Examining the Role of the Pallidostriatal Microcircuit in Modulating Beta Oscillations in Parkinson's Disease

项目摘要 帕金森氏病(PD)是一种毁灭性的神经疾病，困扰着5000多万人 全世界都有运动迟缓、震颤和僵硬。帕金森病的特征是基础脑区的多巴胺耗竭(DD) 神经节，直接导致运动症状，改变基底节神经回路，增加β 许多原子核中的振荡(13-30赫兹)。然而，这些神经回路改变的机制， 活动模式和运动缺陷的产生，它们之间的联系仍然很差 明白了。DD的一个主要环路重新连接发生在纹状体，那里有快速放电的中间神经元(FSIS)。 选择性地加倍它们与D2受体表达的中棘神经元(MSN)的连接几率。 这些MSN投射到苍白球(GPE)，其神经元向FSIS发送反馈投射， 关闭苍白球纹状体环。这种苍白球纹状体反馈投射已经被很好地描述了 从解剖学和最近的计算学上讲，但它在疾病状态中的作用还没有得到充分的研究 在我们最近发表的计算模型中，我证明了DD诱导的纹状体增加 连通性足以通过机制在整个电路中产生和放大β振荡 这需要苍白球纹状体的反馈投射。这种新型的β振荡放大模型具有主要的 对理解帕金森氏病病理学的启示。这项研究的目标是调查如何 苍白球纹状体环路在DD中起作用，并与其他慢性振荡的基底节相互作用 通过理论和活体研究获得原子核。 在目标1中，我们将研究如何扰乱帕金森病小鼠模型的苍白球纹状体环路 疾病影响GPE中的振荡动力学。这将测试苍白球纹状体环路是否倾向于 β频率的共振对DD的病理振荡有产生、放大或破坏的作用。 在目标2中，我们使用计算和实验双管齐下的方法来研究 苍白球纹状体环路与GPE与大脑皮质的反复连接产生的振荡相互作用 丘脑底核(STN)。通过在体内操纵苍白球纹状体回路，同时从 STN，我们将确定苍白质纹状体回路对振荡的影响是否可以转移到其他 如果与苍白球纹状体β同步相互作用的振荡来自于 STN-GPE环路或其他地方。将其与我们的计算模型的扩展相配对将提供细节 关于无法通过实验测量的变量，并通过 这些电路相互作用。彻底了解苍白球纹状体环路在导致 帕金森病的病理振荡同步性将为更好地了解基底节功能和 疾病中的功能障碍，并可能阐明新的靶点和干预措施，以帮助治疗人类患者的帕金森病。

Project Summary Parkinson’s disease (PD) is a devastating neurological disorder, afflicting over 50 million people worldwide with bradykinesia, tremor, and rigidity. PD is characterized by dopamine depletion (DD) in the basal ganglia, which leads directly to motor symptoms, changes in basal ganglia neural circuits, and increased β oscillations (13-30 Hz) in many nuclei. However, the mechanisms by which these neural circuit changes, activity patterns, and motor deficits are generated and the connections between them remain poorly understood. One major circuit rewiring in DD occurs in the striatum, where fast spiking interneurons (FSIs) selectively double their connection probability to D2-receptor-expressing medium spiny neurons (MSNs). These MSNs project to the globus pallidus externa (GPe) whose neurons send feedback projections to FSIs, closing the pallidostriatal loop. This pallidostriatal feedback projection has been well-characterized anatomically and more recently, computationally, but its role in disease states has been understudied In our recently published computational model, I demonstrated that DD-induced increases in striatal connectivity are sufficient to generate and amplify β oscillations throughout the circuit through a mechanism which requires the pallidostriatal feedback projection. This novel model of β oscillation amplification has major implications in understanding Parkinson’s disease pathology. The goal of this study is to investigate how the pallidostriatal circuit functions in DD and interacts with other chronically oscillating basal ganglia nuclei through theoretical and in vivo investigations. In Aim 1, we will investigate how disrupting the pallidostriatal circuit in a mouse model of Parkinson’s disease affects oscillatory dynamics in the GPe. This will test whether the pallidostriatal circuit’s propensity to resonate at β frequencies has a generating, amplifying, or destructive effect on pathological oscillations in DD. In Aim 2, we employ a two-pronged computational and experimental approach to investigate how the pallidostriatal circuit interacts with oscillations generated by the GPe’s recurrent connections with the subthalamic nucleus (STN). Through in vivo manipulations of the pallidostriatal circuit while recording from the STN, we will determine whether the pallidostriatal circuit’s effects on oscillations can be transferred to other basal ganglia nuclei and if the oscillations which interact with pallidostriatal β synchrony are derived from the STN-GPe loop or elsewhere. Pairing this with an extension of our computational model will provide details about variables impossible to measure experimentally and give insights into the underlying mechanisms by which these circuits interact. A thorough understanding of the pallidostriatal circuit’s role in causing pathological oscillatory synchrony in PD will provide a better understanding of basal ganglia function and dysfunction in disease, and may illuminate new targets and interventions to help treat PD in human patients.