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

Abstract

Trigeminal neuralgia (TN) is debilitating and is usually accompanied by mood disorders. The lateral habenula (LHb) is considered to be involved in the modulation of pain and mood disorders, and the present study aimed to determine if and how the LHb participates in the development of pain and anxiety in TN. To address this issue, a mouse model of partial transection of the infraorbital nerve (pT-ION) was established. pT-ION induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors that correlated with the increased excitability of LHb neurons. Adeno-associated virus (AAV)-mediated expression of hM4D(Gi) in glutamatergic neurons of the unilateral LHb followed by clozapine-N-oxide application relieved pT-ION-induced anxiety-like behaviors but not allodynia. Immunofluorescence validated the successful infection of AAV in the LHb, and microarray analysis showed changes in gene expression in the LHb of mice showing allodynia and anxiety-like behaviors after pT-ION. Among these differentially expressed genes was Tacr3, the downregulation of which was validated by RT-qPCR. Rescuing the downregulation of Tacr3 by AAV-mediated Tacr3 overexpression in the unilateral LHb significantly reversed pT-ION-induced anxiety-like behaviors but not allodynia. Whole-cell patch clamp recording showed that Tacr3 overexpression suppressed nerve injury-induced hyperexcitation of LHb neurons, and western blotting showed that the pT-ION-induced upregulation of p-CaMKII was reversed by AAVmediated Tacr3 overexpression or chemicogenetic inhibition of glutamatergic neurons in the LHb. Moreover, not only anxiety-like behaviors, but also allodynia after pT-ION were significantly alleviated by chemicogenetic inhibition of bilateral LHb neurons or by bilateral Tacr3 overexpression in the LHb. In conclusion, Tacr3 in the LHb plays a protective role in treating trigeminal nerve injury-induced allodynia and anxiety-like behaviors by suppressing the

Effects of Voluntary Running Wheel Exercise-Induced Extracellular Vesicles on Anxiety

“…Tacr3 overexpression in the unilateral habenula significantly reduced anxiety-like behavior NV, non-restrained vehicle-injected group (n = 3); RS, restraint-stressed sedentary EV-injected group (n = 4); RE, restraint-stressed exercise EV-injected group (n = 4). (Cui et al, 2020). By contrast, Tacr3 expression in the amygdala of the NIH-HS rat was higher in a high-anxious group compared with a low-anxious group (Díaz-Morán et al, 2013).…”

“…Exercise-induced EVs injected restrained group exhibited higher levels of the neuroactive ligand-receptor interaction genes (Tacr3, Gabrr1, Cysltr1, Oprm1, and Trhr) than sedentary-derived EVs injected group. Tacr3 overexpression in the unilateral habenula significantly reduced anxiety-like behavior (Cui et al, 2020 ). By contrast, Tacr3 expression in the amygdala of the NIH-HS rat was higher in a high-anxious group compared with a low-anxious group (Díaz-Morán et al, 2013 ).…”

Effects of Urban Particulate Matter on the Olfactory System in a Mouse Model

“…American Journal of Rhinology & Allergy 36 (1) trigeminal nerve injury-induced allodynia and anxiety-like behaviors. 26 The results of staining substance P and TACR3, which are markers to visualize the trigeminal nerve, as well as results of the Western blot, demonstrated an increase in TACR3. In particular, TACR3 demonstrated a significant increase in the mRNA analysis performed on week 3 (during the recovery phase when the mouse is no longer exposed to UPM exposure to UPM lasts for 2 weeks, followed by a week of no exposure), which is suggestive that the trigeminal nerve plays a role in the olfactory loss and recovery process following UPM exposure.…”

Trigeminal neuralgia and genetics: A systematic review

“…Genes coding for proteins in the tachykinin family have recently been examined in two separate studies. 57 , 58 Neurokinin 3 receptor and hemokinin-1 receptor, coded by Tacr3 and Tac4 respectively, are suggested to contribute to development of trigeminal neuropathic pain. Downregulation of Tacr3 worked protective against pain, while upregulation of Tac4 was seen after CFA-injection in mice.…”