Neural Architecture of the Murine and Human Temporomandibular Joint

摘要： 颞下颌关节紊乱病（TMDs）是最常见的慢性口面疼痛，影响5%的 美国成年人了尽管在这一领域有大量的临床和研究兴趣，但识别和靶向 TMDs的病理生理机制进展缓慢。这种平淡的进展在很大程度上是由于 我们对神经系统的基本神经解剖学、分子和生理学特征的相对原始的理解， 感觉传入存在于颞下颌关节（TMJ）组织内。恢复关节健康和 减轻疼痛功能（RE-JOIN）联盟旨在通过形成 跨学科团队，可以定义关节和关节周围组织的神经支配， 组成颌关节。为此，MPI项目Donnelly（杜克大学医学院）、Emrick （密歇根大学牙科学院）和蔡（密歇根大学医学院）合作， 一起全面绘制颞下颌关节组织的周围神经结构 关节（TMJ）在小鼠和人类。使用MRI引导的立体定向方法递送逆行染料和病毒 示踪剂的时空精度，我们将研究外周感觉的分子特性， 神经元，支配不同的组织内的小鼠颞下颌关节在稳态和TMD条件下，使用 利用这些信息建立新的交叉遗传小鼠模型， 光片显微术此外，使用交叉遗传学方法结合化学遗传学， 在体内Ca 2+成像和行为表型，我们将表征的生理/功能特性， TMJ神经支配的感觉神经元，使我们能够确定神经元亚群，有助于慢性 TMD疼痛为了解决小鼠和人类之间的翻译差距，我们将建立TMJ生物库 来自无TMD的健康人供体和来自临床表型分型患者队列的组织， 选择性TMJ手术治疗慢性关节内TMD，然后对 在每个队列中跨TMJ组织的外周传入亚型。最后，我们将建立一个免费的，用户友好的网站- 基于平台，以整合所得转录组学、功能和宏观成像数据集， 这些数据的广泛传播，我们预计将产生一个感官的工作模型， 小鼠和人类颞下颌关节组织的结构，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.