SEROTONERGIC MODULATION OF NORADRENERGIC CIRCUITS INVOLVED IN FUTILITY-INDUCED PASSIVITY IN LARVAL ZEBRAFISH

Behavioral transitions are essential for adaptive decision-making, yet how different neuromodulatory systems cooperate to trigger and modulate state changes remains unclear. In larval zebrafish, futility-induced passivity is a robust behavioral transition elicited by visual–motor mismatch during swimming. Prior work identified a noradrenergic–astroglial circuit that integrates mismatch signals in the absence of visual feedback to suppress swimming, but the upstream computations that gate noradrenergic recruitment remain unresolved. Here we combine electron microscopy reconstructions of larval zebrafish with associated functional activity measurements, whole-brain imaging during behavior, pharmacology, and optogenetic perturbation experiments to examine the contribution of the serotonergic dorsal raphe nucleus (5HT-DRN) to futility-induced passivity. Connectomics reveals direct projections from 5HT-DRN neurons to the locus coeruleus (LC). In matched functional recordings, raphe input is distinctive among LC afferents, showing prominent anticorrelation with LC activity. Whole-brain imaging suggests that tph2-positive 5HT-DRN neurons are inhibited by forward visual gratings and show reduced activity in open-loop conditions lacking appropriate visual feedback. These dynamics are consistent with 5HT-DRN tracking visual feedback and shaping noradrenergic engagement during ongoing actions. To test this hypothesis, we are assessing the behavioral effects of agonists and antagonists targeting candidate serotonin receptors expressed in LC and other noradrenergic populations that could mediate inhibitory serotonergic modulation. In parallel, we are testing whether swim-triggered optogenetic stimulation of 5HT-DRN neurons in the absence of visual feedback can inhibit futility-associated activation of noradrenergic populations. Together, these observations outline a candidate 5HT-raphe→NE-LC mechanism for gating futility-induced passivity in larval zebrafish.