Comprehensive functional phenotyping of trigeminal neurons innervating temporomandibular joint (TMJ) tissues in male, female, and aged mice, primates and humans, with and without TMJ disorders (TMJD)

The knowledge of the function, types, distributions, and plasticity of afferent neurites innervating temporomandibular joint (TMJ) tissues is needed to understand the underlying mechanisms controlling the development of temporomandibular joint disorder (TMJD) pain. The objective of this proposal is to address this critical gap in knowledge by comprehensively elucidating the functions, types, neuroanatomical distributions, and plasticity of trigeminal (TG) neurons innervating the muscles, tendons, and fascia of the masseter (MM) and lateral pterygoid (LPM) muscles, as well as the cartilage, joint capsule, and ligament around TMJ condyle in male, female and aged mice, primates, and humans with and without TMJD pain conditions. In support of this proposal, we have demonstrated that TMJ tissues are innervated by trigeminal (TG) neurons with unique and distinct properties, distributions and molecular signatures compared to previously described TG and dorsal root ganglia (DRG) neurons. Based on supporting data and the expertise of our multi-disciplinary team, we anticipate that this project will map the location and elucidate the phenotype and plasticity for TG neurons innervating TMJ tissues in male, female, and aged mice, primates and humans with and without TMJD pain conditions. We also expect candidate therapeutic target identification in TMJD patients’ TMJ tissues, which could ultimately lead to possible new treatments for TMJD. This study will be conducted in four interconnected yet independent aims. Aim 1 identifies the molecular signature, function and plasticity of TG neurons innervating TMJ tissues in male, female and aged mice with and without TMJD. Aim 2 maps afferent neurites innervating TMJ tissues in mice with and without TMJD. Aim 3 maps the location of neurites and define the phenotype and plasticity of TG neurons innervating TMJ tissues in non-human primates (NHP) with and without TMJD. Aim 4 examines TMJ tissue nerves and cell plasticity in TMJD patients. Substantial amount of data generated by this work will have a substantial positive impact by achieving most objectives of the RE-JOIN program, including (1) mapping the location of the afferent neurites in TMJ tissues; (2) phenotyping and functionally characterizing TG neurons innervating a variety of TMJ tissues; (3) identifying TMJD-induced plasticity of these TG neurons in male, female and aged mice, primates and humans; (4) identifying novel candidate therapeutic targets in biopsies from TMJD patients; and (5) increasing study translatability by validating data from TMJD mouse models in primate and human tissues. The proposed experiments will create large, integrated, annotated datasets and metadata and develop advanced approaches, which will be shared with the research community conducting similar studies.