Visual object detection biases escape trajectories following acoustic startle in larval zebrafish.

In this study, we investigated whether the larval zebrafish is sensitive to the presence of obstacles in its environment. Zebrafish execute fast escape swims when in danger of predation. We posited that collisions with solid objects during escape would be maladaptive to the fish, and therefore, the direction of escape swims should be informed by the locations of barriers. To test this idea, we developed a closed-loop imaging rig outfitted with barriers of various qualities. We show that when larval zebrafish escape in response to a non-directional vibrational stimulus, they use visual scene information to avoid collisions with obstacles. Our study demonstrates that barrier avoidance rate corresponds to the absolute distance of obstacles, as distant barriers outside of collision range elicit less bias than nearby collidable barriers that occupy the same amount of visual field. The computation of barrier avoidance is covert: the fact that fish will avoid barriers during escape cannot be predicted by its routine swimming behavior in the barrier arena. Finally, two-photon laser ablation experiments suggest that excitatory bias is provided to the Mauthner cell ipsilateral to approached barriers, either via direct excitation or a multi-step modulation process. We ultimately propose that zebrafish detect collidable objects via an integrative visual computation that is more complex than retinal occupancy alone, laying a groundwork for understanding how cognitive physical models observed in humans are implemented in an archetypal vertebrate brain. VIDEO ABSTRACT.

High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy.

How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species.