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

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 found that these neurons exhibit diverse projection patterns, ranging from broadly distributed to spatially confined, and identified two projection-defined subpopulations, targeting either the telencephalon or the spinal cord. Longitudinal analysis revealed that the gross architecture of 5-HT neurons remained stable during early development, although region-specific remodeling occurred in all neurons. Furthermore, exposure to early life stress during the first week of development, but not thereafter, altered the density of 5-HT DRN projections in a region-specific manner, suggesting a critical window of increased plasticity. Altogether, our study sheds new light on how the serotonergic circuitry develops, matures and adapts to stress, which is critical for better understanding the pathophysiology of mental disorders.