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 7

Optogenetic activation of inhibitory neurons in the dmPFC reversed activation of dmPFC/vlPAG pathway–induced analgesic and antianxiety behaviors.

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Optogenetic activation of inhibitory neurons in the dmPFC reversed activ...
(A and B) Representative schematic diagrams of hChR2 and hM3Dq viruses injected into the dmPFC of C57 mice, retro-Cre virus injected into the vlPAG of C57BL/6J mice, and the procedures for the behavioral tests. (C) The triple staining of EGFP (green), mCherry (red), and DAPI (blue) in the dmPFC. Scale bar: 100 μm. (D) Representative recordings of action potential firing of inhibitory neurons in response to 5 Hz, 10 Hz, and 20 Hz light photostimulation. (E) Whole-cell current-clamp recording from hM3Dq-expressing dmPFC-vlPAG projection neurons. A brief bath application of 40 μM CNO (red box) caused a depolarization and action potential firing. (F and G) Sample traces showing that light-evoked IPSCs in dmPFC-vlPAG projection neurons were blocked by bath application of PTX (***P < 0.01, Student’s t test). (H) Mechanical thresholds of injured hind paws with CNO injection and blue light stimulation 7 days after CPNL (CNO, F(3, 15) = 27.14, P < 0.001, ***P < 0.01; saline: F(3, 9) = 1.03, P = 0.426; 1-way, repeated-measures ANOVA with Tukey’s post hoc test; ###P < 0.001, Student’s t test). (I and J) Total distance traveled and percentage of time in the central area in the OF with CNO injection and blue light stimulation 14 days after CPNL (I: CNO, F(3, 21) = 2.64, P > 0.05; saline: F(3, 9) = 1.03, P = 0.426; J: CNO, F(3, 21) = 5.25, P < 0.01, *P < 0.05; saline: F(3, 9) = 11.47, P < 0.01, $$P < 0.01; 1-way, repeated-measures ANOVA with Tukey’s post hoc test). (K and L) The percentage of time in and percentage of entries into the OAs in the EPM with CNO injection and blue light stimulation at 14 days after CPNL (K: CNO, F(3, 15) = 55.60, P < 0.001, ***P < 0.01; saline: F(3, 9) = 4.86, P = 0.028, $P < 0.05; L: CNO, F(3, 15) = 83.05, P < 0.001, ***P < 0.01; saline: F(3, 9) = 6.38, P = 0.013, $P < 0.05; 1-way, repeated-measures ANOVA with Tukey’s post hoc test; ###P < 0.001, Student’s t test).