Activation of ventrolateral orbital cortex improves mouse neuropathic pain–induced anxiodepression
Hai-Yan Sheng, Su-Su Lv, Ya-Qi Cai, Wu Shi, Wei Lin, Ting-Ting Liu, Ning Lv, Hong Cao, Ling Zhang, Yu-Qiu Zhang
Hai-Yan Sheng, Su-Su Lv, Ya-Qi Cai, Wu Shi, Wei Lin, Ting-Ting Liu, Ning Lv, Hong Cao, Ling Zhang, Yu-Qiu Zhang
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Research Article Neuroscience

Activation of ventrolateral orbital cortex improves mouse neuropathic pain–induced anxiodepression

Abstract

Depression and anxiety are frequently observed in patients suffering from neuropathic pain. The underlying mechanisms remained unclear. The ventrolateral orbital cortex (VLO) has attracted considerable interest in its role in antidepressive effect in rodents. In the present study, we further investigated the role of the VLO in the anxiodepressive consequences of neuropathic pain in a chronic constriction injury of infraorbital nerve–induced trigeminal neuralgia (TN) mouse model. Elevated plus maze, open field, forced swimming, tail suspension, and sucrose preference tests were used to evaluate anxiodepressive-like behaviors. The results show that chemogenetic activation of bilateral VLO neurons, especially CaMK2A+ pyramidal neurons, blocked the TN-induced anxiodepressive-like behaviors. Chemogenetic and optogenetic activation of VGLUT2+ or inhibition of VGAT+ VLO neurons was sufficient to produce an antianxiodepressive effect in TN mice. Pharmacological activation of D1-like receptors (D1Rs) but not D2Rs in the VLO significantly alleviated TN-induced depressive-like behaviors. Electrophysiological recordings revealed a decreased excitability of VLO excitatory neurons following neuropathic pain. Furthermore, activation of submedius thalamic nucleus–VLO (Sm-VLO) projection mimicked the antianxiodepressive effect of VLO excitation. Conversely, activation of VLO-periaqueductal gray matter (PAG) projection had no effect on TN-induced anxiodepressive behaviors. This study provides a potentially novel mechanism–based therapeutic strategy for the anxiodepressive consequences of neuropathic pain.

Authors

Hai-Yan Sheng, Su-Su Lv, Ya-Qi Cai, Wu Shi, Wei Lin, Ting-Ting Liu, Ning Lv, Hong Cao, Ling Zhang, Yu-Qiu Zhang

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Figure 1

Trigeminal neuralgia induced mechanical allodynia and anxiodepressive-like behaviors in mice.

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Trigeminal neuralgia induced mechanical allodynia and anxiodepressive-li...
(A) Schematic showing chronic constriction injury of infraorbital nerve. CION, arrow points to the ligation site. TG, trigeminal ganglion. (B) Following the trigeminal neuralgia (TN) that developed, mechanical stimulation response scores were increased to both 0.02 g (left) and 0.16 g (right) von Frey filaments stimuli on the ipsilateral vibrissa pad. **P < 0.01, ***P < 0.001, 2-way RM ANOVA followed by post hoc Student-Newman-Keuls test; n = 5 (both sham and CION). (C) Mechanical response threshold of the ipsilateral vibrissa pad decreased markedly on day 14 after CION. **P < 0.01, 1-way ANOVA followed by post hoc Student-Newman-Keuls test; n = 12 (sham) and 13 (CION). (D) Schematic of the protocol for the experiments in E–I. (E–G) The TN mice showed anxiety-like behaviors in elevated plus maze (EPM) test (E) and open field test (OFT, F). *P < 0.05, **P < 0.01, 1-way ANOVA followed by post hoc Student-Newman-Keuls test; n = 13 (naive), 11 (sham), and 9 (CION). (G) Example track plots from naive, sham, and CION mice in EPM (above) and OFT (below). (H and I) The TN mice showed depressive-like behaviors in forced swimming test (FST, H) and tail suspension test (TST, I). ***P < 0.001, 1-way ANOVA followed by post hoc Student-Newman-Keuls test; n = 13 (naive), 11 (sham), and 9 (CION). (J and K) The TN mice showed depressive-like behaviors in sucrose preference test (SPT). *P < 0.05, 1-way ANOVA followed by post hoc Student-Newman-Keuls test; n = 7 (naive), 9 (sham), and 9 (CION).