Brain-wide cell-type-specific noradrenergic modulation of the transcriptome

Neuromodulatory systems such as the locus coeruleus–norepinephrine (LC-NE) system exert a widespread influence on brain function, yet the transcriptional consequences of such neuromodulatory perturbations remain largely unknown across the many unique cell types in the brain. In this study, we establish a generalizable framework to map brain-wide, cell-type-specific gene expression changes in mice following in vivo chemogenetic activation or inhibition of LC neurons. Single-nucleus RNA sequencing revealed that LC perturbation induces widespread but highly cell type- and region-specific transcriptional program changes, shaped by the distribution of adrenergic receptor subtypes. These findings support a model in which a shared global signal of neuromodulatory tone can produce discrete, context-dependent cellular outcomes through distinct molecular gating mechanisms of cell-type-specific adrenergic receptor subtype combinations. By establishing gene expression as a quantifiable metric of neuromodulatory control, this study lays the foundation for transcriptionally informed interventions capable of modulating brain functions with cellular precision.