title: Chemical modulation of memory formation in larval zebrafish.
abstract: Whole organism-based small-molecule screens have proven powerful in identifying novel therapeutic chemicals, yet this approach has not been exploited to identify new cognitive enhancers. Here we present an automated high-throughput system for measuring nonassociative learning behaviors in larval zebrafish. Using this system, we report that spaced training blocks of repetitive visual stimuli elicit protein synthesis-dependent long-term habituation in larval zebrafish, lasting up to 24 h. Moreover, repetitive acoustic stimulation induces robust short-term habituation that can be modulated by stimulation frequency and instantaneously dishabituated through cross-modal stimulation. To characterize the neurochemical pathways underlying short-term habituation, we screened 1,760 bioactive compounds with known targets. Although we found extensive functional conservation of short-term learning between larval zebrafish and mammalian models, we also discovered several compounds with previously unknown roles in learning. These compounds included a myristic acid analog known to interact with Src family kinases and an inhibitor of cyclin dependent kinase 2, demonstrating that high-throughput chemical screens combined with high-resolution behavioral assays provide a powerful approach for the discovery of novel cognitive modulators.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Wolman
authors.forename: Roshan A
authors.initials: RA
authors.lastname: Jain
authors.forename: Laura
authors.initials: L
authors.lastname: Liss
authors.forename: Michael
authors.initials: M
authors.lastname: Granato
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D007814:Larva / Q000187:drug effects / Q000502:physiology; D007837:Latency Period, Psychological; D008322:Mammals; D008568:Memory / Q000187:drug effects*; D010775:Photic Stimulation; D014176:Protein Biosynthesis / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013997:Time Factors; D015027:Zebrafish / Q000502:physiology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D054852:Small Molecule Libraries