Striatal Mechanisms of Dyskinesia and Impulse Control in Parkinson’s Disease

项目摘要 帕金森氏病(PD)的运动症状通常用多巴胺替代疗法治疗， 例如多巴胺前体左旋多巴或多巴胺受体激动剂。虽然对一些人来说非常有效 主要的运动特征，这些药物可以导致两个主要的并发症：左旋多巴引起的运动障碍 (LID)和冲动控制障碍(ICD)。LID由药物引起的异常不自主运动组成， 与左旋多巴密切相关。ICD表现为冲动和/或强迫行为的综合征，如 如病态赌博、性欲亢进或暴饮暴食，并与多巴胺D2/3R密切相关 激动剂。人们对这两种疾病的突触或回路机制知之甚少，尽管取得了实质性的进展 通过使用PD/LID的动物模型制作了盖子。在我们之前的工作中，我们发现一个 纹状体直接通路中棘神经元的亚群在体内获得高的左旋多巴诱发的放电频率，这 与小鼠模型中的运动障碍相关并引起运动障碍。其他混合的直接通路神经元相互关联 左旋多巴的治疗效果。我们最近还开发了一种PD/ICD的小鼠模型，基于 延迟折扣任务和多巴胺激动剂普拉克索的给药，这将允许更多 机械学研究。在这项建议中，我们将探讨LID和ICD的一些细胞和电路机制，使用 体内和体外小鼠模型的电生理学、光遗传学和化学遗传学。这项提议旨在 为了(1)测试局部纹状体抑制性突触是否在LID中改变并参与LID，(2)确定 从苍白球到纹状体的外源性抑制性突触在LID中发生改变并参与LID，以及(3) 开始探讨ICD的纹状体机制。这些研究将建立在我们先前在LID中所做的工作的基础上，以揭开其 细胞机制，但也决定了ICD是由相似还是不同的过程介导的。加在一起，这些 研究将为新的帕金森病治疗方法奠定基础，这种疗法利用多巴胺的好处，而不是 并发症。

Project Abstract The motor symptoms of Parkinson’s Disease (PD) are frequently treated with dopamine replacement therapies, such as the dopamine precursor levodopa or dopamine receptor agonists. While very effective for some of the cardinal motor features, these medications can cause two major complications: levodopa-induced dyskinesia (LID) and impulse control disorder (ICD). LID consists of drug-induced abnormal involuntary movements, and is closely associated with levodopa. ICD manifests as a syndrome of impulsive and/or compulsive behaviors, such as pathological gambling, hypersexuality, or binge eating, and is closely associated with dopamine D2/3R agonists. Little is known about the synaptic or circuit mechanisms of either disorder, though substantial progress has been made on LID through the use of animal models of PD/LID. In our prior work, we have found that a subset of striatal direct pathway medium spiny neurons achieve high levodopa-evoked firing rates in vivo, which correlate with and cause dyskinesia in the mouse model. Other intermingled direct pathway neurons correlate with the therapeutic effects of levodopa. We have also recently developed a mouse model of PD/ICD, based on a delay discounting task and administration of the dopamine agonist pramipexole, which will permit more mechanistic studies. In this proposal we will explore some cellular and circuit mechanisms of LID and ICD, using in vivo and ex vivo electrophysiology, optogenetics, and chemogenetics in mouse models. This proposal aims to (1) test whether local striatal inhibitory synapses are altered in and contribute to LID, (2) determine whether extrinsic inhibitory synapses from the globus pallidus to the striatum are altered in and contribute to LID, and (3) begin to explore the striatal mechanisms of ICD. These studies will build on our prior work in LID to unravel its cellular mechanisms, but also determine if ICD is mediated by similar or distinct processes. Together, these studies will lay the groundwork for new PD treatments that harness the benefits of dopamine without the complications.