Transmission of Abnormal Bursting along the Nigro-thalamo-cortical Pathway

异常爆发沿黑质-丘脑-皮质通路的传播

基本信息

批准号：
8398096
负责人：
Collin Jethro Lobb
金额：
$ 4.92万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8398096
关键词：
Affect Animal Disease Models Animal Model Animals Area Automobile Driving Basal Ganglia Bradykinesia Brain Cell Nucleus Cognition Contralateral Disease Effectiveness Etiology Fire - disasters Foundations Frequencies Functional disorder Gait Gastrocnemius Muscle Generations Goals Grooming Head Implant Incidence Intervention Link Liquid substance Measures Methods Motor Motor Activity Motor Cortex Movement Mus Muscle Rigidity Neurologic Neurons Operative Surgical Procedures Optics Output Oxidopamine Parkinson Disease Parkinsonian Disorders Pathway interactions Patients Pattern Population Rattus Recovery Research Rest Tremor Rewards Role Scientist Signal Transduction Signs and Symptoms Solid Substantia nigra structure Symptoms Testing Thalamic structure Therapeutic Time Training United States Urethane Wakefulness age related career cost design dopaminergic neuron expectation in vivo nonhuman primate pressure relating to nervous system sample fixation transmission process

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating, age-related neurological condition affecting nearly 1% of the population and growing with a projected annual cost of over $50 billion in the United States alone by 2040. The motor signs of the disease include muscular rigidity, bradykinesia, akinesia, shuffled and unstable gait, and resting tremor. Electrophysiological studies in Parkinsonian patients, 6-OHDA rats, and MPTP-treated, non- human primates have consistently found increased incidences of bursting and an increase in synchronization between basal ganglia neurons. It is likely that this abnormal activity reaches the motor cortex through the thalamus since basal ganglia output neurons strongly project to the motor thalamus. These studies have also suggested that this abnormal activity may underlie the motor symptoms seen in the disease and that interventions that disrupt this activity may be therapeutic. The difficulties in understanding the relationship between abnormal basal ganglia activity and motor dysfunction in Parkinsonian patients and in animal models of the disease is that brain activity changes in these subjects are widespread so that a link between specific basal ganglia activity and the emergence of Parkinsonian signs and symptoms cannot be made with certainty. If abnormal bursting emanating from the basal ganglia is responsible for motor dysfunction in PD then experimentally generating bursts in basal ganglia output neurons should be sufficient to cause motor dysfunction in healthy controls. The proposed research is designed to test this hypothesis in normal mice. Specifically, we will investigate the classic PD symptoms of muscular rigidity and akinesia/bradykinesia. We will first determine how motor thalamic neurons integrate bursts that are pharmacologically or optogenetically evoked in the major output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNpr), in anesthetized mice during cortical slow-wave activity and a cortically-activated, desynchronized state. We will next determine how evoked bursting in the SNpr can cause rigidity using a combination of simultaneous neural and electromyographic recordings. Finally, we will also investigate how evoked SNpr bursting can cause akinesia/bradykinesia in mice performing a lever-pressing task. The contribution of the proposed research is that it will provide a detailed understanding of the relationship between abnormal burst firing in basal ganglia output nuclei and motor dysfunction. PUBLIC HEALTH RELEVANCE: Parkinson's disease is a debilitating, age-related neurological condition with motor signs that may include muscular rigidity, bradykinesia, shuffled and unstable gait, and resting tremor. These motor symptoms may be due to abnormal bursting and oscillatory activity in the basal ganglia that is transmitted to the cortex via the motor thalamus. The proposed research will investigate how thalamic neurons integrate bursts evoked in basal ganglia output nuclei and how faithful propagation of this abnormal activity to the motor cortex can cause motor dysfunction in healthy mice.

描述（由申请人提供）：帕金森病 (PD) 是一种使人衰弱、与年龄相关的神经系统疾病，影响着近 1% 的人口，预计到 2040 年，仅在美国，每年的费用就将超过 500 亿美元。该疾病的症状包括肌肉强直、运动迟缓、运动不能、拖慢步态和不稳定步态以及静止性震颤。对帕金森病患者、6-OHDA 大鼠和 MPTP 治疗的非人类灵长类动物进行的电生理学研究一致发现，基底神经节神经元之间的爆发发生率增加，同步性增加。这种异常活动很可能通过丘脑到达运动皮层，因为基底神经节输出神经元强烈投射到运动丘脑。这些研究还表明，这种异常活动可能是疾病中所见运动症状的基础，而破坏这种活动的干预措施可能具有治疗作用。理解帕金森病患者和该疾病动物模型中基底神经节异常活动与运动功能障碍之间的关系的困难在于，这些受试者的大脑活动变化很普遍，因此特定基底神经节活动与帕金森病体征的出现之间的联系和无法确定症状。如果基底神经节发出的异常爆发是帕金森病运动功能障碍的原因，那么在基底神经节输出神经元中实验产生的爆发应该足以导致健康对照的运动功能障碍。拟议的研究旨在在正常小鼠中检验这一假设。具体来说，我们将研究典型的帕金森病症状：肌肉僵硬和运动不能/运动迟缓。我们将首先确定运动丘脑神经元如何整合在皮质慢波活动和皮质激活期间麻醉小鼠的基底神经节主要输出核、黑质网状部（SNpr）中药理学或光遗传学诱发的爆发。去同步状态。接下来，我们将结合同步神经和肌电图记录来确定 SNpr 中诱发的爆发如何导致僵化。最后，我们还将研究诱发的 SNpr 爆发如何导致执行杠杆按压任务的小鼠运动不能/运动迟缓。拟议研究的贡献在于它将提供对基底节输出核异常爆发放电与运动功能障碍之间的关系。公共卫生相关性：帕金森病是一种使人衰弱、与年龄相关的神经系统疾病，其运动症状可能包括肌肉僵硬、运动迟缓、步态拖沓和不稳定以及静止性震颤。这些运动症状可能是由于基底神经节异常的爆发和振荡活动引起的，这些活动通过运动丘脑传递到皮质。拟议的研究将研究丘脑神经元如何整合基底神经节输出核中诱发的爆发，以及这种异常活动如何忠实地传播到运动皮层，从而导致健康小鼠的运动功能障碍。