Pontine motor circuits

描述（由申请人提供）：帕金森综合征是帕金森病和其他相关神经退行性疾病（例如，多系统萎缩、进行性核上性麻痹和路易体痴呆）。帕金森综合征包括静止性震颤、强直、姿势异常、步态障碍和运动迟缓/运动不能。虽然传统的帐户强调的作用，减少多巴胺（DA）的传输在基底神经节（继发于中脑A9多巴胺神经元的损失）在这些疾病的运动缺陷，最近的数据支持的概念，脑干电路的退化超出中脑DA组可能是重要的贡献者帕金森氏症的发展，因此提出了一个潜在的治疗目标。本建议的目的是描绘的中脑运动区（MLR），脑桥结构连接基底神经节输出与脊髓运动电路，在帕金森病的病理生理学的作用。为了实现这一目标，我们设计了三个具体的目标，结合联合收割机神经解剖学，神经化学和神经发生学的方法来描绘的MLR和两个相邻地区的脑桥被盖外侧，脚桥被盖核（PPT）和中脑锥体外系区（MEA），在运动控制的作用。基于我们的初步数据，我们假设两个主要途径连接关键的基底神经节输出核与脊髓运动回路：（1）伸肌回路调节肢体伸肌的姿势张力和（2）屈肌回路，运动和执行特定任务所必需的。伸肌回路利用从黑质网状部（SNc）到腹侧MLR的可能的多巴胺能输入，而伸肌回路由从黑质网状部（SNr）到多巴胺能MEA的可能的GABA能投射组成，并且从那里到背侧MLR中的神经元。伸肌和屈肌回路都由直接支配脊髓的交感神经能神经元提供服务。通过阐明中脑运动区将基底神经节输出中继到脊髓运动脊髓回路的神经解剖学连接和神经化学机制，可以为患有帕金森症和可能的其他运动障碍如cataerosis的个体开发治疗和诊断策略。

DESCRIPTION (provided by applicant): Parkinsonism characterizes the motor symptoms of Parkinson's disease and other related neurodegenerative conditions (e.g., multiple system atrophy, progressive supranuclear palsy and dementia with Lewy bodies) to varied degrees. Parkinsonism includes resting tremor, rigidity, postural abnormalities, gait disturbances and bradykinesia/akinesia. Although traditional accounts emphasize the role of reduced dopamine (DA) transmission in the basal ganglia (secondary to loss of midbrain A9 dopamine neurons) in the motoric defects of these disorders, more recent data support the concept that degeneration of brainstem circuitry beyond the midbrain DA group may be important contributors to the development of parkinsonism and therefore present a potential therapeutic target. The objective of the present proposal is to delineate the role of the mesencephalic locomotor region (MLR), a pontine structure linking basal ganglia output with spinal cord motor circuitry, in the pathophysiology of Parkinsonism. To accomplish this objective, we have designed three specific aims that combine neuroanatomical, neurochemical and neurogenetic approaches to delineate the roles of the MLR and two adjacent areas of the lateral pontine tegmentum, the pedunculopontine tegmental nucleus (PPT) and the midbrain extrapyramidal area (MEA), in motor control. Based upon our preliminary data, we hypothesize two major pathways linking key basal ganglia output nuclei with spinal cord motor circuitry: (1) an extensor circuit regulating postural tone by extensor muscles in the limbs and (2) a flexor circuit, necessary for locomotion and to perform specific tasks. The extensor circuit utilizes a presumably dopaminergic input from the substantia nigra pars compacta (SNc) to the ventral MLR while the extensor circuit is comprised of a presumably GABAergic projection from the substantia nigra pars reticulata (SNr) to the glutamatergic MEA, and from there to neurons in the dorsal MLR. Both the extensor and flexor circuits are then served by glutamatergic neurons that directly innervate the spinal cord. By elucidating the neuroanatomic connections and neurochemical mechanisms by which the mesencephalic locomotor region relays basal ganglia output to spinal motor cord circuitry, therapeutic and diagnostic strategies may be developed for individuals suffering from Parkinsonism and possibly other movement disorders such as cataplexy.