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NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA

Molecular Psychiatry (2024)Cite this article

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Abstract

Major depressive disorder (MDD) is characterized by diverse debilitating symptoms that include loss of motivation and anhedonia. If multiple medications, psychotherapy, and electroconvulsive therapy fail in some patients with MDD, their condition is then termed treatment-resistant depression (TRD). MDD can be associated with abnormalities in the reward-system–dopaminergic mesolimbic pathway, in which the nucleus accumbens (NAc) and ventral tegmental area (VTA) play major roles. Deep brain stimulation (DBS) applied to the NAc alleviates the depressive symptoms of MDD. However, the mechanism underlying the effects of this DBS has remained elusive. In this study, using the chronic unpredictable mild stress (CUMS) mouse model, we investigated the behavioral and neurobiological effects of NAc-DBS on the multidimensional depression-like phenotypes induced by CUMS by integrating behavioral, in vivo microdialysis coupled with high-performance liquid chromatography–electrochemical detector (HPLC-ECD), calcium imaging, pharmacological, and genetic manipulation methods in freely moving mice. We found that long-term and repeated, but not single, NAc-DBS induced robust antidepressant responses in CUMS mice. Moreover, even a single trial NAc-DBS led to the elevation of the γ-aminobutyric acid (GABA) neurotransmitter, accompanied by the increase in dopamine (DA) neuron activity in the VTA. Both the inhibition of the GABAA receptor activity and knockdown of the GABAA-α1 gene in VTA-GABA neurons blocked the antidepressant effect of NAc-DBS in CUMS mice. Our results showed that NAc-DBS could disinhibit VTA-DA neurons by regulating the level of GABA and the activity of VTA-GABA in the VTA and could finally correct the depression-like behaviors in the CUMS mouse model.

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Fig. 1: Long-term and high-frequency-dependent nucleus accumbens deep brain stimulation (NAc-DBS) attenuated depression-like behaviors in chronic unpredictable mild stress (CUMS) mice.
Fig. 2: A single trial of high-frequency-dependent nucleus accumbens deep brain stimulation (NAc-DBS) increased both the level of the γ-aminobutyric acid (GABA) neurotransmitter and dopaminergic neuron activity in the ventral tegmental area (VTA).
Fig. 3: Chronic optical stimulation of VTA-GABA-projecting MSN terminals of NAc alleviates the depression-like behavior in CUMS mice.
Fig. 4: Pharmacological characterization of bicuculline showing that it can block the antidepressant effect of long-term and high-frequency-dependent nucleus accumbens deep brain stimulation (NAc-DBS).
Fig. 5: Knockdown of γ-aminobutyric acid A subunit alpha 1 (GABAA-α1) receptors blocked the antidepressant effect of long-term and high-frequency-dependent nucleus accumbens deep brain stimulation (NAc-DBS).
Fig. 6: GABAA-α1 receptors in VTA-GABA neurons mediate the process of NAc-DBS disinhibition of VTA-DA neurons.

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Acknowledgements

We thank Academician Yizheng Wang and his team from the Center of Military Brain Science, Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences for their support of the experiment.

Funding

The study was supported by the Beijing Natural Science Foundation (Grant No. 7244369).

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Authors and Affiliations

  1. Center of Cognition and Brain Science, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China

    Nan Song, Yan Gao, Shanshan Lu, Shenglian Yang & Chao Yuan

  2. Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China

    Nan Song

  3. Institute for Brain Disorders, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China

    Zhenhong Liu

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NS, SY, YG and ZL initiated and designed the research. NS wrote the manuscript. NS, SL, CY and ZL performed all experiments and analyzed and interpreted the results. All the authors approved the submission.

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Song, N., Liu, Z., Gao, Y. et al. NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02476-x

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