Striatal Origin of Pathological Beta Oscillations in Parkinson's Disease

描述（由申请方提供）：帕金森病（PD）是一种神经退行性疾病，以黑质黑质（SNpc）多巴胺神经元变性为标志，导致主要运动功能障碍：静息性震颤、运动迟缓（自主运动缓慢）、肌肉僵硬和步态不稳。SNpc多巴胺神经元大量投射到纹状体，基底神经节的主要输入核。多巴胺耗竭被认为通过两个投射中型多棘神经元群体上的不同多巴胺受体来改变两个拮抗性纹状体输出通路之间的平衡，这导致运动功能的皮质控制的总体减少。此外，多巴胺耗竭通过调节胆碱能中间神经元而导致胆碱能张力上调，并且不平衡的多巴胺-乙酰胆碱相互作用也被认为在PD病理生理学中至关重要。在20世纪70年代左旋多巴治疗开发之前，抗胆碱能药物是唯一可用的PD药物，至今仍在临床使用。较新的治疗方法，如脑深部电刺激（DBS），突出了PD涉及神经网络病理学的事实。PD患者的颅内记录显示皮质-基底神经节回路在β频率（11-30 Hz）下的过度振荡。放大的β振荡与关键的PD运动缺陷密切平行，并且在很大程度上被有效的多巴胺替代治疗或DBS抑制。总之，这些证据建立了皮质-基底节-丘脑网络内的β振荡与PD运动症状之间的明确联系。然而，它仍然是未知的放大β振荡的原因或相关的运动缺陷，以及在哪里和如何β振荡出现在PD。我们以前的研究结合数学和药理学的方法已经证明，纹状体神经网络能够产生β振荡后，纹状体乙酰胆碱上调。在这里，我们的目的是测试新的假设，在帕金森病纹状体胆碱能过度激活发挥了关键作用，产生病理性β振荡，β振荡发挥因果作用，PD运动病理。这一新的假说将多巴胺诱导的胆碱能功能障碍与神经回路病理和运动缺陷直接联系起来。由于该项目的探索性质，我们认为R21供资机制在现阶段最适合该项目。 公共卫生相关性：帕金森病是一种神经退行性疾病，仅在美国就影响超过100万患者，每年有超过50，000名新诊断的患者。本研究旨在了解帕金森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.