Neuron- and Circuit-Specific Mechanisms and Adaptations Regulating Motor Function in Parkinson Disease Models

描述(由申请人提供)：选择适当行动的能力对于灵活的适应行为至关重要。在脊椎动物中，多个神经系统已经进化，以协调运动选择、执行和学习的不同方面。这些系统中的关键是基底节，这是一组对运动规划和习惯学习至关重要的皮质下核团， 它们还与帕金森病(PD)有关，帕金森病是最常见的运动障碍之一。基底节的解剖连接被很好地描述，并提出了关于基底节功能和多巴胺作用的一般假设。然而，帕金森病患者基础神经节环路功能障碍的机制尚不清楚。为了对基底节的功能障碍有新的认识，我们将针对基底节回路的两个新的未被研究的方面：(1)从丘脑到纹状体的输入；(2)从黑质/内侧脚核到脚桥脑被盖(PPTg)的输出。我们已经获得了令人信服的初步证据，表明这些区域参与了帕金森病动物模型的运动功能障碍，我们建议深入研究这种功能障碍背后的细胞、突触和回路机制。其目标是确定治疗帕金森病的新的治疗目标和策略，而不会出现与长期使用多巴胺替代疗法相关的令人衰弱的副作用。

DESCRIPTION (provided by applicant): The ability to select proper actions is critical for flexible adaptive behavior. In vertebrates, multiple neural systems have evolved to coordinate different aspects of motor selection, execution, and learning. Key among these systems is the basal ganglia, a set of subcortical nuclei that are critical for motor planning and habit learning, and which are also implicated in Parkinson disease (PD), among the most commonly-diagnosed movement disorders. The anatomical connectivity of the basal ganglia is well characterized, and general hypotheses about basal ganglia function and the role of dopamine have been proposed. However, the mechanisms underlying dysfunction of basal ganglia circuits in PD is not well understood. In order to gain new insight into the dysfunction of the basal ganglia, we will target two new understudied aspects of basal ganglia circuitry: (1) the inputs from the thalamus to the striatum, and (2) the outputs from the substantia nigra reticulata/entopeduncular nucleus to the pedunculopontine tegmentum (PPTg). We have obtained compelling preliminary evidence that these regions are involved in motor dysfunction in animal models of PD, and we propose to thoroughly investigate the cellular, synaptic, and circuit mechanisms that underlie this dysfunction. The goal is to identify new therapeutic targets and strategies for treating PD, without the debilitating side effects associated with long-term use of dopamine replacement therapy.