Rebecca Voss¹, Rebecca Osbaldeston², Matt Curran², Kevin Villafañe², Cole Roland², Roshan A. Jain^1,2

Serotonin (5-HT) regulates many aspects of behavior including mood, sleep, appetite, social interactions, and decision-making. A major challenge in untangling serotonin’s many distinct functions in humans is determining which of its 14 receptors are responsible for these diverse processes. We are modeling serotonin’s decision-making role through a simple response selection of zebrafish larvae, where serotonin modulates how zebrafish larvae bias their selection between two different acoustically evoked escape behaviors: an explosive short-latency response (SLC) and a kinematically and neuronally distinct long-latency response (LLC). Through a pharmacological screen, we found that 5-HT2B/2C receptor agonists shift behavioral bias towards SLC responses and antagonists shift bias towards LLC responses. To distinguish which specific receptors drive this modulation of decision-making, we used CRISPR-directed mutagenesis to disrupt each of the three zebrafish genes encoding 5-HTR2B/C subtypes, and then assessed the behavioral impacts. Mosaic larvae in which htr2cl1 was disrupted showed a behavioral shift towards LLC response, consistent with the drug data. In contrast, disrupting htr2b and htr2cl2 produced the opposite shift in escape behavior selection bias phenotype, towards SLC responses. Because mosaic G0 individuals may vary in the degree and type of molecular disruption, we have generated a set of novel germline-transmitted htr2b, htr2cl1, and htr2cl2 mutations. We are now using this set of mutations to clarify the individual and combined roles of 5-HTR2 receptors in simple acoustic decision-making. Together, our pharmacological and genetic results support a model in which 5-HT2B and 5-HT2C receptors bidirectionally modulate vertebrate decision-making following acoustic threat.

1 Bi-College Interdisciplinary Neuroscience Program, Haverford College, Haverford, PA 19041

2 Department of Biology, Haverford College, Haverford, PA 19041