Behavioral Fingerprinting

Science Signaling  19 Jan 2010:
Vol. 3, Issue 105, pp. ec22
DOI: 10.1126/scisignal.3105ec22

Drug discovery methods often rely on in vitro assays to identify compounds with specific types of biochemical activity, but predicting how a psychoactive drug will affect behavior requires direct testing of candidate compounds in animal models. Rihel et al. devised a high-throughput screen to identify compounds that affect rest-wake activity in zebrafish larvae and quantify the behavioral effects. They sorted the compounds into clusters based on their “behavioral fingerprint,” a set of behavioral changes elicited by each compound. Analysis of the data revealed that compounds that elicit similar behavioral changes often affect the same molecular targets or pathways, and compounds of similar structure produced similar behavioral effects in vivo. The authors were able to use the data set to predict the biological targets of uncharacterized compounds based on those of well-characterized compounds with which they cluster in the behavioral fingerprint analysis. The screen demonstrated that many aspects of neuropharmacology are conserved between mammals and zebrafish, so this model might also be useful for biochemically characterizing the regulation and pharmacology of complex behaviors. The results also suggested additional pathways that might be involved in modulating rest-wake activities. For example, several anti-inflammatory compounds increased wakeful activity during the day but not at night, suggesting that anti-inflammatory signaling pathways not only increase sleep in response to infection but also modulate daytime activity under normal conditions. These findings might enable researchers to predict biological targets or behavioral effects of novel compounds based on structural or biochemical aspects shared with well-characterized drugs, and they may also inform rational drug design.

J. Rihel, D. A. Prober, A. Arvanites, K. Lam, S. Zimmerman, S. Jang, S. J. Haggarty, D. Kokel, L. L. Rubin, R. T. Peterson, A. F. Schier, Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation. Science, 327, 348–351 (2010). [Abstract] [Full Text]