dmPFC-vlPAG projection neurons contribute to pain threshold maintenance and antianxiety behaviors
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
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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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 6

Chemogenetic activation of inhibitory neurons in the dmPFC worsens CPNL-induced mechanical hyperalgesia and anxiety-like behaviors.

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Chemogenetic activation of inhibitory neurons in the dmPFC worsens CPNL-...
(A and B) Representative schematic diagrams of hM3Dq virus injection into the dmPFC of Vgat-Cre mice and the procedures for the behavioral test. (C–J) Triple staining of mCitrin (green), GAD67 (red), and FOS (blue) in the dmPFC after CNO i.p. injection. White arrowheads indicate the coexpression of mCitrin, GAD67, and FOS. Scale bars: 40 μm (C–F); 10 μm ( G–J). (K and L) Mechanical thresholds of the bilateral hind paws following injection of control virus or hM3Dq virus and CNO 1 mg/kg i.p. injection (hM3Dq virus, ipsilateral: F(1, 56) = 19.53, P < 0.001; contralateral: F(1, 56) = 5.65, P < 0.05; control virus, ipsilateral: F(1, 56) = 1.46, P = 0.24; contralateral: F(1, 56) = 1.09, P = 0.31; &P < 0.05 and &&&P < 0.001; *P < 0.05; 2-way, repeated-measures ANOVA with Bonferroni’s post hoc test; n = 8 mice per group). (M–P) Total distance traveled and percentage of time spent in the central area in the OF test and percentage of time in and percentage of entries into the OAs in the EPM test with CNO injection under normal conditions (M: F(1, 12) = 5.13, P < 0.05, t = 3.71; N: F(1, 12) = 6.22, P < 0.05, t = 2.99; O: F(1, 12) = 8.85, P < 0.01, t = 4.22; P: F(1, 12) = 10.55, P < 0.01, t = 4.22; *P < 0.05 and **P < 0.01; 2-way, repeated-measures ANOVA with Bonferroni’s post hoc test; n = 4 mice per group). (Q–T) Total distance traveled and percentage of time spent in the central area in the OF test and percentage of time spent in and percentage of entries into the OAs in the EPM test with CNO injection, 14 days after CPNL (Q: F(1, 12) = 12.87, P < 0.01, t = 4.23; R: F(1, 12) = 5.92, P < 0.05, t = 2.83; S: F(1, 12) = 5.32, P < 0.05, t = 2.95; T: F(1, 12) = 5.05, P < 0.05, t = 4.14; *P < 0.05 and **P < 0.01; 2-way, repeated-measures ANOVA with Bonferroni’s post hoc test; n = 4 mice per group).