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Optogenetic activation of the lateral habenulaD1R–ventral tegmental area circuit induces depression-like behavior in mice

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European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

A number of different receptors are distributed in glutamatergic neurons of the lateral habenula (LHb). These glutamatergic neurons are involved in different neural pathways, which may identify how the LHb regulates various physiological functions. However, the role of dopamine D1 receptor (D1R)-expressing habenular neurons projecting to the ventral tegmental area (VTA) (LHbD1R–VTA) remains not well understood. In the current study, to determine the activity of D1R-expressing neurons in LHb, D1R-Cre mice were used to establish the chronic restraint stress (CRS) depression model. Adeno-associated virus was injected into bilateral LHb in D1R-Cre mice to examine whether optogenetic activation of the LHb D1R-expressing neurons and their projections could induce depression-like behavior. Optical fibers were implanted in the LHb and VTA, respectively. To investigate whether optogenetic inhibition of the LHbD1R–VTA circuit could produce antidepressant-like effects, the adeno-associated virus was injected into the bilateral LHb in the D1R-Cre CRS model, and optical fibers were implanted in the bilateral VTA. The D1R-expressing neuronal activity in the LHb was increased in the CRS depression model. Optogenetic activation of the D1R-expressing neurons in LHb induced behavioral despair and anhedonia, which could also be induced by activation of the LHbD1R–VTA axons. Conversely, optogenetic inhibition of the LHbD1R–VTA circuit improved behavioral despair and anhedonia in the CRS depression model. D1R-expressing glutamatergic neurons in the LHb and their projections to the VTA are involved in the occurrence and regulation of depressive-like behavior.

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The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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Acknowledgements

We thank members of the Neuroscience Research Center, First Hospital of Jilin University for the technical support.

Funding

This study was supported by the National Natural Science Foundation of China (32171145), the Program for JLU Science and Technology Innovative Research Team (JLUSTIRT:2017TD-30), Natural Science Foundation of Jilin Province (Grant no. 20200201330JC). The funding bodies had no role in study design, sample collection, data analysis, interpretation, and manuscript preparation.

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Authors and Affiliations

  1. Department of Physiology, College of Basic Medical Sciences, Jilin University, Xinmin Street No. 126, Changchun, 130021, People’s Republic of China

    Xiaowei Chen, Xuxin Wang, Qiang Zhang & Hua Zhao

  2. Department of Rehabilitation Medicine, First Hospital of Jilin University, Changchun, 130021, People’s Republic of China

    Xiaowei Chen & Jiaming Zhang

  3. Neuroscience Research Center, First Hospital of Jilin University, Changchun, 130021, People’s Republic of China

    Xiaofeng Liu, Yulei Hao & Hua Zhao

  4. Department of Mental Health, First Hospital of Jilin University, Changchun, 130021, People’s Republic of China

    Shuxin Luan

  5. Department of Neurology, First Hospital of Jilin University, Changchun, 130021, People’s Republic of China

    Ying Zhang

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  1. Xiaowei Chen
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Chen, X., Liu, X., Luan, S. et al. Optogenetic activation of the lateral habenulaD1R–ventral tegmental area circuit induces depression-like behavior in mice. Eur Arch Psychiatry Clin Neurosci (2024). https://doi.org/10.1007/s00406-023-01743-2

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