CRCNS: Propagation of beta oscillations in cortico-basal ganglia-thalamic loop

CRCNS：皮质基底节丘脑环中β振荡的传播

• 批准号: 8826834
• 负责人: Michelle M McCarthy
• 金额: $ 25.35万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826834
• 关键词: Adverse effects; Affect; Alternative Therapies; Basal Ganglia; Beta Rhythm; Bradykinesia; Cell Nucleus; Characteristics; Chronic; Cognitive; Corpus striatum structure; Data; Deep Brain Stimulation; Disease; Dopamine; Dyskinetic syndrome; Dystonia; Frequencies; Functional disorder; Gait; Ganglia; Generations; Gilles de la Tourette syndrome; Globus Pallidus; Huntington Disease; Impairment; Individual; Levodopa; Mental Depression; Methods; Modeling; Motor; Motor Cortex; Movement; Mus; Muscle Rigidity; Neurons; Obsessive-Compulsive Disorder; Output; Parkinson Disease; Parkinsonian Disorders; Pathologic; Play; Public Health; Replacement Therapy; Research; Rest Tremor; Role; Schizophrenia; Site; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Thalamic structure; Therapeutic; Therapeutic Intervention; Work; addiction; cholinergic; design; disability; dopaminergic neuron; insight; mathematical model; motor control; nervous system disorder; novel therapeutics; optogenetics; pars compacta; research study; response; transmission process

DESCRIPTION (provided by applicant): Parkinson's disease is a chronic, disabling neurologic disorder causing resting tremor, muscular rigidity, bradykinesia and impairment of gait. It is estimated that 5 million people worldwide have Parkinson's disease, and this number is projected to reach 8.7 million by 2030. A pathologic hallmark of Parkinson's disease is degeneration of the dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum. Treatment often consists of dopamine replacement therapy with L-dopa. However, its efficacy is limited by the "wearing off" phenomenon and its potential to engender potentially disabling dyskinesias . The search for alternative therapies has begun to focus on the interactions of networks within the cortico-basal ganglia-thalamic loop. The efficacy of new treatments such as deep brain stimulation (DBS) to the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) highlights the fact that Parkinson's disease is a network disorder, involving alteration of the dynamics within and between the nuclei of the basal ganglia, the thalamus and the cortex. Intellectual Merit: This proposed research is designed to characterize the network dynamics that allow the propagation of beta oscillations through the cortico-basal ganglia-thalamic loop in both the normal and parkinsonian states. Modulation of beta oscillations occurs with normal movement, and exaggeration of beta oscillations in the basal ganglia and cortex are characteristic of Parkinson's disease. Furthermore, there exists correlation between the exaggerated beta oscillations and the bradykinesia and rigidity characteristic of the parkinsonian state. Thus, we seek to understand the networks supporting transmission of beta oscillations in the normal cortico-basal ganglia-thalamic loop and then determine how the network interactions are altered to allow the exaggeration and abnormal propagation of beta oscillations in the parkinsonian state. This will help us understand not only points of interception of the pathologic beta rhythm in Parkinson's disease, which may help alleviate symptoms of motor disability, but also identify how to minimize side effects of potential therapeutic interventions such as DBS that are thought to interfere with the transmission of beta oscillations in Parkinson's disease. Drs. Han and McCarthy have successfully worked together integrating mathematical modeling and experimentation to put forth a new hypothesis for the origin of the pathologic beta rhythm in Parkinson's disease. Their previous analyses revealed that the striatum is capable of generating robust beta oscillations in response to high cholinergic tone, a state highly relevant to the parkinsonian striatum. The research proposed here will make use of their model of striatal beta rhythm generation to understand the propagation of beta oscillations throughout the cortico-basal ganglia-thalamic loop in both the normal and low dopamine states. They propose to extend this model to include mathematical models of each of the nuclei of the cortico-basal ganglia-thalamic loop. The dynamics of our model neurons will be constrained by the experiments of Dr. Han, who will induce beta oscillations in the striatum in both normal and parkinsonian mice and record simultaneously from the striatum, STN and cortex. The results of the combined mathematical and experimental work will promote insight into the networks both within and between the nuclei of the cortico-basal ganglia-thalamic loop that support the propagation of beta rhythms in the normal dopamine state and the alterations that occur to these networks in the parkinsonian state. Broader Impact: Dysfunction of cortico-basal ganglia-thalamic loop has been implicated in other disorders of importance on both the individual and societal levels including Parkinson's disease, schizophrenia, Huntington's disease, depression, obsessive-compulsive disorder, addiction, Tourette's syndrome, dystonias and dyskinesias. Defining the micro-circuitry of the cortio-basal ganglia-thalamic loop is not only a critical step towards understanding alternative therapeutic interventions in Parkinson's disease, it has the potential to advance new therapeutic options for individuals with other disorders with basal ganglia involvement. Elucidating the dynamical aspects of disease, though the combination of mathematical modeling and experimentation, will expand our understanding of the network mechanisms at work not only in the normal basal ganglia and their dysfunction in Parkinson's disease but also the role they play in other disorders of the cortico-basal ganglia-thalamic loop.

