Pontine motor circuits

描述（由申请人提供）：帕金森病以帕金森病和其他相关神经退行性疾病（如多系统萎缩、进行性核上性麻痹和路易体痴呆）不同程度的运动症状为特征。帕金森病包括静息性震颤、强直、姿势异常、步态障碍和运动迟缓。虽然传统的说法强调在这些疾病的运动缺陷中基底节区多巴胺（DA）传递减少（继发于中脑A9多巴胺神经元的丧失）的作用，但最近的数据支持这样的概念，即脑干回路在中脑DA组之外的退化可能是帕金森病发展的重要因素，因此提供了一个潜在的治疗靶点。本研究的目的是描述中脑运动区（MLR）在帕金森病病理生理中的作用。中脑运动区是连接基底节区输出和脊髓运动回路的脑桥结构。为了实现这一目标，我们设计了三个具体的目标，结合神经解剖学、神经化学和神经遗传学的方法来描述MLR和两个相邻的桥脑外侧被盖核（PPT）和中脑锥体外系区（MEA）在运动控制中的作用。根据我们的初步数据，我们假设有两条主要通路将基底神经节关键输出核与脊髓运动回路连接起来：(1)通过四肢伸肌调节姿势张力的伸肌回路；(2)运动和执行特定任务所必需的屈肌回路。伸肌回路可能利用从黑质致密部（SNc）到腹侧MLR的多巴胺能输入，而伸肌回路可能由从黑质网状部（SNr）到谷氨酸能MEA的gaba能投射组成，并从那里到MLR背侧的神经元。伸肌和屈肌回路都由直接支配脊髓的谷氨酸能神经元服务。通过阐明中脑运动区将基底神经节输出传递到脊髓运动回路的神经解剖学联系和神经化学机制，可以为帕金森病和其他运动障碍（如中风）患者制定治疗和诊断策略。

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.