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

Rihel, Jason; Prober, David A.; Arvanites, Anthony C.; Lam, Kelvin; Zimmerman, Steven; Jang, Sumin; Haggarty, Stephen J.; Kokel, David; Rubin, Lee L.; Peterson, Randall T.; Schier, Alexander F.

doi:10.1126/science.1183090

Cited by 697 publications

(700 citation statements)

References 20 publications

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“…For instance, serotonergic nuclei are densely innervated by hypocretin immunoreactive neurons (Kaslin et al 2004;Panula et al 2010). Detailed behavioral studies revealed conservation between fish and mammalian responses to pharmacological agents that promote or antagonize sleep (Rihel et al 2010;Sigurgeirsson et al 2011).…”

Section: Fish Sleepmentioning

confidence: 99%

Sleep and Development in Genetically Tractable Model Organisms

Kayser

Biron

2016

Genetics

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Sleep is widely recognized as essential, but without a clear singular function. Inadequate sleep impairs cognition, metabolism, immune function, and many other processes. Work in genetic model systems has greatly expanded our understanding of basic sleep neurobiology as well as introduced new concepts for why we sleep. Among these is an idea with its roots in human work nearly 50 years old: sleep in early life is crucial for normal brain maturation. Nearly all known species that sleep do so more while immature, and this increased sleep coincides with a period of exuberant synaptogenesis and massive neural circuit remodeling. Adequate sleep also appears critical for normal neurodevelopmental progression. This article describes recent findings regarding molecular and circuit mechanisms of sleep, with a focus on development and the insights garnered from models amenable to detailed genetic analyses.

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Section: Fish Sleepmentioning

confidence: 99%

Sleep and Development in Genetically Tractable Model Organisms

Kayser

Biron

2016

Genetics

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“…They hatch from their chorions by 2-3 days post fertilization (dpf), develop fully functioning organs by 4-5 dpf, and exhibit a large number of behaviors by 7 dpf 5,6 . Zebrafish larvae are ideally suited for high-throughput analyses because of their small size 7,8 . Software is commercially available for automated analyses of behavior in larval and adult zebrafish [9][10][11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Automated High-throughput Behavioral Analyses in Zebrafish Larvae

Richendrfer

Créton

2013

JoVE

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We have created a novel high-throughput imaging system for the analysis of behavior in 7-day-old zebrafish larvae in multi-lane plates. This system measures spontaneous behaviors and the response to an aversive stimulus, which is shown to the larvae via a PowerPoint presentation. The recorded images are analyzed with an ImageJ macro, which automatically splits the color channels, subtracts the background, and applies a threshold to identify individual larvae placement in the lanes. We can then import the coordinates into an Excel sheet to quantify swim speed, preference for edge or side of the lane, resting behavior, thigmotaxis, distance between larvae, and avoidance behavior. Subtle changes in behavior are easily detected using our system, making it useful for behavioral analyses after exposure to environmental toxicants or pharmaceuticals.

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“…In signature-based approaches, a series of drug-induced molecular/phenotypic measurements are made in an experimental system. Collections of measurements from many small molecules form multivariate signatures that aim to fingerprint drugs based on their relative signature similarity (8)(9)(10)(11)(12)(13). In several landmark studies using Saccharomyces cerevisiae; gene expression compendia (8); and, later, barcoded loss of function/ORF libraries (9,10), large signatures were shown to characterize individual small molecule mechanisms of action effectively.…”

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confidence: 99%

Defining principles of combination drug mechanisms of action

Pritchard¹,

Bruno²,

Gilbert³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

156

137

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Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 y, yet even successful regimens fail to cure many patients. Although their singledrug components are well studied, the mechanisms by which drugs work together in clinical combination regimens are poorly understood. Here, we combine RNAi-based functional signatures with complementary informatics tools to examine drug combinations. This approach seeks to bring to combination therapy what the knowledge of biochemical targets has brought to single-drug therapy and creates a statistical and experimental definition of "combination drug mechanisms of action." We show that certain synergistic drug combinations may act as a more potent version of a single drug. Conversely, unlike these highly synergistic combinations, most drugs average extant single-drug variations in therapeutic response. When combined to form multidrug regimens, averaging combinations form averaging regimens that homogenize genetic variation in mouse models of cancer and in clinical genomics datasets. We suggest surprisingly simple and predictable combination mechanisms of action that are independent of biochemical mechanism and have implications for biomarker discovery as well as for the development of regimens with defined genetic dependencies.chemotherapy | lymphoma | RNAi signature | systems biology C urrent rationales for the design of combination chemotherapy regimens were developed in the 1940s and 1950s (1-5) and, remarkably, were concurrent with the identification of DNA as the genetic material. The development of these regimens in the absence of any knowledge of cancer genomics was a remarkable achievement. However, although our knowledge of the genetic drivers of cancer and the mechanisms of drug action has increased dramatically over the past 30 y, this information has been difficult to adapt to clinical practice. As such, even very successful combination regimens often fail to cure many patients (6, 7). We hypothesize that part of this failure is due to the absence of mechanistic information about how drugs in regimens interact to promote combination effects (we term these effects "combination mechanisms of action"). We sought to address this gap by investigating specific hypotheses concerning the "mechanisms of action" of combination therapy.The classic term "drug mechanism of action" refers to the description of a specific biochemical event, which is often the activation or inhibition of an enzymatic effect. However, in recent years, "signature"-based prediction has provided a powerful new strategy for examining drug mechanism. In signature-based approaches, a series of drug-induced molecular/phenotypic measurements are made in an experimental system. Collections of measurements from many small molecules form multivariate signatures that aim to fingerprint drugs based on their relative signature similarity (8-13). In several landmark studies using Saccharomyces cerevisiae; gene expression compendia (8); and, later, barcoded loss o...

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

Cited by 697 publications

References 20 publications

Sleep and Development in Genetically Tractable Model Organisms

Sleep and Development in Genetically Tractable Model Organisms

Automated High-throughput Behavioral Analyses in Zebrafish Larvae

Defining principles of combination drug mechanisms of action

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