Bidirectional interactions between neuromodulatory systems and the cerebellum in brain function

Given that both the cerebellum and neuromodulatory systems impact multiple brain regions and are implicated in diverse functions-including sensorimotor, cognitive, and affective processes-they are likely closely interrelated through mutual regulation, cooperation, or antagonism, potentially enabling highly precise control of these functions. Early studies demonstrated the presence of neuromodulatory fibers and receptors in the cerebellum, as well as cerebellar outputs targeting neuromodulator-producing regions, raising the possibility of reciprocal regulation between these systems through feedback loops. More recent studies have shown that neuromodulatory systems influence cerebellar neuronal activity, with detailed cellular and circuit mechanisms increasingly linked to behavioral consequences. Conversely, other recent studies have gradually revealed that the cerebellum can modulate neuromodulatory systems via direct projections, thereby contributing to neuromodulator function. Despite the lack of direct evidence for feedback-based reciprocal regulation between the cerebellum and neuromodulatory systems and of a comprehensive understanding of their interactions, these recent findings underscore the importance of their interplay. In this narrative review article, we summarize current findings on regulation in both directions, focusing on four major neuromodulators: serotonin, norepinephrine, dopamine, and acetylcholine. We then highlight key open questions extending beyond these findings to stimulate further investigation into multidimensional interactions between the cerebellum and neuromodulatory systems and their functional significance.