Abstract
The zebrafish (Danio rerio) is a cost-effective vertebrate model system amenable to pharmacological investigation. Many of the available drug assays are relatively straightforward to perform, as small molecules dissolved directly in the water can be directly taken up by the zebrafish to elicit biological effects in target tissues. The low cost and ease of drug administration have especially enabled the adoption of high-throughput pharmacological screening in whole, intact animals. In addition, a fully sequenced genome and numerous tools to manipulate genes allow for the rapid generation of zebrafish disease models. Finally, the high conservation between zebrafish and mammalian drug targets facilitates bringing zebrafish pharmacological discoveries into the clinic.
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References and Further Reading
General Considerations
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Heart Regeneration
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Hair Cell Damage and Regeneration
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Retinal Regeneration
Ariga J, Walker SL, Mumm JS (2010) Multicolor time-lapse imaging of transgenic zebrafish: visualizing retinal stem cells activated by targeted neuronal cell ablation. J Vis Exp 43. pii: 2093
Bernardos RL, Barthel LK, Meyers JR, Raymond PA (2007) Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells. J Neurosci 27:7028–7040
Cameron DA (2000) Cellular proliferation and neurogenesis in the injured retina of adult zebrafish. Vis Neurosci 17:789–797
Fimbel SM, Montgomery JE, Burket CT, Hyde DR (2007) Regeneration of inner retinal neurons after intravitreal injection of ouabain in zebrafish. J Neurosci 27:1712–1724
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Taylor S, Chen J, Luo J, Hitchcock P (2012a) Light-induced photoreceptor degeneration in the retina of the zebrafish. Methods Mol Biol Clifton NJ 884:247–254
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Zhao X-F, Wan J, Powell C, Ramachandran R, Myers MG, Goldman D (2014b) Leptin and IL-6 family cytokines synergize to stimulate Müller glia reprogramming and retina regeneration. Cell Rep 9:272–284
Spinal Cord Regeneration
Becker T, Wullimann MF, Becker CG, Bernhardt RR, Schachner M (1997) Axonal regrowth after spinal cord transection in adult zebrafish. J Comp Neurol 377:577–595
Dias TB, Yang Y-J, Ogai K, Becker T, Becker CG (2012) Notch signaling controls generation of motor neurons in the lesioned spinal cord of adult zebrafish. J Neurosci 32:3245–3252
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Reimer MM, Sörensen I, Kuscha V, Frank RE, Liu C, Becker CG, Becker T (2008) Motor neuron regeneration in adult zebrafish. J Neurosci 28:8510–8516
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Brain Puncture Injury and Regeneration
Kizil C, Kaslin J, Kroehne V, Brand M (2012a) Adult neurogenesis and brain regeneration in zebrafish. Dev Neurobiol 72:429–461
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Kizil C, Kyritsis N, Dudczig S, Kroehne V, Freudenreich D, Kaslin J, Brand M (2012c) Regenerative neurogenesis from neural progenitor cells requires injury-induced expression of Gata3. Dev Cell 23:1230–1237
Kroehne V, Freudenreich D, Hans S, Kaslin J, Brand M (2011) Regeneration of the adult zebrafish brain from neurogenic radial glia-type progenitors. Dev Camb Engl 138:4831–4841
Kyritsis N, Kizil C, Zocher S, Kroehne V, Kaslin J, Freudenreich D, Iltzsche A, Brand M (2012) Acute inflammation initiates the regenerative response in the adult zebrafish brain. Science 338:1353–1356
