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

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 received 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. Our findings reveal widespread alterations in synaptic function and neuronal connectivity, particularly in glutamate receptor-expressing neurons in the NAc, which play a key role in the reward circuitry. Functional enrichment analysis highlighted changes in transporter activity and glutamate receptor binding in brain regions such as the anterior cingulate cortex and lateral septal nucleus. Single-cell resolution mapping further identified key molecular players, including Nlgn1, Snca, PDE10a, and Syt1, which 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.