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.

Grant Number: 3UC2AR082195-02S1
NIH Institute/Center: NIH
Principal Investigator: ARMEN AKOPIAN