Neural Architecture of the Murine and Human Temporomandibular Joint

摘要： 颞下颌关节紊乱病(TMD)是慢性口面部疼痛的最常见形式，影响5% 美国成年人。尽管在这一领域有很大的临床和研究兴趣，但识别和确定目标的进展 TMDS的病理生理机制一直很缓慢。这种平淡无奇的进展在很大程度上要归功于 到我们对神经解剖学、分子和生理学基本特征的相对原始的了解 感觉传入存在于颞下颌关节(TMJ)组织中。恢复关节健康和 减少疼痛的功能(REJOIN)联盟试图通过形成 跨学科团队，可以定义关节和关节周围组织的神经支配，这些组织共同 补好下巴关节。为此，Emrick的MPIS Donnelly(杜克大学医学院)项目 (密歇根大学牙科学院)和CAI(密歇根大学医学院)已经合作 一起全面绘制出颞颌组织的周围神经构筑图 小鼠和人类的关节(TMJ)。应用MRI引导的立体定向方法运送逆行染料和病毒 具有时空精确度的示踪剂，我们将研究周围感觉的分子特性 在稳态和TMD条件下，支配小鼠TMJ内不同组织的神经元，使用 这些信息用于建立新的交叉遗传小鼠模型，以允许使用 光片显微镜。此外，使用交叉遗传方法与化学遗传学相结合， 在体内的钙离子成像和行为表型，我们将表征生理/功能特性 TMJ-支配感觉神经元，使我们能够识别与慢性阻塞性肺疾病有关的神经元亚群 TMD疼痛。为了解决老鼠和人类之间的翻译鸿沟，我们将建立一个TMJ生物库 来自无TMD的健康人类捐赠者和一组临床表型患者的组织 选择TMJ手术来处理慢性关节内TMD情况，随后对 各队列中TMJ组织的外周传入亚型。最后，我们将建立一个免费的、用户友好的网络- 基于平台来集成所产生的转录、功能和宏观成像数据集，以允许 这些数据的广泛传播，我们预计将产生感官的工作模型 小鼠和人类颞下颌关节组织的构筑，包括TMD的改变 与稳态条件相比。

ABSTRACT: Temporomandibular disorders (TMDs) are the most common form of chronic orofacial pain, affecting 5% of U.S. adults. Despite substantial clinical and research interest in this area, progress to identify and target pathophysiological mechanisms underlying TMDs has been slow. This lackluster progress is owed in large part to our relatively primitive understanding of the basic neuroanatomical, molecular, and physiological features of sensory afferents present within the temporomandibular joint (TMJ) tissues. The Restoring Joint Health and Function to Reduce Pain (RE-JOIN) Consortium seeks to address this knowledge gap through the formation of interdisciplinary teams which can define the innervation of articular and peri-articular tissues that collectively make up the jaw joint. To this end, project MPIs Donnelly (Duke University School of Medicine), Emrick (University of Michigan School of Dentistry), and Cai (University of Michigan Medical School) have partnered together to comprehensively map the peripheral neural architecture of the tissues of the temporomandibular joint (TMJ) in mice and humans. Using MRI-guided stereotactic approaches to deliver retrograde dyes and viral tracers with spatiotemporal precision, we will investigate the molecular properties of peripheral sensory neurons which innervate distinct tissues within the murine TMJ in both steady-state and TMD conditions, using this information to build new intersectional genetic mouse models to permit whole-TMJ mapping using lightsheet microscopy. In addition, using intersectional genetic approaches in conjunction with chemogenetics, in vivo Ca2+ imaging, and behavioral phenotyping, we will characterize the physiological/functional properties of TMJ-innervating sensory neurons, allowing us to identify neuronal subpopulations which contribute to chronic pain in TMD. To address the translational gap between mice and humans, we will establish a biobank of TMJ tissues from TMD-free healthy human donors and from a cohort of clinically-phenotyped patients pursuing elective TMJ surgeries to manage chronic intraarticular TMD conditions, followed by quantitative analysis of peripheral afferent subtypes across TMJ tissues in each cohort. Finally, we will build a free, user-friendly web- based platform to integrate the resulting transcriptomic, functional, and macroscopic imaging datasets to permit widespread dissemination of these data, which we anticipate will yield a working model of the sensory architecture of the temporomandibular joint tissues in mice and humans, including alterations in TMDs compared to steady-state conditions.