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到协调运动选择，执行和学习的不同方面。这些系统中的关键是基底神经节，这是一组皮质下核团，对运动规划和习惯学习至关重要， 并且也与帕金森病（PD）有关，帕金森病是最常诊断的运动障碍之一。基底神经节的解剖学连接特征很好，并且已经提出了关于基底神经节功能和多巴胺作用的一般假设。然而，基底神经节回路功能障碍在PD的机制还没有得到很好的理解。为了获得对基底神经节功能障碍的新见解，我们将针对基底神经节回路的两个新的未充分研究的方面：（1）从丘脑到纹状体的输入，以及（2）从黑质网状核/脚内核到脚桥被盖（PPTg）的输出。我们已经获得了令人信服的初步证据表明，这些地区参与运动功能障碍的PD动物模型，我们建议彻底调查的细胞，突触和电路机制，这种功能障碍的基础。目的是确定新的治疗靶点和治疗PD的策略，而不会出现与长期使用多巴胺替代疗法相关的衰弱副作用。

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.