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D1 receptor-expressing neurons in ventral tegmental area alleviate mouse anxiety-like behaviors via glutamatergic projection to lateral septum

Molecular Psychiatry volume 28, pages 625–638 (2023)Cite this article

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Abstract

Dopamine (DA) acts as a key regulator in controlling emotion, and dysfunction of DA signal has been implicated in the pathophysiology of some psychiatric disorders, including anxiety. Ventral tegmental area (VTA) is one of main regions with DA-producing neurons. VTA DAergic projections in mesolimbic brain regions play a crucial role in regulating anxiety-like behaviors, however, the function of DA signal within VTA in regulating emotion remains unclear. Here, we observe that pharmacological activation/inhibition of VTA D1 receptors will alleviate/aggravate mouse anxiety-like behaviors, and knockdown of VTA D1 receptor expression also exerts anxiogenic effect. With fluorescence in situ hybridization and electrophysiological recording, we find that D1 receptors are functionally expressed in VTA neurons. Silencing/activating VTA D1 neurons bidirectionally modulate mouse anxiety-like behaviors. Furthermore, knocking down D1 receptors in VTA DA and glutamate neurons elevates anxiety-like state, but in GABA neurons has the opposite effect. In addition, we identify the glutamatergic projection from VTA D1 neurons to lateral septum is mainly responsible for the anxiolytic effect induced by activating VTA D1 neurons. Thus, our study not only characterizes the functional expression of D1 receptors in VTA neurons, but also uncovers the pivotal role of DA signal within VTA in mediating anxiety-like behaviors.

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Fig. 1: Manipulating VTA D1 receptors bidirectionally regulates mouse anxiety-like behaviors.
Fig. 2: Functional expression of D1 receptors in VTA neurons.
Fig. 3: Optogenetic activation of VTA D1 neurons relieves mouse anxiety-like behaviors.
Fig. 4: Chemogenetic manipulation of VTA D1 neurons and blocking synaptic transmission of VTA D1 neurons change mouse anxiety-like behaviors.
Fig. 5: Lowering D1 receptor expression in VTA DA, GABA, and glutamate neurons differently changes mouse anxiety-like behaviors.
Fig. 6: Glutamatergic projection of VTA D1 neurons to LS is responsible for alleviating mouse anxiety-like behaviors.

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Acknowledgements

We thank Dr. Ping Zheng for D1-Cre mice, Dr. Xiaohong Xu for DAT-Cre mice, Dr. Miao He for Vgat-Cre and Vglut2-Cre mice, and the members of Xiao laboratory for their valuable input. We thank Dr. Lan Ma, Dr. Yevgenia Kozorovitskiy, Dr. Xin Jin, Dr. Qingjian Han, and Dr. Ting Lu for feedback on this manuscript. This work was supported by grants from the National Natural Science Foundation of China (81970727, 31900738, 31970908), Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01), ZJ Lab, and Shanghai Center for Brain Science and Brain-Inspired Technology.

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  1. The State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, 200032, China

    Qiuping Tong, Xiao Cui, Hao Xu, Xiaoshuang Zhang, Songhui Hu, Fang Huang & Lei Xiao

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  1. Qiuping Tong
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Contributions

LX designed and supervised the study. QT and LX planned the experiments and analyzed the data. QT, XC, and XZ performed the behavioral experiments. QT and XC carried out FISH experiments. LX, HX, and SH carried out the electrophysiology experiments. QT, FH, and LX wrote the manuscript, and all of the authors helped with the revision of the manuscript.

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Correspondence to Lei Xiao.

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Tong, Q., Cui, X., Xu, H. et al. D1 receptor-expressing neurons in ventral tegmental area alleviate mouse anxiety-like behaviors via glutamatergic projection to lateral septum. Mol Psychiatry 28, 625–638 (2023). https://doi.org/10.1038/s41380-022-01809-y

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