Organization, development, and plasticity of the serotonergic dorsal raphe nucleus projectome

Abstract

The dorsal raphe nucleus (DRN) is the main source of serotonin (5-HT) in the central nervous system. 5-HT DRN neurons modulate a wide range of physiological functions and brain states via their widespread and heterogeneous projections. Yet the organizational logic, developmental dynamics, and experience-dependent plasticity of these projections remain poorly understood. By reconstructing the whole brain projections of 81 individual 5-HT DRN neurons across developmental stages in the larval zebrafish, we find that these neurons exhibit diverse projection patterns, ranging from broadly distributed to spatially confined. We identify two previously uncharacterized, projection-defined subpopulations within the larval dorsal raphe nucleus, which selectively target either the telencephalon or the spinal cord. This organization is consistent with the existence of anatomically distinct serotonergic pathways that may differentially influence forebrain and sensorimotor circuits. Longitudinal analysis revealed that the gross architecture of 5-HT neurons remained stable during larval development, although region-specific remodeling occurred in all neurons. Importantly, stress exposure during the first week of development, but not thereafter, altered the density of 5-HT DRN projections to telencephalic regions, suggesting a critical window of increased plasticity during early life. Collectively, our findings clarify the developmental trajectory, maturation, and stress-induced plasticity of the serotonergic circuitry, providing important insights for deciphering the pathophysiology of stress-related mental disorders.