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.

PROJECT NARRATIVE The proposed research will define the properties of sensory neurons that innervate tissues which form the temporomandibular joint. This work is relevant to public health and the missions of the NIH because it will lead to an understanding of the neurological mechanisms that underlie chronic orofacial pain in patients with temporomandibular disorders, thereby facilitating the development of new therapeutic approaches to treat temporomandibular disorders and associated pain.