Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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} (A.F.S.); rihel{at} (J.R.)

Neuropeptidergic Signaling Partitions Arousal Behaviors in Zebrafish.
I. G. Woods, D. Schoppik, V. J. Shi, S. Zimmerman, H. A. Coleman, J. Greenwood, E. R. Soucy, and A. F. Schier (2014)
J. Neurosci. 34, 3142-3160
   Abstract »    Full Text »    PDF »
Multidimensional In Vivo Hazard Assessment Using Zebrafish.
L. Truong, D. M. Reif, L. St Mary, M. C. Geier, H. D. Truong, and R. L. Tanguay (2014)
Toxicol. Sci. 137, 212-233
   Abstract »    Full Text »    PDF »
The Contribution of Mechanistic Understanding to Phenotypic Screening for First-in-Class Medicines.
D. C. Swinney (2013)
J Biomol Screen 18, 1186-1192
   Abstract »    Full Text »    PDF »
Systematic profiling of Caenorhabditis elegans locomotive behaviors reveals additional components in G-protein G{alpha}q signaling.
H. Yu, B. Aleman-Meza, S. Gharib, M. K. Labocha, C. J. Cronin, P. W. Sternberg, and W. Zhong (2013)
PNAS 110, 11940-11945
   Abstract »    Full Text »    PDF »
Small-Molecule Screen in Adult Drosophila Identifies VMAT as a Regulator of Sleep.
A. H. Nall and A. Sehgal (2013)
J. Neurosci. 33, 8534-8540
   Abstract »    Full Text »    PDF »
A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation.
F. Mahmood, S. Fu, J. Cooke, S. W. Wilson, J. D. Cooper, and C. Russell (2013)
Brain 136, 1488-1507
   Abstract »    Full Text »    PDF »
A dictionary of behavioral motifs reveals clusters of genes affecting Caenorhabditis elegans locomotion.
A. E. X. Brown, E. I. Yemini, L. J. Grundy, T. Jucikas, and W. R. Schafer (2013)
PNAS 110, 791-796
   Abstract »    Full Text »    PDF »
Defining principles of combination drug mechanisms of action.
J. R. Pritchard, P. M. Bruno, L. A. Gilbert, K. L. Capron, D. A. Lauffenburger, and M. T. Hemann (2013)
PNAS 110, E170-E179
   Abstract »    Full Text »    PDF »
High-Throughput Screening of Zebrafish Embryos Using Automated Heart Detection and Imaging.
W. Spomer, A. Pfriem, R. Alshut, S. Just, and C. Pylatiuk (2012)
Journal of Laboratory Automation 17, 435-442
   Abstract »    Full Text »    PDF »
The Conserved Dopaminergic Diencephalospinal Tract Mediates Vertebrate Locomotor Development in Zebrafish Larvae.
A. M. Lambert, J. L. Bonkowsky, and M. A. Masino (2012)
J. Neurosci. 32, 13488-13500
   Abstract »    Full Text »    PDF »
MicroRNAs control neurobehavioral development and function in zebrafish.
T. L. Tal, J. A. Franzosa, S. C. Tilton, K. A. Philbrick, U. T. Iwaniec, R. T. Turner, K. M. Waters, and R. L. Tanguay (2012)
FASEB J 26, 1452-1461
   Abstract »    Full Text »    PDF »
Automated Zebrafish Chorion Removal and Single Embryo Placement: Optimizing Throughput of Zebrafish Developmental Toxicity Screens.
D. Mandrell, L. Truong, C. Jephson, M. R. Sarker, A. Moore, C. Lang, M. T. Simonich, and R. L. Tanguay (2012)
Journal of Laboratory Automation 17, 66-74
   Abstract »    Full Text »    PDF »
Hypokinesia and Reduced Dopamine Levels in Zebrafish Lacking {beta}- and {gamma}1-Synucleins.
C. Milanese, J. J. Sager, Q. Bai, T. C. Farrell, J. R. Cannon, J. T. Greenamyre, and E. A. Burton (2012)
J. Biol. Chem. 287, 2971-2983
   Abstract »    Full Text »    PDF »
Adverse Outcome Pathways during Early Fish Development: A Conceptual Framework for Identification of Chemical Screening and Prioritization Strategies.
D. C. Volz, S. Belanger, M. Embry, S. Padilla, H. Sanderson, K. Schirmer, S. Scholz, and D. Villeneuve (2011)
Toxicol. Sci. 123, 349-358
   Abstract »    Full Text »    PDF »
Chemical modulation of memory formation in larval zebrafish.
M. A. Wolman, R. A. Jain, L. Liss, and M. Granato (2011)
PNAS 108, 15468-15473
   Abstract »    Full Text »    PDF »
Second-generation high-throughput forward genetic screen in mice to isolate subtle behavioral mutants.
V. Kumar, K. Kim, C. Joseph, L. C. Thomas, H. Hong, and J. S. Takahashi (2011)
PNAS 108, 15557-15564
   Abstract »    Full Text »    PDF »
Automated measurement of zebrafish larval movement.
C. L. Cario, T. C. Farrell, C. Milanese, and E. A. Burton (2011)
J. Physiol. 589, 3703-3708
   Abstract »    Full Text »    PDF »
Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery.
U. B. Pandey and C. D. Nichols (2011)
Pharmacol. Rev. 63, 411-436
   Abstract »    Full Text »    PDF »
The zebrafish embryo as a model for assessing off-target drug effects.
U. Strahle and C. Grabher (2010)
Dis. Model. Mech. 3, 689-692
   Abstract »    Full Text »    PDF »
Finding New Cures for Neurological Disorders: A Possible Fringe Benefit of Biodefense Research?.
D. A. Jett (2010)
Science Translational Medicine 2, 23ps12
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882