描述（由申请人提供）：帕金森病是一种慢性致残性神经系统疾病，导致静息性震颤、肌肉强直、运动迟缓和步态障碍。据估计，全球有 500 万人患有帕金森病，预计到 2030 年，这一数字将达到 870 万人。帕金森病的病理特征是黑质致密部投射到纹状体的多巴胺能神经元退化。治疗通常包括使用左旋多巴的多巴胺替代疗法。然而，其功效受到“逐渐消失”现象及其可能引起潜在致残性运动障碍的限制。对替代疗法的研究已开始集中于皮质基底节丘脑环内网络的相互作用。新疗法（例如针对丘脑底核（STN）或苍白球内段（GPi）的深部脑刺激（DBS））的功效凸显了帕金森病是一种网络疾病的事实，涉及内部和之间的动态变化基底神经节、丘脑和皮质的核团。智力优点：这项拟议的研究旨在描述网络动力学特征，该网络动力学允许在正常和帕金森状态下通过皮质-基底节-丘脑环路传播β振荡。正常运动时会发生β振荡的调节，基底神经节和皮质中β振荡的夸大是帕金森病的特征。此外，夸大的β振荡与帕金森状态的运动迟缓和僵硬特征之间存在相关性。因此，我们试图了解支持正常皮质-基底节-丘脑环路中β振荡传输的网络，然后确定如何改变网络相互作用以允许帕金森状态下β振荡的夸大和异常传播。这不仅有助于我们了解帕金森病中病理性β节律的截断点（这可能有助于减轻运动障碍的症状），而且还有助于确定如何最大限度地减少潜在的副作用 DBS 等治疗干预措施被认为可以干扰帕金森病中 β 振荡的传播。 博士。汉和麦卡锡成功地合作，将数学模型和实验结合起来，提出了帕金森病病理性β节律起源的新假设。他们之前的分析表明，纹状体能够响应高胆碱能张力而产生强大的β振荡，这种状态与帕金森病纹状体高度相关。这里提出的研究将利用他们的纹状体β节律生成模型来了解在正常和低多巴胺状态下β振荡在整个皮质基底节丘脑环中的传播。他们建议扩展该模型以包括皮质基底节丘脑环的每个核的数学模型。我们的模型神经元的动力学将受到 Han 博士的实验的限制，他将在正常和帕金森病小鼠的纹状体中诱导 β 振荡，并同时从纹状体、STN 和皮质进行记录。数学和实验相结合的结果将促进对皮质基底节丘脑环核内部和核之间网络的深入了解，这些网络支持正常多巴胺状态下β节律的传播以及这些网络发生的改变在帕金森状态。更广泛的影响：皮质基底神经节丘脑环的功能障碍与其他对个人和社会层面都很重要的疾病有关，包括帕金森病、精神分裂症、亨廷顿病、抑郁症、强迫症、成瘾、抽动秽语综合征、肌张力障碍和运动障碍。定义皮质-基底节-丘脑环路的微电路不仅是了解帕金森病替代治疗干预措施的关键一步，而且有可能为患有基底节受累的其他疾病的个体提供新的治疗选择。通过数学建模和实验的结合来阐明疾病的动力学方面，将扩大我们对网络机制的理解，不仅在正常基底神经节及其在帕金森病中的功能障碍中，而且在它们在其他疾病中发挥的作用。皮质-基底节-丘脑环。