DBS Protocols for Long-Lasting Therapeutic Benefit in Mouse and Primate Models of Parkinson's Disease

摘要 脑深部刺激(DBS)是治疗晚期帕金森病最有效的治疗方法之一 疾病(PD)。丘脑底核(STN)高频电刺激的改善作用 帕金森氏症的运动症状，通常在几秒钟内，但如果刺激，疗效很快就会消失 停止了，通常在几分钟内。症状缓解的这种暂时性强调了这样一个事实，即现有的星展银行 方案掩盖了症状，但不能缓解潜在的电路功能障碍。一种改进的DBS协议，称为 协调重置(CR-DBS)，已显示出提供持续数天至数周的治疗益处的潜力 在刺激后，但这种方案转化为广泛的临床应用一直很慢，因为(1)多- 现场，实现它所需的伪随机刺激模式不能用现有设备和 (2)其作用机制仍然不明确，阻碍了人们对CR-DBS的参数应该是什么的洞察 调整以确保参与长期持久的影响。最近，在帕金森病的小鼠模型中，我们发现了一种细胞- 基于策略，通过使用光遗传学来针对特定的干预措施来诱导持久的运动恢复 外侧苍白球(GPE)的神经元亚群，它是STN的解剖邻居。持久耐用 运动救援是通过同时增加GPE神经元的放电率的干预措施来诱导的 富含小白蛋白(PV-GPE)并降低LIM Homeobox 6富含GPE神经元的放电频率 (Lhx6-GPE)。有趣的是，在生理水平上，GPE中的这些细胞类型的特定干预汇聚在一起 与CR-DBS相似的机制，通过改善基底节神经活动的病理模式 与帕金森氏症运动缺陷有关的输出核团。这项提议将利用知识 从我们发现的通过GPE中细胞型定向干预而获得的长期救援中获得 合理设计和审问适合人类的DBS形式，可能会产生类似的长期持续 治疗效果。我们的实验将测试一个新的机械论假说，基于支持初步的 数据表明，电DBS的模式可以被调整，以驱动镜像的GPE中的细胞类型特定反应 以前发现的那些足以用光遗传学诱导长时间的运动救援。实验在 目标1将研究STN的时相刺激唤起细胞类型的细胞机制 GPE(目标1.1)中的特定响应，并使用机器学习方法来识别刺激方案 使这种细胞类型的特异性反应最大化(目标1.2)。Aim 2中的实验将测试治疗效果 阶段刺激方案与传统DBS的比较，使用行为和生理分析在 小鼠(Aim 2.1)和灵长类(Aim 2.2)帕金森病模型。综上所述，这些实验将推进我们的 理解常规刺激与阶段性刺激的根本区别 神经系统，具有细胞类型特异性和突触特异性分辨率，可以提供新的 可以迅速转化为人类的治疗策略。

Abstract Deep brain stimulation (DBS) is one of the most effective treatments for patients with advanced Parkinson's disease (PD). Delivery of high frequency electrical stimulation to the subthalamic nucleus (STN) ameliorates parkinsonian motor symptoms, often within seconds, but therapeutic effects wear off quickly if stimulation is stopped, often within minutes. This transient nature of symptomatic relief underscores the fact that existing DBS protocols mask symptoms but do not alleviate underlying circuit dysfunction. A modified DBS protocol, called coordinated reset (CR-DBS), has shown potential to provide long-lasting therapeutic benefits for days to weeks after stimulation, but this protocol has been slow to translate into widespread clinical use because (1) the multi- site, pseudorandom stimulation patterns required to implement it cannot be delivered with existing devices and (2) its mechanisms of action remain obscure, hindering insights into what parameters of CR-DBS should be tuned to ensure engagement of long-lasting effects. Recently, in a mouse model of PD, we discovered a cellular- based strategy to induce long-lasting motor recovery, by using optogenetics to target interventions to specific neuronal subpopulations in the external globus pallidus (GPe), an anatomical neighbor of the STN. Long-lasting motor rescue was induced by interventions that simultaneously increased the firing rates of GPe neurons enriched in parvalbumin (PV-GPe) and decreased the firing rates of GPe neurons enriched in lim homeobox 6 (Lhx6-GPe). Interestingly, at the physiological level, these cell-type specific interventions in the GPe converged upon a similar mechanism as CR-DBS, by ameliorating pathological patterns of neural activity in basal ganglia output nuclei that have been associated with parkinsonian motor deficits. This proposal will use knowledge gained from our discovery of long-lasting rescue through cell-type directed interventions in GPe to guide rational design and interrogation of human-applicable forms of DBS that may yield similarly long-lasting therapeutic benefit. Our experiments will test a novel, mechanistic hypothesis, based on supporting preliminary data, that the pattern of electrical DBS can be tuned to drive cell-type specific responses in the GPe that mirror those previously found to be sufficient to induce of long-lasting motor rescue with optogenetics. Experiments in Aim 1 will investigate the cellular mechanisms through which phasic stimulation in the STN evokes cell-type specific responses in the GPe (Aim 1.1) and use a machine learning approach to identify stimulation protocols that maximize this cell-type specific response (Aim 1.2). Experiments in Aim 2 will test the therapeutic efficacy of phasic stimulation protocols compared to conventional DBS, using behavioral and physiological assays in mouse (Aim 2.1) and primate (Aim 2.2) models of PD. Taken together, these experiments will advance our understanding of the fundamental differences between how conventional vs. phasic stimulation impacts the nervous system, with cell-type specific and synapse-specific resolution, and could provide novel therapeutic strategies that can be rapidly translated into humans.