Malocclusion Generates Anxiety-Like Behavior Through a Putative Lateral Habenula–Mesencephalic Trigeminal Nucleus Pathway

Abstract

Malocclusion is an important risk factor for temporomandibular disorder (TMD), a series of disorders characterized by dysfunction in the orofacial region involving the temporomandibular joint (TMJ) and jaw muscles. We recently showed that experimental unilateral anterior crossbite (UAC) produced masseter hyperactivity through a circuit involving the periodontal proprioception, trigeminal mesencephalic nucleus (Vme), and trigeminal motor nucleus (Vmo). Anxiety is a common complication in patients with TMD. The lateral habenula (LHb) is involved in emotional modulation and has direct projections to the Vme. Therefore, the present research examined whether UAC facilitates excitatory input from the LHb to the Vme and, subsequently, anxiety-like behaviors in rats. The LHb activation was evaluated by the electrophysiological recording, assessment of vesicular glutamate transporter-2 (VGLUT2) mRNA expression, and measurement of anxiety-like behaviors. The effects of LHb activity on Vme were evaluated by electrophysiological recording from Vme neurons and local changes in VGLUT2 protein density. UAC produced anxiety in modeled rats and increased neuronal activity in the LHb. VGLUT2 mRNA expression was also increased in the LHb. Further, VGLUT2-positive boutons were observed in close apposite upon parvalbumin (PV)-labeled Vme neurons. VGLUT2 protein expression was also increased in the Vme. Significantly, injection of VGLUT2-targeted shRNA into the LHb reduced the expression of VGLUT2 protein in the Vme, attenuated UAC-associated anxiety-like behaviors, and attenuated electrophysiological changes in the Vme neurons. In conclusion, we show that UAC activates the LHb neurons as well as the periodontal proprioceptive pathway to provide excitatory input to the Vme and produce anxiety in rats. These findings provide a rationale for suppressing activity of the LHb to attenuate both the physical and psychological effects of TMD.

Effect of dental malocclusion on cerebellar neuron activation via the dorsomedial part of the principal sensory trigeminal nucleus

“…The dental occlusion contribution to postural control has been proposed to depend on external disturbances [ 39 , 40 ]. Our published data [ 14 , 25 , 35 , 41 ] and the present work bring about supportive evidence. The existence of an ascending pathway mediating proprioception from the periodontal region to the cerebellum provides a possible neuroanatomical basis for the trigeminal mechanism of somatic movement and balance.…”

“…This makes it possible for the projections of neurons in the Vme to target many other neurons in the brainstem. The neurons of Vme innervate spindles in the jaw‐closing muscles and periodontal pressoreceptors [ 25 , 35 , 41 , 43 ]. Axons involved in trigeminal proprioception from periodontal mechanoreceptors and spindles in the jaw‐closing muscles directly bypass the trigeminal ganglion and leave their cell bodies in all the rostro‐caudal levels of the entire mesencephalon [ 44 ].…”

Tacr3 in the lateral habenula differentially regulates orofacial allodynia and anxiety-like behaviors in a mouse model of trigeminal neuralgia

“…Stereological and 3D morphological analysis showed atrophy and reduced numbers of glial cells in the bilateral LHb of rats with chronic stress-related anxiety [17]. Moreover, the LHb was reported to be activated and to contribute to the induction of anxiety-like behaviors in temporomandibular disorders, which are dysfunctions of the orofacial region [26]. However, whether and how the LHb participates in the pathogenesis of pain and anxiety in TN is unknown.…”

Animal Models of Temporomandibular Disorder

“…Recently, a study shows that UAC activates the lateral habenula (LHb) neurons as well as the periodontal proprioceptive pathway to provide excitatory input to the trigeminal afferents (Vme) and produces anxiety in rats, which provides a possible explanation of malocclusion patients experiencing emotional stress and masseter hyperactivity, a common situation in TMD patients. 69 Despite the created UAC prosthesis seldom occurs clinically, this model provides evidence that abnormal anterior occlusion plays a role in the development of TMJ-OA, and provides an experimental basis for studies on treatments of TMD.…”