dmPFC-vlPAG projection neurons contribute to pain threshold maintenance and antianxiety behaviors
Jun-Bin Yin, … , Yu-Lin Dong, Yun-Qing Li
Jun-Bin Yin, … , Yu-Lin Dong, Yun-Qing Li
Published August 25, 2020
Citation Information: J Clin Invest. 2020;130(12):6555-6570. https://doi.org/10.1172/JCI127607.
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Research Article Neuroscience

dmPFC-vlPAG projection neurons contribute to pain threshold maintenance and antianxiety behaviors

Abstract

The dorsal medial prefrontal cortex (dmPFC) has been recognized as a key cortical area for nociceptive modulation. However, the underlying neural pathway and the function of specific cell types remain largely unclear. Here, we show that lesions in the dmPFC induced an algesic and anxious state. Using multiple tracing methods including a rabies-based transsynaptic tracing method, we outlined an excitatory descending neural pathway from the dmPFC to the ventrolateral periaqueductal gray (vlPAG). Specific activation of the dmPFC/vlPAG neural pathway by optogenetic manipulation produced analgesic and antianxiety effects in a mouse model of chronic pain. Inhibitory neurons in the dmPFC were specifically activated using a chemogenetic approach, which logically produced an algesic and anxious state under both normal and chronic pain conditions. Antagonists of the GABAA receptor (GABAAR) or mGluR1 were applied to the dmPFC, which produced analgesic and antianxiety effects. In summary, the results of our study suggest that the dmPFC/vlPAG neural pathway might participate in the maintenance of pain thresholds and antianxiety behaviors under normal conditions, while silencing or suppressing the dmPFC/vlPAG pathway might be involved in the initial stages and maintenance of chronic pain and the emergence of anxiety-like behaviors.

Authors

Jun-Bin Yin, Shao-Hua Liang, Fei Li, Wen-Jun Zhao, Yang Bai, Yi Sun, Zhen-Yu Wu, Tan Ding, Yan Sun, Hai-Xia Liu, Ya-Cheng Lu, Ting Zhang, Jing Huang, Tao Chen, Hui Li, Zhou-Feng Chen, Jing Cao, Rui Ren, Ya-Nan Peng, Juan Yang, Wei-Dong Zang, Xiang Li, Yu-Lin Dong, Yun-Qing Li

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Figure 8

Suppression of GABAAR and mGluR1 in the dmPFC reverses CPNL-induced mechanical hyperalgesia and anxiety-like behaviors.

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Suppression of GABAAR and mGluR1 in the dmPFC reverses CPNL-induced mech...
(A and B) Representative schematic diagram of cannula placement in the dmPFC and the behavioral testing procedure. (C–E) Double staining of FOS-ir neurons (red) and DAPI (blue) in the dmPFC after drug infusion. Scale bar: 200 μm (E) (applied in C and D) Can., cannula; fmi, forceps minor of the corpus callosum (F and G) Mechanical thresholds of the bilateral hind paws following dmPFC injections of saline, bicuculline 0.1 μg or LY 367385 0.4 nmol at baseline and 7 days after CPNL (ipsilateral, F(2, 15) = 6.87, P < 0.001: baseline t = 0.51, t = 0.14; CPNL t = 4.55, t = 4.55; contralateral, F(2, 15) = 7.56, P < 0.001: baseline t = 0.56, t = 0.31; CPNL t = 3.98, t = 3.60; #P < 0.05 and ##P < 0.01; ***P < 0.001; 2-way, repeated-measures ANOVA with Bonferroni’s post hoc test; n = 6 mice per group). (H and I) The total distance traveled and percentage of time in the central area in the OF following dmPFC injection of saline, bicuculline or LY 367385 at baseline and 14 days after CPNL (total distance, F(2,15) = 10.60, P < 0.01: baseline t = 3.79, t = 0.55; CPNL t = 2.85, t = 0.38; time percentage in the central area, F(2, 15) = 6.56, P < 0.01: baseline t = 2.91, t = 0.77; CPNL t = 2.52, t = 2.80; #P < 0.05; *P < 0.05 and **P < 0.01; $$P < 0.01; 2-way, repeated-measures ANOVA with Bonferroni’s post hoc test; n = 6 mice per group). (J and K) The percentage of time in and percentage of entries into the OAs in the EPM following dmPFC injection of saline, bicuculline, or LY 367385 at baseline and 14 days after CPNL (time percentage in the OAs, F(2, 15) = 2.96, P > 0.05: baseline t = 0.43, t = 0.21; CPNL t = 2.86, t = 2.78; entries percentage in the OAs, F(2, 15) = 2.35, P > 0.05: baseline t = 0.33, t = 0.66; CPNL t = 3.04, t = 2.64; #P < 0.05; *P < 0.05 and**P < 0.01; 2-way, repeated-measures ANOVA with Bonferroni’s post hoc test; n = 6 mice per group).