März M, Schmidt R, Rastegar S, Strähle U (2011) Regenerative response following stab injury in the adult zebrafish telencephalon. Dev Dyn 240:2221–2231
Morcos PA, Li Y, Jiang S (2008) Vivo-morpholinos: a non-peptide transporter delivers morpholinos into a wide array of mouse tissues. Biotechniques 45:613–614, 616, 618 passim
Schmidt R, Beil T, Strähle U, Rastegar S (2014) Stab wound injury of the zebrafish adult telencephalon: a method to investigate vertebrate brain neurogenesis and regeneration. J Vis Exp 90:e51753
Birefringence
Bassett DI, Bryson-Richardson RJ, Daggett DF, Gautier P, Keenan DG, Currie PD (2003) Dystrophin is required for the formation of stable muscle attachments in the zebrafish embryo. Development 130:5851–5860
Berger J, Sztal T, Currie PD (2012) Quantification of birefringence readily measures the level of muscle damage in zebrafish. Biochem Biophys Res Commun 423:785–788
Gibbs EM, Horstick EJ, Dowling JJ (2013) Swimming into prominence: the zebrafish as a valuable tool for studying human myopathies and muscular dystrophies. FEBS J 280:4187–4197
Goody MF, Kelly MW, Reynolds CJ, Khalil A, Crawford BD, Henry CA (2012) NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy. PLoS Biol 10:e1001409
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Hall TE, Bryson-Richardson RJ, Berger S, Jacoby AS, Cole NJ, Hollway GE, Berger J, Currie PD (2007) The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin alpha2-deficient congenital muscular dystrophy. Proc Natl Acad Sci U S A 104:7092–7097
Johnson NM, Farr GH, Maves L (2013) The HDAC inhibitor TSA ameliorates a zebrafish model of Duchenne muscular dystrophy. PLoS Curr 5. pii: ecurrents.md.8273cf41db10e2d15dd3ab827cb4b027
Kawahara G, Guyon JR, Nakamura Y, Kunkel LM (2010) Zebrafish models for human FKRP muscular dystrophies. Hum Mol Genet 19:623–633
Kawahara G, Karpf JA, Myers JA, Alexander MS, Guyon JR, Kunkel LM (2011) Drug screening in a zebrafish model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 108:5331–5336
Kawahara G, Kunkel LM (2013) Zebrafish based small molecule screens for novel DMD drugs. Drug Discov Today Technol 10:e91–e96
Kawahara G, Gasperini MJ, Myers JA, Widrick JJ, Eran A, Serafini PR, Alexander MS, Pletcher MT, Morris CA, Kunkel LM (2014) Dystrophic muscle improvement in zebrafish via increased heme oxygenase signaling. Hum Mol Genet 23:1869–1878
Li M, Andersson-Lendahl M, Sejersen T, Arner A (2014) Muscle dysfunction and structural defects of dystrophin-null sapje mutant zebrafish larvae are rescued by ataluren treatment. FASEB J 28:1593–1599
Maves L (2014) Recent advances using zebrafish animal models for muscle disease drug discovery. Expert Opin Drug Discov 9:1033–1045
Mitsuhashi H, Mitsuhashi S, Lynn-Jones T, Kawahara G, Kunkel LM (2013) Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Hum Mol Genet 22:568–577
Smith LL, Beggs AH, Gupta VA (2013) Analysis of skeletal muscle defects in larval zebrafish by birefringence and touch-evoke escape response assays. J Vis Exp 82:e50925
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Winder SJ, Lipscomb L, Angela Parkin C, Juusola M (2011) The proteasomal inhibitor MG132 prevents muscular dystrophy in zebrafish. PLoS Curr 3:RRN1286
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Foetal Alcohol Syndrome
Ali S, Champagne DL, Alia A, Richardson MK (2011a) Large-scale analysis of acute ethanol exposure in zebrafish development: a critical time window and resilience. PLoS One 6:e20037
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Bilotta J, Saszik S, Givin CM, Hardesty HR, Sutherland SE (2002a) Effects of embryonic exposure to ethanol on zebrafish visual function. Neurotoxicol Teratol 24:759–766
