Nicotine and tobacco smoke reshape neuronal signaling networks at a single-cell perspective

Nicotine and cigarette smoke exposure significantly impact brain function, yet their distinct cellular and molecular mechanisms remain unclear. To address this, we conducted comprehensive single-nucleus RNA sequencing (snRNA-seq) analysis on whole-brain samples and specifically on the ventral tegmental area (VTA) of adult C57BL/6 mice following nicotine or smoke exposure. Our study identified 18 major transcriptionally distinct cell populations across the whole brain and 27 distinct clusters within the VTA, covering major neuronal and glial cell types. Differential gene expression and KEGG pathway enrichment analyses revealed distinct transcriptional responses: nicotine prominently activated synaptic and addiction-related signaling pathways in neuronal populations, including dopaminergic and glutamatergic pathways, whereas smoke exposure triggered broader metabolic, immune, and endocrine responses. CellChat-based network analysis demonstrated significant remodeling of intercellular communication, notably enhanced oligodendrocyte-to-neuron signaling via the Neurexin (NRXN) pathway under nicotine exposure, contrasted with diffuse and attenuated signaling under smoke exposure. Additionally, oligodendrocytes exhibited pronounced metabolic adaptation, highlighted by upregulation of mitochondrial enzyme PISD, indicating lipid remodeling and stress adaptation in response to smoke exposure. Collectively, our findings provide novel insights into the cell-type-specific transcriptomic reprogramming and intercellular communication dynamics induced by nicotine and smoke, offering critical mechanistic understanding relevant to tobacco addiction and related neuroadaptations.