Striatal Microcircuit Mechanisms of Tardive Dyskinesia

项目摘要/摘要 长期服用多巴胺D2/D3受体拮抗剂(抗精神病药物)通常会导致 不自主的口面部运动(嘴唇拍打、舌头突出)，称为迟发性运动障碍 (TD)。一旦成立，TD往往是不可逆转的。考虑到这些药物在治疗中的关键作用 精神疾病的治疗，以及它们在胃肠道疾病中的常见用法， 偏头痛等情况，不幸的是TD相当常见。然而，我们对此知之甚少 关于其诱导或表达的生理基础。长期的理论焦点 关于D2受体的阻断和上调，但许多用于发展这些理论的工具不能 区分D2和D3受体，以及在多个细胞中表达的受体的作用 类型。因此，目前还不清楚哪些多巴胺受体在TD的诱导中起关键作用。 此外，现有的研究表明，多巴胺信号与急性和慢性反应有关。 抗精神病药物，但很少有研究测量多巴胺的释放或生理活性 其纹状体靶点在经历TD的自由活动的动物身上。为了解决这些差距中的一些问题 我们对TD的了解，建议的项目将使用一个既定的TD鼠标模型，基于 氟哌啶醇长期给药与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 Td的表达，通过在特定细胞类型中的靶向缺失。第二，我们将检验 纹状体多巴胺释放在自由活动小鼠TD的诱导和表达中的监测 多巴胺与荧光多巴胺传感器、dLight和操纵多巴胺 化学遗传学。第三，我们将通过监测或检测纹状体投射神经元在TD中的作用 使用特定细胞类型的电生理学和光度学来操纵神经活动，或者 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 行为检测，以识别高时间分辨率的个别口腔运动障碍。 这最后一项创新将使运动障碍运动与纹状体多巴胺释放保持一致。 和神经活动。通过这些努力，我们希望测试长期存在的关于 TD的起源，但更重要的是识别个体运动障碍的生理相关性 动静。我们希望这些发现将为治疗发展指明新的领域，但也 加深我们对纹状体微回路功能如何有助于控制 自愿的(与非自愿的)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.