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

帕金森病运动障碍和冲动控制的纹状体机制

基本信息

批准号：
10735816
负责人：
Alexandra Nelson
金额：
$ 39.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735816
关键词：
Acute Agonist Animal Model Animals Attenuated Behavior Binge Eating Brain Compulsive Behavior Corpus striatum structure Coupled Decision Making Disease Dopamine Dopamine Agonists Dose Drug-Induced Abnormalities Dyskinetic syndrome Electrophysiology (science)Funding Gambling Genetic Globus Pallidus Hyperactivity Impulse Control Disorders Impulsive Behavior Impulsivity Individual Inhibitory Synapse Involuntary Movements L-DOPA induced dyskinesia Levodopa Measurement Measures Mediating Motor Movement Mus Nature Neurons Optics Parkinson Disease Parkinsonian Disorders Pars Externa Pathologic Pathological Gambling Pathway interactions Pattern Persons Pharmaceutical Preparations Process Risk Behaviors Role Severities Shapes Signal Transduction Symptoms Synapses Syndrome Testing Therapeutic Therapeutic Effect United States National Institutes of Health Work abnormal involuntary movement brain cell cell type discounting dopamine replacement therapy human imaging imaging study improved in vivo motor behavior motor symptom mouse model neural neural correlate optogenetics parkinsonian rodent pramipexol response side effect therapy development tool

项目摘要

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.

项目摘要帕金森病（PD）的运动症状经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，主要的运动功能，这些药物可导致两个主要并发症：左旋多巴引起的运动障碍 (LID)冲动控制障碍（Impulse Control Disorder，ICD）LID包括药物引起的异常不自主运动，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，例如病理性赌博、性欲亢进或暴饮暴食，并与多巴胺D2/3R密切相关激动剂尽管取得了实质性进展，但对这两种疾病的突触或电路机制知之甚少已经通过使用PD/LID的动物模型对LID进行了研究。在我们以前的工作中，我们发现，纹状体直接通路中等多棘神经元亚群在体内实现了高左旋多巴诱发的放电率，与小鼠模型中的运动障碍相关并导致运动障碍。其他混合的直接通路神经元左旋多巴的治疗效果我们最近还开发了一种PD/ICD小鼠模型，延迟折扣任务和多巴胺激动剂普拉克索的管理，这将允许更多的机械研究。在这个建议中，我们将探讨LID和ICD的一些细胞和电路机制，使用在小鼠模型中的体内和离体电生理学、光遗传学和化学遗传学。这项建议旨在为了（1）测试局部纹状体抑制性突触是否在LID中改变并促成LID，（2）确定是否从苍白球到纹状体的外源性抑制性突触在LID中发生改变并促成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中的工作基础上，以揭示其细胞机制，而且还确定ICD是否由相似或不同的过程介导。所有这些这些研究将为新的PD治疗奠定基础，这些治疗可以利用多巴胺的益处，而不需要并发症

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in parkinsonian mice.

DOI：
10.7554/elife.75253
发表时间：
2022-07-04
期刊：
ELIFE
影响因子：
7.7
作者：
Schor, Jonathan S.;Montalvo, Isabelle Gonzalez;Spratt, Perry W. E.;Brakaj, Rea J.;Stansil, Jasmine A.;Twedell, Emily L.;Bender, Kevin J.;Nelson, Alexandra B.
通讯作者：
Nelson, Alexandra B.