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Dopaminergic Projection from Ventral Tegmental Area to Substantia Nigra Pars Reticulata Mediates Chronic Social Defeat Stress–Induced Hypolocomotion

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Abstract

Numerous human clinical studies have suggested that decreased locomotor activity is a common symptom of major depressive disorder (MDD), as well as other psychiatric diseases. In MDD, the midbrain ventral tegmental area (VTA) dopamine (DA) neurons are closely related to regulate the information processing of reward, motivation, cognition, and aversion. However, the neural circuit mechanism that underlie the relationship between VTA-DA neurons and MDD-related motor impairments, especially hypolocomotion, is still largely unknown. Herein, we investigate how the VTA-DA neurons contribute to the hypolocomotion performance in chronic social defeat stress (CSDS), a mouse model of depression-relevant neurobehavioral states. The results show that CSDS could affect the spontaneous locomotor activity of mice, but not the grip strength and forced locomotor ability. Chemogenetic activation of VTA-DA neurons alleviated CSDS-induced hypolocomotion. Subsequently, quantitative whole-brain mapping revealed decreased projections from VTA-DA neurons to substantia nigra pars reticulata (SNr) after CSDS treatment. Optogenetic activation of dopaminergic projection from VTA to SNr with the stimulation of phasic firing, but not tonic firing, could significantly increase the locomotor activity of mice. Moreover, chemogenetic activation of VTA-SNr dopaminergic circuit in CSDS mice could also rescued the decline of locomotor activity. Taken together, our data suggest that the VTA-SNr dopaminergic projection mediates CSDS-induced hypolocomotion, which provides a theoretical basis and potential therapeutic target for MDD.

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Data Availability

Data will be made available on reasonable request.

All animal handling and experiments were performed in accordance with NIH guidelines and reviewed by the Ethics Committees of Huazhong University of Science and Technology (HUST).

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Acknowledgements

The authors wish to acknowledge Dr. Xutao Zhu, Dr. Sen Jin (Center for Brain Science, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, 430071 China), and Dr. Manfei Deng (Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, P. R. China) for their technical assistance with this project.

Funding

This work was supported financially by grants from National Natural Science Foundation of China (Nos. 31871073, 31571044 to B.T., and No. 31600821 to P.Z.), Program for New Century Excellent Talents in University (No. NCET-10–0415 to B.T.), and the Fundamental Research Funds for the Central Universities (HUST: 2019kfyXJJS081 to P.Z.).

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Authors and Affiliations

  1. Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China

    Feng He, Pei Zhang, Qian Zhang, Guangjian Qi, Hongwei Cai, Tongxia Li, Ming Li, Jiazhen Lu, Jiaen Lin & Bo Tian

  2. Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China

    Pei Zhang & Bo Tian

  3. Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, Hubei Province, 430030, People’s Republic of China

    Pei Zhang & Bo Tian

  4. Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technolog, Wuhan, Hubei Province, 430022, People’s Republic of China

    Jie Ming

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Contributions

F.H.: investigation, methodology, data curation, formal analysis, writing—original draft, visualization. P.Z.: conceptualization, methodology, data curation, formal analysis, writing—review and editing, visualization, project administration, funding acquisition. Q.Z.: investigation, methodology, formal analysis, validation, visualization. G.J.Q.: validation, data curation, formal analysis, visualization. H.W.C.: investigation, formal analysis, validation, data curation. T.X.L.: investigation, validation, data curation. M.L.: investigation, validation, data curation. J.Z.L.: investigation, formal analysis. J.E.L.: investigation, formal analysis. J.M.: conceptualization, resources, supervision. B.T.: conceptualization, methodology, resources, writing—review and editing, visualization, supervision, project administration, funding acquisition.

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Correspondence to Jie Ming or Bo Tian.

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Feng He and Pei Zhang contributed equally to this work.

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He, F., Zhang, P., Zhang, Q. et al. Dopaminergic Projection from Ventral Tegmental Area to Substantia Nigra Pars Reticulata Mediates Chronic Social Defeat Stress–Induced Hypolocomotion. Mol Neurobiol 58, 5635–5648 (2021). https://doi.org/10.1007/s12035-021-02522-7

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