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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00174

Malocclusion Generates Anxiety-Like Behaviour through a Putative Lateral Habenula-Mesencephalic Trigeminal Nucleus Pathway

 Xin Liu1, 2,  Kaixiang Zhou3, Nannan Yin2, Chunkui Zhang3, Minghong Shi1, Hongyun Zhang1, Dongmei Wang4, Zijun Xu5, Jingdong Zhang6,  Jin-lian Li3 and Meiqing Wang1*
  • 1Department of Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, China
  • 2Department of Stomatology, The 456th Hospital of People's Liberation Army, China
  • 3KK Leung Brain Research Centre, Fourth Military Medical University, China
  • 4Department of Oral Medicine, School of Stomatology, Xinxiang Medical University, China
  • 5School of Medicine, South China University of Technology, China
  • 6Department of Anesthesiology, University of Cincinnati College of Medicine, United States

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 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 modelled 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-labelled 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.

Keywords: Anxiety, Lateral habenula, Trigeminal mesencephalic nucleus, unilateral anterior cross bite, vesicular glutamate transporter-2

Received: 11 Apr 2019; Accepted: 01 Jul 2019.

Edited by:

Hans-Georg Breitinger, German University in Cairo, Egypt

Reviewed by:

Thomas Hnasko, University of California, San Diego, United States
Maria G. Piancino, University of Turin, Italy  

Copyright: © 2019 Liu, Zhou, Yin, Zhang, Shi, Zhang, Wang, Xu, Zhang, Li and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Meiqing Wang, Department of Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi’an, China,