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 2

Projections from the dmPFC to the VGLUT2-containing neurons in the vlPAG.

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Projections from the dmPFC to the VGLUT2-containing neurons in the vlPAG...
(A) Schematic diagram of retrograde tracing of projection neurons in the dmPFC, which were labeled with FG injected into the vlPAG. (B–E) Images show different coronal dmPFC sections with double staining of FG (red) injected into the vlPAG and NeuN (green). L1–L6, layers 1–6; fmi, forceps minor of the corpus callosum; VO, ventral orbital cortex. Scale bar: 100 μm. (F–H) Schematics of rabies-based transsynaptic tracing. (F and G) VGLUT2-Cre mice were transduced with 2 AAVs in the vlPAG followed by EnvA-pseudotyped, rabies virus glycoprotein–deleted (RVG-deleted), and dsRed-expressing rabies virus. (H) Schematic of sagittal section of the mouse brain shows VGLUT2 starter cells labeled in yellow and presynaptic partners throughout the brain in red. (I–L) Coronal sections through the vlPAG of a brain with VGLUT2-Cre tracing show the location of starter cells (yellow), which were double stained with GFP (green) and dsRed (red). Scale bars: 100 μm (I); 20 μm (enlarged insets in J–L). Aq, aqueduct. (M–P) Images of a coronal section through the dmPFC and a section through the ACC show dsRed-labeled presynaptic projection neurons. The areas in the white frames in M and O were magnified in N and P. Scale bars: 300 μm (M and O); 50 μm (N and P). All experiments were repeated 3 times and yielded consistent results.