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 10

Optogenetic activation of VLO-vlPAG projection pathway had no effect on TN-induced anxiodepressive-like behaviors.

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Optogenetic activation of VLO-vlPAG projection pathway had no effect on ...
(A) Schematic of the protocol for experiments in C–M. (B) Sagittal schematic diagrams and photomicrograph of coronal section showing retro-AAV-DIO-ChR2-mCherry injection into the bilateral vlPAG of CaMK2A-Cre mouse (left) and CaMK2A+ neurons expressing ChR2-mCherry in the VLO (right). Scale bar: 500 μm. (C) An example showing that action potentials induced through blue light stimulation (473 nm, 5 mW, 20 Hz) on VLO CaMK2A+ neurons expressing ChR2-mCherry. (D–G) Optogenetic activation of VLO CaMK2A+ neurons projecting to vlPAG did not affect TN-induced anxiodepressive effect in EPM (D), OFT (E), FST (F), and TST (G). Two-sided Student’s t test; n = 6 (mCherry) and 7 (ChR2). (H) Sagittal schematic diagrams and photomicrograph of coronal section showing injection of AAV-DIO-ChR2-mCherry into the bilateral VLO of CaMK2A-Cre mouse (left) and CaMK2A+ terminal expressing ChR2-mCherry in the vlPAG (right). Scale bar: 500 μm. (I–L) Optogenetic activation of the VLO-vlPAG excitatory projection had no effect on TN-induced anxiodepressive effect in EPM (I), OFT (J), FST (K), and TST (L). Two-sided Student’s t test; n = 5 (mCherry) and 6 (ChR2).