A regulatory closed loop between serotonergic signaling and sensory processing

Serotonin (5-HT) shapes sensory, cognitive and emotional functions, partly by regulating the excitation–inhibition balance of neural circuits. Whether sensory experience in turn regulates cortical serotonergic signaling is unknown. Here we combine column- and layer-resolved transcriptomics of the juvenile mouse barrel cortex with network analysis and whole-cell recordings. Two weeks of whisker deprivation suppresses transcription of genes governing 5-HT metabolism, reuptake and release. These changes are layer-specific, extend to neighboring columns and reverse two columns away, where serotonin receptor transcripts are upregulated. Network analysis identifies experience-dependent hub genes, including Spr , Snca and Maoa , that couple serotonergic and dopaminergic pathways. Activation of 5-HT1F, a receptor whose gene Htr1f is differentially transcribed across the deprived barrel field, reduces excitability of layer 2/3 pyramidal neurons by depolarizing the spike threshold. Sensory experience thus shapes the cortical serotonergic transcriptome, which in turn controls neuronal excitability, suggesting a regulatory closed loop between sensory processing and neuromodulation.