CRCNS: Propagation of beta oscillations in 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，可引起静止性震颤、肌肉强直、运动迟缓和步态障碍。据估计，全世界有500万人患有帕金森病，预计到2030年这一数字将达到870万。帕金森病的病理标志是黑质丘脑部投射到纹状体的多巴胺能神经元变性。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”现象及其可能产生潜在致残性运动障碍的限制。替代疗法的研究已经开始关注皮质-基底节-丘脑回路内网络的相互作用。新的治疗方法，如脑深部电刺激（DBS）对丘脑底核（DBS）或苍白球（GPi）的内部部分的疗效突出了帕金森病是一种网络疾病的事实，涉及基底神经节，丘脑和皮质的核内和核之间的动力学改变。智力优势：这项拟议的研究的目的是表征网络的动态特性，允许通过皮质基底神经节丘脑回路在正常和帕金森病状态下的β振荡的传播。β振荡的调制发生在正常运动中，并且基底神经节和皮质中的β振荡的放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-基底神经节-丘脑回路中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病状态中β振荡的夸大和异常传播。这将有助于我们不仅了解帕金森病病理性β节律的拦截点，这可能有助于减轻运动障碍的症状，而且还可以确定如何最大限度地减少潜在的副作用。 治疗性干预，如DBS，被认为会干扰帕金森病中β振荡的传递。 Drs. Han和McCarthy成功地结合了数学建模和实验，提出了帕金森病病理性β节律起源的新假设。他们之前的分析显示，纹状体能够产生强大的β振荡，以响应高胆碱能紧张，一种与帕金森病纹状体高度相关的状态。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正常和低多巴胺状态下β振荡在整个皮质-基底神经节-丘脑回路中的传播。他们建议扩展该模型，以包括皮质-基底神经节-丘脑回路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，并同时记录纹状体，纹状体和皮层。数学和实验相结合的工作的结果将促进洞察网络内和之间的皮质基底神经节丘脑环的核，支持在正常多巴胺状态下的β节律的传播和发生这些网络的帕金森状态的改变。更广泛的影响：皮质-基底神经节-丘脑环的功能障碍已经涉及在个体和社会水平上重要的其它病症，包括帕金森病、精神分裂症、亨廷顿病、抑郁症、强迫症、成瘾、图雷特综合征、肌张力障碍和运动障碍。定义皮质-基底神经节-丘脑回路的微电路不仅是了解帕金森病替代治疗干预的关键一步，而且有可能为基底神经节受累的其他疾病患者提供新的治疗选择。阐明疾病的动力学方面，虽然数学建模和实验相结合，将扩大我们的理解网络机制的工作不仅在正常的基底神经节和他们的功能障碍帕金森氏病，但也发挥作用，在其他疾病的皮质基底神经节丘脑回路。

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.