Abstract
BACKGROUND: Chronically implanted electrodes offer a promising approach for treating neurological disorders via brain-computer interfaces, yet their long-term efficacy is compromised by the neuroinflammatory foreign body response. While neurons are central to both electrode function and inflammatory regulation, their specific responses post-implantation remain poorly characterized. Here, we combined single-nucleus RNA sequencing (snRNA-seq) and immunofluorescence to delineate the spatiotemporal dynamics of neuronal subtypes in the rat motor cortex at 3, 25, and 50 days after electrode implantation. RESULTS: We identified 22 distinct neuronal subpopulations, among which clusters 5, 6, and 8 emerged as injury-responsive subtypes during the acute phase (3 days), exhibiting a specific upregulation of Tmsb4x, a key regulator of neuronal plasticity and repair. Furthermore, our analysis revealed activated signaling pathways mediating neuron-glia communication, most notably the Ptn-Sdc4 and Il34/Csf1-Csf1R axes between neurons and astrocytes. CONCLUSIONS: These findings provide a high-resolution map of neuronal adaptation to intracortical implants, uncovering previously unknown repair-associated neuronal subtypes and specific ligand-receptor pairs that coordinate the neuroinflammatory microenvironment, which offers novel insights and potential therapeutic targets for improving the biocompatibility and long-term stability of neural electrodes. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13062-025-00719-7.