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 7

Selective inhibition of VLO GABAergic neurons produced the an antianxiodepressive effect in TN mice.

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Selective inhibition of VLO GABAergic neurons produced the an antianxiod...
(A) Schematic and photomicrograph of coronal section showing AAV-DIO-hM4Di-mCherry injection into the bilateral VLO of Vgat-IRES-Cre mice. Scale bar: 500 μm. (B) Schematic of the protocol for experiments in D–I. (C) An example showing that bath CNO (500 nM) suppressed action potentials (APs) firing in VGAT+ neurons expressing hM4Di-mCherry. (D–H) Inhibition of bilateral VLO VGAT+ neurons by chemogenetic manipulation produced an antianxiodepressive effect in EPM (D and F), FST (G), and TST (H), but not in OFT (E). *P < 0.05, **P < 0.01, ***P < 0.001, 2-sided Student’s t test; n = 8–9 (mCherry) and 8 (hM4Di). (I) Inhibition of bilateral VLO VGAT+ neurons by chemogenetic manipulation did not affect sucrose preference in SPT (2-sided Student’s t test; n = 5 mCherry and 8 hM4Di). (J) Schematic and photomicrograph of coronal section showing the site of optical fiber implantation and AAV-DIO-MAC-mCherry injection into the bilateral VLO of Vgat-IRES-Cre mice. Scale bar: 500 μm. (K) Schematic of the protocol for experiments in M–P. (L) Patch clamp recording in VLO slice showing that APs were suppressed through blue light stimulation (473 nm, 5 mW, continuous) on VLO VGAT+ neurons expressing MAC-mCherry. (M–O) Optogenetic inhibition of bilateral VLO VGAT+ neurons induced an antianxiodepressive effect in EPM (M and N) and TST (O). *P < 0.05, ***P < 0.01, 1-way ANOVA followed by post hoc Student-Newman-Keuls test; n = 4 (mCherry-light), 4, (MAC-light) and 5 (MAC-no light). (P) Light stimulation of VLO VGAT+ neurons expressing MAC-mCherry reduced the freezing time in TST with lights on for 3 minutes. *P < 0.05, 2-sided paired t test; n = 4.