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，引起静息性震颤、肌肉僵硬、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。帕金森氏病的病理特征是向纹状体投射的黑质致密部多巴胺能神经元的退化。治疗通常包括左旋多巴胺替代疗法。然而，它的功效受到“逐渐消失”现象的限制，并有可能导致潜在的运动障碍。寻找替代疗法已经开始关注皮质-基底神经节-丘脑回路内网络的相互作用。对丘脑下核（STN）或苍白球（GPi）内部段进行脑深部刺激（DBS）等新疗法的疗效突出了这样一个事实，即帕金森病是一种网络障碍，涉及基底节区、丘脑和皮质核内部和之间的动力学改变。智力优势：这项拟议的研究旨在描述在正常和帕金森状态下允许β振荡通过皮质-基底神经节-丘脑环路传播的网络动力学。β振荡的调节发生在正常的运动中，基底神经节和皮层的β振荡的放大是帕金森病的特征。此外，放大的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，我们试图了解在正常的皮质-基底神经节-丘脑环路中支持β振荡传输的网络，然后确定网络相互作用如何被改变，以允许帕金森状态下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中病理β节律的截获点，这可能有助于减轻运动障碍的症状，而且还可以确定如何将潜在的副作用最小化

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.