System-level synchronization and subtype-specific modules govern brain-wide serotonin axon innervation

Abstract

Significance Serotonin shapes nearly every brain circuit and is a major target of psychiatric drugs, yet how its widespread pathways are assembled has remained unclear. We combined whole-brain developmental mapping with single-cell RNA profiling to show that forebrain-projecting serotonin neurons are specified into subtypes before birth and then wire the brain through two coordinated postnatal programs: an early, brain-wide synchronization of axon growth and region-specific terminal maturation. This framework replaces the traditional nonspecific “space-filling” view with a genetically guided, staged developmental plan that is conserved across species. Our four-dimensional atlas and molecular timelines identify critical developmental windows and mechanisms that can inform models of circuit function, vulnerability, and therapeutic timing.