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: 8484472
• 负责人: Michelle M McCarthy
• 金额: $ 24.46万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484472
• 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）：帕金森氏病是一种慢性致残的神经系统疾病，导致静止震颤，肌肉僵硬，头肌动力和步态障碍。据估计，全世界有500万人患有帕金森氏病，到2030年，这一数字预计将达到870万。治疗通常包括用L-DOPA的多巴胺替代疗法。但是，其功效受到“磨损”现象的限制及其可能导致潜在的运动障碍的潜力。寻找替代疗法的搜索已开始集中在Cortico-Basal神经节丘脑环内的网络相互作用上。新疗法（例如深脑刺激（DBS））对丘脑下核（STN）或Globus Pallidus（GPI）的内部段的功效强调了帕金森氏病是一种网络疾病，涉及内部和基本神经神经神经神经神经化神经神经神经神经神经化的动力学的变化。知识分子的优点：这项拟议的研究旨在表征网络动力学，使β振荡通过正常和帕金森氏派国家的皮质 - 基质神经节丘脑环路传播。 β振荡的调节是随着正常运动而发生的，基底神经节和皮层中β振荡的夸张是帕金森氏病的特征。此外，夸张的β振荡与帕金森氏派国家的头肌动力和僵化特征之间存在相关性。因此，我们试图了解支持在正常皮质 - 基质神经节丘脑环中传播β振荡的网络，然后确定如何改变网络相互作用，以允许parkinsonian州中β振荡的夸张和异常传播。这将有助于我们了解帕金森氏病中病理β节奏的截留点，这可能有助于减轻运动障碍的症状，而且还确定了如何最大程度地减少潜在的副作用 被认为会干扰帕金森氏病中β振荡的DB等治疗干预措施。 博士。 Han和McCarthy成功地合作整合了数学建模和实验，以提出帕金森氏病病理β节奏的起源的新假设。他们以前的分析表明，纹状体能够响应高胆碱能张力，这是与帕金森氏纹状体高度相关的状态。此处提出的研究将利用其纹状体β节律产生模型来了解整个皮质 - 基底神经节 - 丘脑 - 丘脑丘脑环中的β振荡的传播。他们建议将此模型扩展到包括皮质 - 基质神经节丘脑环的每个核的数学模型。我们模型神经元的动力学将受到Han博士的实验的限制，Han博士将在正常和帕金森氏症小鼠中诱导纹状体中的β振荡，并同时从纹状体，STN和皮层记录下记录。组合数学和实验性工作的结果将促进对网络内部以及在皮质 - 基质神经节 - 丘脑丘脑核之间的洞察力，这些丘脑 - 丘脑 - 丘脑环路支持正常多巴胺状态下β节奏的传播以及这些网络在帕克森尼国家中发生的变化。更广泛的影响：皮质 - 巴萨神经节 - 丘脑循环的功能障碍与对个体和社会层面的其他重要性有关，包括帕金森氏病，精神分裂症，亨廷顿氏病，抑郁症，抑郁症，强迫症，成瘾，Tourette's Clantictic，Tourette's Clansdrome，domentonias和Dyskineas和Dyskinesias和Dyskinesias。定义Cortio-Basal神经节丘脑环的微路不仅是了解帕金森氏病的替代治疗干预措施的关键一步，它有可能促进患有基底神经节介入的其他疾病的人的新治疗选择。尽管数学建模和实验的结合，阐明疾病的动力学方面将扩大我们对正常基底神经节的网络机制的理解及其在帕金森氏病中的功能障碍，而且还可以在Cortico-basasal神经神经神经神经节 - thalamic-thalamic-thalamic-loop中发挥作用。