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Science 327 (5963): 348-351

Copyright © 2010 by the American Association for the Advancement of Science

Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation

Jason Rihel,1,*,{dagger} David A. Prober,1,*,{ddagger} Anthony Arvanites,2 Kelvin Lam,2 Steven Zimmerman,1 Sumin Jang,1 Stephen J. Haggarty,3,4,5 David Kokel,6 Lee L. Rubin,2 Randall T. Peterson,3,6,7 Alexander F. Schier1,2,3,8,9,{dagger}

Abstract: A major obstacle for the discovery of psychoactive drugs is the inability to predict how small molecules will alter complex behaviors. We report the development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish. We found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. In addition, behavioral profiling implicated new factors such as ether-a-go-go–related gene (ERG) potassium channels and immunomodulators in the control of rest and locomotor activity. These results demonstrate the power of high-throughput behavioral profiling in zebrafish to discover and characterize psychotropic drugs and to dissect the pharmacology of complex behaviors.

1 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
2 Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
3 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
4 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
5 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
6 Developmental Biology Laboratory, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
7 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
8 Division of Sleep Medicine, Harvard Medical School, Boston, MA 02215, USA.
9 Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.

* These authors contributed equally to this work.

{ddagger} Present address: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

{dagger} To whom correspondence should be addressed. E-mail: schier{at}fas.harvard.edu (A.F.S.); rihel{at}fas.harvard.edu (J.R.)


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