A Forward Genetic Screen in Zebrafish Identifies the G-Protein-Coupled Receptor CaSR as a Modulator of Sensorimotor Decision Making

• Published in: Current biology 2018-05, Vol.28 (9), p.1357-1369.e5
• Main Authors: Jain, Roshan A., Wolman, Marc A., Marsden, Kurt C., Nelson, Jessica C., Shoenhard, Hannah, Echeverry, Fabio A., Szi, Christina, Bell, Hannah, Skinner, Julianne, Cobbs, Emilia N., Sawada, Keisuke, Zamora, Amy D., Pereda, Alberto E., Granato, Michael
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation; Animals; AP2S1; behavior choice; Behavior, Animal; Calcium - metabolism; calcium-sensing receptor; CaSR; Choice Behavior - physiology; decision making; genetic screen; Genetic Testing; Mutation; Psychomotor Performance; Receptors, Calcium-Sensing - genetics; Receptors, Calcium-Sensing - physiology; startle response; zebrafish; Zebrafish - embryology; Zebrafish - physiology; Zebrafish Proteins - genetics; Zebrafish Proteins - physiology
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2018.03.025

Animals continuously integrate sensory information and select contextually appropriate responses. Here, we show that zebrafish larvae select a behavioral response to acoustic stimuli from a pre-existing choice repertoire in a context-dependent manner. We demonstrate that this sensorimotor choice is modulated by stimulus quality and history, as well as by neuromodulatory systems—all hallmarks of more complex decision making. Moreover, from a genetic screen coupled with whole-genome sequencing, we identified eight mutants with deficits in this sensorimotor choice, including mutants of the vertebrate-specific G-protein-coupled extracellular calcium-sensing receptor (CaSR), whose function in the nervous system is not well understood. We demonstrate that CaSR promotes sensorimotor decision making acutely through Gαi/o and Gαq/11 signaling, modulated by clathrin-mediated endocytosis. Combined, our results identify the first set of genes critical for behavioral choice modulation in a vertebrate and reveal an unexpected critical role for CaSR in sensorimotor decision making. [Display omitted] •Zebrafish larvae exhibit robust acoustically evoked decision making•Forward genetic screen identifies sensorimotor decision-making mutants•Screen reveals a previously unknown role for the G-protein-coupled receptor CaSR•CaSR acutely regulates sensorimotor decision making through Gαi/o and Gαq signaling Using larval zebrafish, Jain et al. establish and validate a simple sensorimotor decision-making paradigm. Using this paradigm, they perform a forward genetic screen that identifies the first set of vertebrate sensorimotor decision-making genes, including the calcium-sensing receptor, which acts as a bidirectional regulator of sensorimotor choice.