Striatal Microcircuit Mechanisms of Tardive Dyskinesia

项目总结/摘要 多巴胺D2/D3受体拮抗剂（神经抑制剂）的长期治疗通常会导致 不自主的口面运动（咂唇、舌头突出），称为迟发性运动障碍 （TD）。一旦确立，TD往往是不可逆转的。考虑到这些药物在 精神疾病的治疗，以及它们在胃肠道疾病中的常见用途， 偏头痛和其他疾病，TD是很常见的。然而，我们所知甚少 关于其诱导或表达的生理基础。长期以来的理论焦点 D2受体阻断和上调，但许多用于发展这些理论的工具不能 D2和D3受体之间的区别，也不是在多个细胞中表达的受体的作用， 类型由于这个原因，目前还不清楚哪些多巴胺受体对TD的诱导至关重要。 此外，现有的研究表明，多巴胺信号在急性和慢性反应， 精神抑制剂，但很少有研究测量多巴胺的释放或生理活性， 在经历TD的自由活动动物中的纹状体靶点。为了解决其中的一些差距， 根据我们对TD的了解，建议的项目将使用已建立的TD小鼠模型， 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受体在诱导中的必要性， TD的表达，通过在特定细胞类型中的靶向缺失。第二，我们将测试 纹状体多巴胺释放在自由活动小鼠TD诱导和表达中的作用，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，我们将测试纹状体投射神经元在TD中的作用， 用细胞类型特异性电生理学和光度学操纵神经活动，或 光遗传学在后面的这些组件中，我们将使用头戴式自拍摄像头和自动 行为检测，以高时间分辨率识别个体运动障碍的嘴部运动。 最后一项创新将使运动障碍运动与纹状体多巴胺释放对齐 和神经活动。通过这些努力，我们希望测试长期存在的假设， TD的起源，而且要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发展指明新的领域， 加深我们对纹状体微电路功能如何有助于控制 自愿（与非自愿）运动。

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.