Striatal Origin of Pathological Beta Oscillations in Parkinson's Disease

描述(申请人提供)：帕金森病(PD)是一种神经退行性疾病，以黑质致密部多巴胺神经元变性(SNPC)为特征，导致主要运动功能障碍：静止性震颤、运动迟缓(自主运动缓慢)、肌肉僵硬和步态不稳定。SNPC多巴胺神经元主要投射到纹状体，纹状体是基底神经节的主要输入核。多巴胺耗竭被认为通过两组投射的中棘神经元上不同的多巴胺受体改变了两条相互拮抗的纹状体输出通路之间的平衡，导致皮质对运动功能的控制全面下降。此外，多巴胺耗竭通过调节胆碱能中间神经元导致胆碱能张力上调，而多巴胺-乙酰胆碱相互作用的失衡也被认为在帕金森病的病理生理学中起着关键作用。在20世纪70年代左旋多巴治疗发展之前，抗胆碱能药物是治疗帕金森病的唯一可用药物，今天仍在临床使用。较新的治疗方法，如脑深部刺激(DBS)，强调了帕金森病涉及神经网络病理的事实。帕金森病患者的颅内记录显示皮层-基底节环路在11-30赫兹的β频率下有夸大的振荡。夸张的β振荡与关键的PD运动缺陷密切相关，并在很大程度上被有效的多巴胺替代治疗或DBS抑制。总之，这些证据在皮质-基底节-丘脑网络内的β振荡和帕金森病运动症状之间建立了明确的联系。然而，目前尚不清楚被夸大的β振荡是否是运动缺陷的原因或相关因素，以及β振荡在帕金森病中出现的位置和方式。我们以前的研究结合了数学和药理学的方法，证明了纹状体神经网络能够在纹状体乙酰胆碱上调时产生β振荡。在这里，我们的目的是检验这一新的假设，即帕金森病纹状体胆碱能过度激活在产生病理性β振荡中起关键作用，而β振荡在帕金森病运动病理中起因果作用。这一新的假说直接将多巴胺引起的胆碱能障碍与神经回路病理和运动障碍联系起来。由于这个项目的探索性，我们觉得R21资助机制在现阶段是最适合这个项目的。 公共卫生意义：帕金森氏症是一种神经退行性疾病，仅在美国就有100多万患者受到影响，每年有超过5万名新诊断患者。本研究旨在了解帕金森氏病病理生理学的神经网络机制。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder with a hallmark of dopamine neuron degeneration in the Substantia Nigra pars compacta (SNpc), resulting in cardinal motor dysfunctions: resting tremor, bradykinesia (slowness of voluntary movement), muscular rigidity, and gait instability. SNpc dopamine neurons project heavily to the striatum, the main input nucleus of the basal ganglia. Dopamine depletion is thought to shift the balance between two antagonistic striatal output pathways through distinct dopamine receptors on the two populations of projecting medium spiny neurons, which results in an overall reduction in the cortical control of motor functions. In addition, dopamine depletion results in an upregulation of cholinergic tone by modulating cholinergic interneurons, and the imbalanced dopamine-acetylcholine interaction has also been suggested to be critical in PD pathophysiology. Anti-cholinergic drugs, the only available drugs for PD before the development of levodopa treatment in the 1970s, remain to be in clinical use today. Newer therapies such as deep brain stimulation (DBS) highlight the fact that PD involves neural network pathology. Intracranial recordings in PD patients revealed exaggerated oscillations in the cortical-basal ganglion circuit at beta frequencies, 11-30 Hz. Exaggerated beta oscillations closely parallel key PD motor deficits, and are largely suppressed by effective dopamine replacement treatment or DBS. Together, these evidences established a clear link between beta oscillations within the cortical-basal ganglia-thalamic network and PD motor symptoms. However, it remains unknown whether the exaggerated beta oscillation is the cause or a correlate of motor deficits, and where and how beta oscillations arise in PD. Our previous studies combining mathematical and pharmacological approaches have demonstrated that the striatum neural network is capable of generating beta oscillations upon upregulation of striatal acetycholine. Here, we aim to test the novel hypothesis that cholinergic over-activation in the Parkinsonian striatum plays a key role in producing pathological beta oscillations, and beta oscillations play a causal role in PD motor pathology. This novel hypothesis directly links dopamine induced cholinergic malfunction to neural circuit pathology and motor deficits. Because of the explorative nature of this project, we feel that the R21 funding mechanism is most appropriate for this project at this stage. PUBLIC HEALTH RELEVANCE: Parkinson's disease, a neural degenerative disorder, affects over 1 million patients in the US alone, with more than 50,000 newly diagnosed patients each year. This research seeks to understand the neural network mechanisms of pathophysiology in Parkinson's disease.