的纹状体神经元，描述每个群体在联想和奖励学习过程中的活动，并操纵这些神经元的放电来研究神经元活动在学习中的作用。有了这些知识，我们希望更好地了解电路功能障碍如何导致与基底神经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.