Pontine motor circuits

脑桥运动电路

基本信息

批准号：
7656466
负责人：
JUN LU
金额：
$ 32.59万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7656466
关键词：
Accounting Acute Address Animals Anterior Area Attention Band Cell Basal Ganglia Behavior Behavioral Bilateral Bradykinesia Brain Brain Stem Cataplexy Cell Nucleus Cells Chemical Stimulation Chemicals Choline Cytomegalovirus Data Data Analyses Defect Development Devices Dextrans Diagnostic Disease Dopamine Dopamine D2 Receptor Dorsal Electric Stimulation Embryonic Lethal Mutation Emotional Exons Felis catus Festinating Gait Flexor Freezing Functional disorder Future Gait Gait abnormality Genes Genetic Genetic Recombination Glutamates Goals Horns Ibotenic Acid Image Immunohistochemistry Immunotoxins Implant In Situ Hybridization Individual Injection of therapeutic agent Injury Knock-out Knockout Mice Label Laboratories Lateral Lesion Levodopa Lewy Body Disease Limb structure Link Location Locomotion Maps Medial Mediating Messenger RNA Midbrain structure Modeling Motor Motor Neurons Movement Disorders Multiple System Atrophy Mus Muscle Muscle Rigidity Muscle Tonus Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Output Parkinson Disease Parkinsonian Disorders Pathway interactions Pattern Pedunculopontine Tegmental Nucleus Pharmacological Treatment Physiological Pontine structure Population Positioning Attribute Posture Progressive Supranuclear Palsy Rattus Reporting Research Rest Tremor Reticular Formation Rewards Role Secondary to Series Signal Transduction Site Sleep Specificity Spinal Spinal Cord Stimulus Structure Substantia nigra structure Suid Herpesvirus 1 Symptoms System Techniques Tegmentum Mesencephali Testing Therapeutic Time Tongue Tracer Transfection Transferase Ventral Horn of the Spinal Cord Video Recording Virus Latency Walking adeno-associated viral vector base behavior change cholinergic cholinergic neuron design dextran dopaminergic neuron drinking feeding gamma-Aminobutyric Acid hypocretin killings motor control neural circuit neurochemistry neurogenetics neurotransmission orexin B receptor pars compacta programs promoter public health relevance receptor recombinase research study response therapeutic development therapeutic target transmission process vesicular glutamate transporter 2

项目摘要

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. PUBLIC HEALTH RELEVANCE The motor symptoms of Parkinson's disease and other related neurodegenerative conditions (e.g., synucleinopathies) are characterized by variable degrees of parkinsonism, which includes resting tremor, rigidity, postural abnormalities, gait disturbances and bradykinesia/akinesia. 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. Results from our studies will provide data important for the development of therapeutic and diagnostic strategies for treating Parkinsonism and possibly other movement disorders such as cataplexy.

描述（由申请人提供）：帕金森症在不同程度上表征了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）的运动症状。帕金森症包括静止性震颤、强直、姿势异常、步态障碍和运动迟缓/运动不能。尽管传统的观点强调基底神经节中多巴胺 (DA) 传输减少（继发于中脑 A9 多巴胺神经元丧失）在这些疾病的运动缺陷中的作用，但最近的数据支持这样的概念：中脑 DA 以外的脑干回路退化该组可能是帕金森病发展的重要贡献者，因此提出了潜在的治疗靶点。本提案的目的是描述中脑运动区（MLR）在帕金森病病理生理学中的作用，中脑运动区是一种连接基底神经节输出与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目标，结合神经解剖学、神经化学和神经遗传学方法来描述 MLR 和桥脑外侧被盖的两个相邻区域、桥脚被盖核 (PPT) 和中脑锥体外系区域 (MEA) 的作用），在电机控制中。根据我们的初步数据，我们假设连接关键基底神经节输出核与脊髓运动回路的两条主要途径：（1）通过四肢伸肌调节姿势张力的伸肌回路和（2）运动和运动所必需的屈肌回路执行特定任务。伸肌回路利用从黑质致密部 (SNc) 到腹侧 MLR 的大概多巴胺能输入，而伸肌回路则由从黑质网状部 (SNr) 到谷氨酸能 MEA 的大概 GABA 能投射组成，并从那里到背侧 MLR 中的神经元。然后，伸肌和屈肌回路都由直接支配脊髓的谷氨酸能神经元提供服务。通过阐明中脑运动区将基底神经节输出传递至脊髓运动神经回路的神经解剖学联系和神经化学机制，可以为患有帕金森症和可能的其他运动障碍（例如猝倒症）的个体制定治疗和诊断策略。公共卫生相关性帕金森病和其他相关神经退行性疾病（例如，突触核蛋白病）的运动症状以不同程度的帕金森病为特征，包括静息性震颤、强直、姿势异常、步态障碍和运动迟缓/运动不能。本提案的目的是描述中脑运动区（MLR）在帕金森病病理生理学中的作用，中脑运动区是一种连接基底神经节输出与脊髓运动回路的脑桥结构。我们的研究结果将为开发治疗帕金森症和可能的其他运动障碍（如猝倒症）的治疗和诊断策略提供重要数据。