Brainstem raphe nuclei and their serotonergic neurons: An integrative review of distribution, function and projection

Serotonergic neurons in the raphe nuclei of the brainstem play a central role in a wide range of physiological and psychological processes. These neurons form intricate neuroregulatory networks via extensive ascending and descending projections to multiple brain regions. They are critically involved in integrating and refining neural signal transmission to sustain normal physiological homeostasis, and they play pivotal roles in higher-order cerebral functions such as emotional processing, cognitive decision-making, and behavioral modulation. Functional dysregulation of serotonergic networks is strongly linked to the onset and progression of neuropsychiatric disorders such as depression, anxiety, and sleep disturbances. A comprehensive understanding of their anatomy, physiology, and regulatory dynamics thus illuminates fundamental principles of brain function, and establishes a critical foundation for designing serotonin-targeted therapeutic strategies. Notwithstanding substantial progress in related investigations, numerous unresolved questions persist regarding the complex regulatory mechanisms of serotoninergic neurons and their dynamic alterations within neural networks. This review details their anatomical distribution and physiological function in emotional regulation, reward processing, cognitive functions, sleep-wake cycle, and behavior control. We further analyze how their ascending and descending projections support these functions and how they are modulated by other brain regions via projections, providing an overall perspective of their dynamic roles in neural networks.