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Glutamatergic Neurons in the Zona Incerta Modulate Pain and Itch Behaviors in Mice

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Abstract

Emerging evidence suggest that parvalbumin neurons in zona incerta (ZI) modulate pain and itch behavior in opposite manners. However, the role of ZI glutamatergic neurons, a unique incertal neuronal subpopulation residing in the caudal division, in pain and itch modulation remains unknown. In the present study, by combining chemogenetic manipulation, fiber photometry, and behavioral tests, we proved that incertal glutamatergic neurons served as an endogenous negative diencephalic modulator for both pain and itch processing. We demonstrated that ZI vesicular glutamate transporter 2 (VGluT2) neurons exhibited increased calcium signal upon hindpaw withdrawal in response to experimental mechanical and thermal stimuli. Behavioral tests further showed that pharmacogenetic activation of this specific type of neurons reduced nocifensive withdrawal responses in both naïve and inflammatory pain mice. Similar neural activity and modulatory role of ZI VGluT2 neurons were also observed upon histaminergic and non-histaminergic acute itch stimuli. Together, our study would expedite our understandings of brain mechanisms underlying somatosensory processing and modulation, and supply a novel therapeutic target for the management of chronic pain and itch disorders.

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Data Availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank the members of our lab for their support and help.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82271243, 82071235 and 82101318), Outstanding Youth Fund of Shaanxi Province (2021JC-32), Youth development programme funding (21QNPY065), support funding from the Fourth Military Medical University (2020AXJHHJ) and Sanming Project of Medicine in Shenzhen (SZSM201911011).

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  1. Jiaqi Li, Shihao Peng and Yiwen Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, Basic Medical Science Academy, Fourth Military Medical University, Xi’an, 710032, China

    Jiaqi Li, Shihao Peng, Yiwen Zhang, Junye Ge, Shasha Gao, Yuanyuan Zhu, Shengxi Wu & Jing Huang

  2. Department of Neurosurgery, General Hospital of Northern Theater Command, Shenyang, 110015, China

    Yang Bai

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  1. Jiaqi Li
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Contributions

JH and S-XW conceived and designed the experiments. J-QL, YB, S-HP performed experiments, analyzed data and wrote the manuscript. S-HP, Y-WZ, S-SG and Y-YZhu assisted J-QL with animal studies and histology. J-QL, J-YG and S-HP interpreted the data and statistical analyses. S-XW and JH conceived this study, analyzed the data and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yang Bai, Shengxi Wu or Jing Huang.

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This study was approved by the Institutional Animal Care and Use Committee of the Fourth Military Medical University and conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.

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Li, J., Peng, S., Zhang, Y. et al. Glutamatergic Neurons in the Zona Incerta Modulate Pain and Itch Behaviors in Mice. Mol Neurobiol 60, 5866–5877 (2023). https://doi.org/10.1007/s12035-023-03431-7

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