Control of wildtype zebrafish optomotor response with a photoswitchable drug

Abstract

For animals to interact effectively with their environment, the brain must integrate sensory information and generate appropriate motor responses. Multiple neuronal circuits contribute to this process, and identifying their roles remains a central focus in neuroscience. The recently developed photoswitchable compound Carbadiazocine controls neuronal firing across species. It modulates larval zebrafish locomotion and alleviates neuropathic pain in rodents in a reversible, light-induced manner. Given its effects on both motor and somatosensory circuits, we investigated the impact of Carbadiazocine on sensorimotor behaviors. We focused on the optomotor response in zebrafish larvae and assessed its potential as a tool for circuit perturbation and behavioral analysis, for the first time combined with photopharmacology. We performed experiments in head-fixed and free-swimming larvae to assess their capacity to detect and follow the direction of optic flow, as well as to characterize swimming speed patterns and individual tail bout properties following administration of the two Carbadiazocine photoisomers. In both paradigms, treatment with the pre-illuminated compound led to a decrease in accuracy in responding to optic flow (correct turning percentage dropping from [~]95 % to [~]80 % in head-fixed experiments and correctness decreasing from [~]65 % to [~]20 % in free-swimming experiments). Speed analysis revealed an increased number and duration of fast movements with a decrease in number and duration of slow movements, even during periods without visual stimulation. Tail bout analysis further showed an increase in 15-30 Hz bout frequencies, corresponding to incomplete, irregular tail movements. All these effects were absent when the dark-relaxed compound was administered. Together, these findings deepen our understanding of sensorimotor transformations and lay the foundations to probe native neuronal circuits underlying behavior in diverse animal species using a wide dynamic range of photostimulation patterns.