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

帕金森病模型中调节运动功能的神经元和电路特异性机制和适应

• 批准号: 8914043
• 负责人: ANATOL KREITZER
• 金额: $ 41.78万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914043
• 关键词: Adaptive Behaviors; Adverse effects; Affect; Animal Model; Area; Association Learning; Basal Ganglia; Behavior; Behavioral; Brain; Brain Stem; Cell Nucleus; Corpus striatum structure; Data; Diagnosis; Disease model; Disinhibition; Dopamine; Electrophysiology (science); Equilibrium; Eye; Functional disorder; Future; Gait; Goals; Head; Health; Intervention; Lead; Learning; Locomotion; Maps; Mediating; Midbrain structure; Modeling; Motor; Movement; Movement Disorders; Mus; Neurons; Output; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Performance; Phenotype; Posture; Process; Replacement Therapy; Role; Slice; Substantia nigra structure; Synapses; Synaptic plasticity; System; Thalamic structure; Therapeutic; Vertebrates; Work; cell type; endopeduncular nucleus; flexibility; habit learning; in vivo; insight; integration site; interdisciplinary approach; locomotor control; locomotor deficit; motor control; motor disorder; motor learning; neural circuit; new therapeutic target; novel; novel therapeutics; optogenetics; pedunculopontine tegmentum; relating to nervous system; research study; response; superior colliculus Corpora quadrigemina; treatment strategy

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.

描述（由申请人提供）：选择正确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来协调运动选择、执行和学习的不同方面。这些系统中的关键是基底神经节，这是一组对于运动规划和习惯学习至关重要的皮层下核团， 并且还与帕金森病（PD）有关，帕金森病是最常见的运动障碍之一。基底神经节的解剖连接性已得到很好的表征，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，PD 基底神经节回路功能障碍的机制尚不清楚。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待研究方面：（1）从丘脑到纹状体的输入，以及（2）从黑质网状核/内脚核到脚桥被盖（PPTg）的输出。我们已经获得了令人信服的初步证据，表明这些区域与帕金森病动物模型中的运动功能障碍有关，我们建议彻底研究这种功能障碍背后的细胞、突触和回路机制。目标是确定治疗帕金森病的新治疗靶点和策略，避免长期使用多巴胺替代疗法带来的衰弱副作用。