Striatal Microcircuit Mechanisms of Tardive Dyskinesia

迟发性运动障碍的纹状体微电路机制

基本信息

批准号：
10634474
负责人：
Alexandra Nelson
金额：
$ 39.79万
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：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634474
关键词：
Acute Address Affinity Aftercare Animal Model Animals Antipsychotic Agents Area Attenuated Basal Ganglia Behavior Binding Biochemistry Bipolar Disorder Brain Chronic Corpus striatum structure Detection Development Dopamine Dopamine Antagonists Dopamine D2 Receptor Dopamine Receptor Dyskinetic syndrome Electrophysiology (science)Face Fiber Formulation Ganglia Gastrointestinal Diseases Genetic Goals Haloperidol Head Individual Intervention Involuntary Movements Knock-out Label Link Lip structure Measures Mental disorders Migraine Modeling Monitor Movement Mus Neurons Optics Oral cavity Output Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Photometry Physiological Play Population Prevention Psychiatric therapeutic procedure Role Schizophrenia Severities Signal Transduction Specificity Tardive Dyskinesia Testing Tetrabenazine Tongue Up-Regulation Upper Extremity antagonist brain cell cell type designer receptors exclusively activated by designer drugs dopamine D3 receptor experience experimental study genetic manipulation in vivo inhibitor innovation integration site mouse model neural neural correlate optogenetics orofacial pharmacologic receptor response sensor temporal measurement theories therapeutic development tool

项目摘要

Project Summary/Abstract Long-term treatment with dopamine D2/D3 receptor antagonists (neuroleptics) often causes involuntary orofacial movements (lip smacking, tongue protrusion), termed tardive dyskinesia (TD). Once established, TD is often irreversible. Given the crucial role these medications play in the treatment of psychiatric disease, as well as their common usage in gastrointestinal disorders, migraine, and other conditions, TD is unfortunately quite common. However, we know very little about the physiological underpinnings of its induction or expression. Longstanding theories focus on D2 receptor blockade and upregulation, but many tools used to develop these theories cannot distinguish between D2 and D3 receptors, nor the role of receptors expressed in multiple cell types. For this reason, it is unclear which dopamine receptors are critical to the induction of TD. In addition, existing studies implicate dopamine signaling in both acute and chronic responses to neuroleptics, but few if any studies have measured dopamine release or the physiological activity of its striatal targets in freely moving animals experiencing TD. To address some of these gaps in our understanding of TD, the proposed project will use an established mouse model of TD, based on chronic administration of haloperidol, in conjunction with cell type-specific genetic and physiological tools. First, we will test the necessity for D2 or D3 receptors in the induction and expression of TD, through targeted deletion in specific cell types. Second, we will test the role of striatal dopamine release in the induction and expression of TD in freely moving mice, monitoring dopamine with the fluorescent dopamine sensor, dLight and manipulating dopamine with chemogenetics. Third, we will test the role of striatal projection neurons in TD by monitoring or manipulating neural activity with cell type-specific electrophysiology and photometry, or optogenetics. In these latter components, we will use a head-mounted selfie-cam and automated behavior detection to identify individual dyskinetic mouth movements at high temporal resolution. This last innovation will permit alignment of dyskinetic movements to striatal dopamine release and neural activity. Through these efforts, we hope to test longstanding hypotheses regarding the origins of TD, but moreover to identify the physiological correlates of individual dyskinetic movements. We hope these findings will point to new areas for therapeutic development, but also deepen our understanding of how striatal microcircuit function contributes to the control of voluntary (versus involuntary) movement.

项目概要/摘要长期使用多巴胺 D2/D3 受体拮抗剂（精神安定药）治疗通常会导致不自主的口面部运动（咂嘴、伸出舌头），称为迟发性运动障碍（TD）。一旦建立，TD往往是不可逆转的。鉴于这些药物在精神疾病的治疗，以及它们在胃肠道疾病中的常见用法，不幸的是，偏头痛和其他疾病很常见。然而我们却知之甚少关于其诱导或表达的生理基础。长期理论焦点关于 D2 受体阻断和上调，但用于发展这些理论的许多工具不能区分 D2 和 D3 受体，也不能区分多个细胞中表达的受体的作用类型。因此，尚不清楚哪些多巴胺受体对于诱导 TD 至关重要。此外，现有研究表明多巴胺信号传导与急性和慢性反应有关。抗精神病药，但很少有研究测量多巴胺释放或生理活性自由活动的 TD 动物的纹状体目标。为了解决其中一些差距根据我们对 TD 的理解，拟议的项目将使用已建立的 TD 小鼠模型，基于长期服用氟哌啶醇，结合细胞类型特异性遗传和生理工具。首先，我们将测试 D2 或 D3 受体在诱导和通过在特定细胞类型中定向删除来表达 TD。其次，我们将测试角色自由活动小鼠 TD 诱导和表达中纹状体多巴胺的释放，监测多巴胺与荧光多巴胺传感器，dLight 和操纵多巴胺与化学遗传学。第三，我们将通过监测或测试纹状体投射神经元在 TD 中的作用。通过细胞类型特异性电生理学和光度测定来操纵神经活动，或光遗传学。在后面的组件中，我们将使用头戴式自拍摄像头和自动摄像头行为检测以高时间分辨率识别个体运动障碍口腔运动。最后一项创新将允许运动障碍运动与纹状体多巴胺释放相一致和神经活动。通过这些努力，我们希望检验长期以来关于 TD 的起源，而且还可以确定个体运动障碍的生理相关性动作。我们希望这些发现将为治疗开发指明新领域，但也加深我们对纹状体微电路功能如何有助于控制的理解自愿（与非自愿）运动。