Brain-Wide Impacts of Sedation on Spontaneous Activity and Auditory Processing in Larval Zebrafish

Despite their widespread use, we have limited knowledge of the mechanisms by which sedatives mediate their effects on brain-wide networks. This is, in part, due to the technical challenge of observing activity across large populations of neurons in normal and sedated brains. In this study, we examined the effects of the sedative dexmedetomidine, and its antagonist atipamezole, on spontaneous brain dynamics and auditory processing in zebrafish larvae, a stage when sex differentiation has not yet occurred. Our brain-wide, cellular-resolution calcium imaging reveals the brain regions involved in these network-scale dynamics and the individual neurons that are affected within those regions. Further analysis reveals a variety of dynamic changes in the brain at baseline, including marked reductions in spontaneous activity, correlation, and variance. The reductions in activity and variance represent a "quieter" brain state during sedation, an effect inducing highly correlated evoked activity in the auditory system to stand out more than it does in unsedated brains. We also observe a reduction in the persistence of auditory information across the brain during sedation, suggesting that the removal of spontaneous activity leaves the core auditory pathway free of impingement from other nonauditory information. Finally, we describe a less dynamic brain-wide network during sedation, with a higher energy barrier and a lower probability of brain state transitions during sedation. Overall, our brain-wide, cellular-resolution analysis shows that sedation leads to a quieter, more stable, and less dynamic brain and, that against this background, responses across the auditory processing pathway become sharper and more prominent.