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Change in brain molecular landscapes following electrical stimulation of the nucleus accumbens

Neuropsychopharmacology (2025)Cite this article

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Abstract

Deep brain stimulation (DBS) targeting the nucleus accumbens (NAc) is a promising therapeutic intervention for treatment-resistant neuropsychiatric disorders such as depression, anxiety, and addiction. However, the molecular mechanisms underlying the clinical efficacy of NAc DBS remain largely unknown. One approach to address this question is by performing spatial gene expression analysis on cells located in different regions of the same circuit following NAc DBS. In this study, we utilized high-resolution spatial transcriptomics (Stereo-seq) to investigate gene expression changes induced by NAc DBS in the mouse brain. Mice were randomly allocated to receive continuous electrical stimulation (0.1 mA, 130 Hz) or sham treatment (electrode implanted, no electrical stimulation given) for one week, and subsequent Stereo-seq analysis identified differentially expressed genes (DEGs) across various brain regions. Functional enrichment analysis highlighted changes in synaptic and neuroplasticity processes as well as stress and inflammatory responses in the NAc circuit. Single-cell resolution mapping further identified key molecular players, including Nlgn1, Snca, Pde10a, and Syt1, particularly in glutamate receptor-expressing neurons in the NAc. These genes are critical for synaptic plasticity and neurotransmitter release, and have been implicated in various psychiatric disorders. These findings shed light on the molecular underpinnings of NAc DBS and provide insights into its therapeutic potential in modulating neural circuits associated with neuropsychiatric disorders.

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Fig. 1: Stereo-seq captures spatially resolved hemispheric gene expression after electrode implantation in the nucleus accumbens.
Fig. 2: Effect of NAc DBS on global gene expression in the mouse brain.
Fig. 3: Electrical stimulation of NAc has differential impacts on gene expressions in various brain regions.
Fig. 4: Stereo-seq dissects differential cell type-specific responses to electrical stimulation in the NAc.
Fig. 5: Putative therapeutic mechanisms of NAc DBS in glutamate receptor expressing neurons.

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Data availability

The raw data generated in this study have been deposited to CNGB Nucleotide Sequence Archive with accession number CNP0006277 (https://db.cngb.org/search/project/CNP0006277). The code used to generate the results of this study is available on the GitHub repository at https://github.com/Hemmings-Wu-Lab/NAc-DBS-Transcriptomics.

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Acknowledgements

We thank Chang Wang for her contribution in experimental procedure in this study.

Funding

This study was funded by the NSFC Research Grant (82171519) and the NSFC Research Grant (82401781) to ZZ.

Author information

Author notes

  1. These authors contributed equally: Chengwei Cai, Lingyun Gao.

Authors and Affiliations

  1. Department of Neurosurgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Chengwei Cai, Lingyun Gao, Zhoule Zhu, Wangyu Chen, Junming Zhu & Hemmings Wu

  2. Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China

    Chengwei Cai, Lingyun Gao, Zhoule Zhu, Wangyu Chen, Junming Zhu & Hemmings Wu

  3. Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou, Zhejiang, China

    Chengwei Cai, Lingyun Gao, Zhoule Zhu, Wangyu Chen, Junming Zhu & Hemmings Wu

  4. Zhejiang Key Laboratory of Research and Transformation for Major Neurosurgical Diseases, Hangzhou, China

    Chengwei Cai, Lingyun Gao, Zhoule Zhu, Wangyu Chen, Junming Zhu & Hemmings Wu

  5. BGI Research, Shenzhen, China

    Fang Zhang

  6. Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang, China

    Chaonan Yu & Kedi Xu

  7. Qiushi Academy for Advanced Studies (QAAS) Zhejiang University, Hangzhou, Zhejiang, China

    Kedi Xu

  8. Zhejiang Provincial Key Laboratory of Cardio Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Key Laboratory of Biomedical Engineering of Education Ministry, Department of Biomedical Engineering, Zhejiang University, Hangzhou, Zhejiang, China

    Kedi Xu

Authors
  1. Chengwei Cai
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  2. Lingyun Gao
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  3. Zhoule Zhu
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  4. Wangyu Chen
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  5. Fang Zhang
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  6. Chaonan Yu
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  7. Kedi Xu
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  8. Junming Zhu
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  9. Hemmings Wu
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Contributions

CC, HW, and JZ conceived and designed the project. CC, LG, and HW contributed to the analysis and interpretation of data and wrote the manuscript. CC and ZZ contributed to the data acquisition, statistical analyses, and prepared the tables and figures. LG, WC, CY, and KX verified the results. LG, HW, and JZ edited the manuscript and provided supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Junming Zhu or Hemmings Wu.

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Competing interests

The authors declare no competing interests.

Ethics approval

All animal procedures were approved by the Second Affiliated Hospital of Zhejiang University—Animal Ethics Committee (Approval No. AIRB-2021-087) and were performed according to the Guiding Principles for the Care and Use of Laboratory Animals Approved by Animal Regulations of National Science and Technology Committee of China.

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Cai, C., Gao, L., Zhu, Z. et al. Change in brain molecular landscapes following electrical stimulation of the nucleus accumbens. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02241-w

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  • DOI: https://doi.org/10.1038/s41386-025-02241-w

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