Neuron- and Circuit-Specific Mechanisms and Adaptations Regulating Striatal Funct

描述（由申请人提供）：控制动作的能力对生活至关重要。涉及基底神经节的神经回路是锥体外运动系统的关键组成部分，是自适应运动控制和程序学习所必需的。这些回路的破坏会导致严重的运动障碍，如帕金森病和亨廷顿病。纹状体是基底神经节的输入核，是活动依赖性可塑性和神经调节的主要部位，尤其是多巴胺。由于纹状体位于其他基底神经节核的上游，该区域的细胞和突触可塑性改变了整个基底神经节回路的信息传递。然而，纹状体功能和功能障碍的研究一直受到主要和中间神经元群体显著异质性的阻碍。我建议利用最近开发的转基因小鼠系来鉴定调节纹状体输出和基底神经节回路功能的细胞类型特异性和可塑性。我还将研究这些特性在多巴胺耗尽的小鼠中是如何改变的，以便深入了解帕金森病基底神经节功能障碍的机制。最后，我将寻求确定能够在体内操纵纹状体输出的药理学靶点，目的是使帕金森小鼠的基底神经节回路活动正常化并恢复正常的运动功能。这些研究的最终目标是发现治疗纹状体脑疾病的新治疗策略。

DESCRIPTION (provided by applicant): The ability to control one's movements is essential to life. Neural circuits involving the basal ganglia are a key component of the extrapyramidal motor system, which is required for adaptive motor control and procedural learning. Disruption of these circuits leads to profound movement disorders, such as Parkinson's disease and Huntington's disease. The striatum, which is the input nucleus of the basal ganglia, is a major site of activity- dependent plasticity and neuromodulation, particularly by dopamine. Because the striatum lies upstream of other basal ganglia nuclei, cellular and synaptic plasticity within this region alters the transfer of information throughout basal ganglia circuits. However, studies of the striatal function and dysfunction have been hampered by significant heterogeneity in both principal and interneuron populations. I propose to utilize recently developed transgenic mouse lines to identify cell-type-specific properties and plasticity that regulate striatal output and basal ganglia circuit function. I will also examine how these properties are altered in dopamine-depleted mice in order to gain insight into the mechanisms underlying basal ganglia dysfunction in Parkinson's disease. Finally, I will seek to identify pharmacological targets that enable in vivo manipulation of striatal output, with the goal of normalizing basal ganglia circuit activity and restoring proper locomotor function in Parkinsonian mice. The ultimate goal of these studies is to uncover novel therapeutic strategies for treating striatal-based brain disorders.