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

描述(申请人提供)：帕金森氏病是一种慢性致残神经疾病，导致静止性震颤、肌肉僵硬、运动迟缓和步态障碍。据估计，全球有500万人患有帕金森氏症，预计到2030年，这一数字将达到870万。帕金森病的一个病理特征是黑质致密部向纹状体投射的多巴胺能神经元变性。治疗通常包括用L-多巴进行多巴胺替代治疗。然而，它的疗效受到“疲惫”现象的限制，以及它可能产生潜在的致残性运动障碍。寻找替代疗法已经开始集中在皮质-基底神经节-丘脑环内网络的相互作用上。对丘脑底核(STN)或苍白球内段(GPI)进行脑深部刺激(DBS)等新疗法的疗效突出表明，帕金森病是一种网络障碍，涉及基底节、丘脑和皮质核团内部和之间的动力学改变。智力价值：这项拟议的研究旨在描述在正常和帕金森状态下，允许通过皮质-基底节-丘脑环路传播β振荡的网络动力学。β振荡的调节发生在正常的运动中，而基底节和皮质中的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直特征之间存在相关性。因此，我们试图了解在正常的皮质-基底节-丘脑环中支持β振荡传递的网络，然后确定网络相互作用是如何改变的，以允许在帕金森状态下β振荡的夸大和异常传播。这将帮助我们不仅了解帕金森氏病病理性β节律的截获点，这可能有助于缓解运动障碍的症状，而且还可以确定如何将潜在的副作用降至最低 治疗干预措施，如DBS，被认为干扰帕金森氏病中β振荡的传递。 韩博士和麦卡锡博士成功地合作，将数学建模和实验相结合，提出了帕金森氏病病理性β节律起源的新假说。他们之前的分析表明，纹状体能够在高胆碱能张力的情况下产生强大的β振荡，这种状态与帕金森氏症纹状体高度相关。这里提出的研究将利用他们的纹状体β节律生成模型来理解在正常和低多巴胺状态下，β振荡在皮质-基底节-丘脑环中的传播。他们建议将这一模型扩展到包括皮质-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韩博士实验的限制，他将在正常和帕金森病小鼠的纹状体诱导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工作结果将促进对皮质-基底节-丘脑环核内和核之间的网络的洞察，这些网络支持正常多巴胺状态下β节律的传播，以及这些网络在帕金森病状态下发生的变化。更广泛的影响：皮质-基底节-丘脑环功能障碍与其他在个人和社会层面上都很重要的疾病有关，包括帕金森氏病、精神分裂症、亨廷顿病、抑郁症、强迫症、成瘾、抽动障碍综合征、肌张力障碍和运动障碍。明确皮质-基底节-丘脑环的微循环不仅是了解帕金森病替代治疗干预措施的关键一步，而且有可能为患有其他基底节受累的其他疾病的患者提供新的治疗选择。通过数学建模和实验的结合，阐明疾病的动力学方面，将扩大我们对网络机制的理解，不仅在帕金森病的正常基底节及其功能障碍中起作用，而且在皮质-基底节-丘脑环的其他障碍中发挥作用。

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.