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O-GlcNAcylation in Ventral Tegmental Area Dopaminergic Neurons Regulates Motor Learning and the Response to Natural Reward

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Abstract

Protein O-GlcNAcylation is a post-translational modification that links environmental stimuli with changes in intracellular signal pathways, and its disturbance has been found in neurodegenerative diseases and metabolic disorders. However, its role in the mesolimbic dopamine (DA) system, especially in the ventral tegmental area (VTA), needs to be elucidated. Here, we found that injection of Thiamet G, an O-GlcNAcase (OGA) inhibitor, in the VTA and nucleus accumbens (NAc) of mice, facilitated neuronal O-GlcNAcylation and decreased the operant response to sucrose as well as the latency to fall in rotarod test. Mice with DAergic neuron-specific knockout of O-GlcNAc transferase (OGT) displayed severe metabolic abnormalities and died within 4–8 weeks after birth. Furthermore, mice specifically overexpressing OGT in DAergic neurons in the VTA had learning defects in the operant response to sucrose, and impaired motor learning in the rotarod test. Instead, overexpression of OGT in GABAergic neurons in the VTA had no effect on these behaviors. These results suggest that protein O-GlcNAcylation of DAergic neurons in the VTA plays an important role in regulating the response to natural reward and motor learning in mice.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31871021, 82021002, 31930046, and 32000671), the China Postdoctoral Science Foundation (2020M670978 and 2021T140127), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), and ZhangJiang Lab.

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  1. Ming-Shuo Shao and Xiao Yang contributed equally to this work.

Authors and Affiliations

  1. Departments of Neurosurgery and Hand Surgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Basic Medical Sciences, Institutes of Brain Science, Fudan University, Shanghai, 200032, China

    Ming-Shuo Shao, Xiao Yang, Chen-Chun Zhang, Chang-You Jiang, Ying Mao, Wen-Dong Xu, Lan Ma & Fei-Fei Wang

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  1. Ming-Shuo Shao
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  2. Xiao Yang
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Correspondence to Lan Ma or Fei-Fei Wang.

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Shao, MS., Yang, X., Zhang, CC. et al. O-GlcNAcylation in Ventral Tegmental Area Dopaminergic Neurons Regulates Motor Learning and the Response to Natural Reward. Neurosci. Bull. 38, 263–274 (2022). https://doi.org/10.1007/s12264-021-00776-8

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  • DOI: https://doi.org/10.1007/s12264-021-00776-8

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