Buske C, Gerlai R (2011a) Early embryonic ethanol exposure impairs shoaling and the dopaminergic and serotoninergic systems in adult zebrafish. Neurotoxicol Teratol 33:698–707
Carvan MJ, Loucks E, Weber DN, Williams FE (2004) Ethanol effects on the developing zebrafish: neurobehavior and skeletal morphogenesis. Neurotoxicol Teratol 26:757–768
Dlugos CA, Rabin RA (2010) Structural and functional effects of developmental exposure to ethanol on the zebrafish heart. Alcohol Clin Exp Res 34:1013–1021
Fernandes Y, Gerlai R (2009a) Long-term behavioral changes in response to early developmental exposure to ethanol in zebrafish. Alcohol Clin Exp Res 33:601–609
Flentke GR, Klingler RH, Tanguay RL, Carvan MJ, Smith SM (2014) An evolutionarily conserved mechanism of calcium-dependent neurotoxicity in a zebrafish model of fetal alcohol spectrum disorders. Alcohol Clin Exp Res 38:1255–1265
Li Y-X, Yang H-T, Zdanowicz M, Sicklick JK, Qi Y, Camp TJ, Diehl AM (2007) Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling. Lab Invest 87:231–240
Lockwood B, Bjerke S, Kobayashi K, Guo S (2004) Acute effects of alcohol on larval zebrafish: a genetic system for large-scale screening. Pharmacol Biochem Behav 77:647–654
Mahabir S, Chatterjee D, Gerlai R (2014) Strain dependent neurochemical changes induced by embryonic alcohol exposure in zebrafish. Neurotoxicol Teratol 41:1–7
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McCarthy N, Wetherill L, Lovely CB, Swartz ME, Foroud TM, Eberhart JK (2013) Pdgfra protects against ethanol-induced craniofacial defects in a zebrafish model of FASD. Development 140:3254–3265
Sarmah S, Muralidharan P, Curtis CL, McClintick JN, Buente BB, Holdgrafer DJ, Ogbeifun O, Olorungbounmi OC, Patino L, Lucas R et al (2013) Ethanol exposure disrupts extraembryonic microtubule cytoskeleton and embryonic blastomere cell adhesion, producing epiboly and gastrulation defects. Biol Open 2:1013–1021
Swartz ME, Wells MB, Griffin M, McCarthy N, Lovely CB, McGurk P, Rozacky J, Eberhart JK (2014) A screen of zebrafish mutants identifies ethanol-sensitive genetic loci. Alcohol Clin Exp Res 38:694–703
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Heart Rate
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Burns CG, Milan DJ, Grande EJ, Rottbauer W, MacRae CA, Fishman MC (2005) High-throughput assay for small molecules that modulate zebrafish embryonic heart rate. Nat Chem Biol 1:263–264
Chan PK, Lin CC, Cheng SH (2009) Noninvasive technique for measurement of heartbeat regularity in zebrafish (Danio rerio) embryos. BMC Biotechnol 9:11
Craig MP, Gilday SD, Hove JR (2006) Dose-dependent effects of chemical immobilization on the heart rate of embryonic zebrafish. Lab Anim (NY) 35:41–47
De Luca E, Zaccaria GM, Hadhoud M, Rizzo G, Ponzini R, Morbiducci U, Santoro MM (2014) ZebraBeat: a flexible platform for the analysis of the cardiac rate in zebrafish embryos. Sci Rep. doi:10.1038/srep04898
Freeman JL, Weber GJ, Peterson SM, Nie LH (2014) Embryonic ionizing radiation exposure results in expression alterations of genes associated with cardiovascular and neurological development, function, and disease and modified cardiovascular function in zebrafish. Front Genet 5:268
Lai Y-C, Chang W-T, Lin K-Y, Liau I (2014) Optical assessment of the cardiac rhythm of contracting cardiomyocytes in vitro and a pulsating heart in vivo for pharmacological screening. Biomed Opt Express 5:1616–1625
Langheinrich U, Vacun G, Wagner T (2003) Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia. Toxicol Appl Pharmacol 193:370–382
Mickoleit M, Schmid B, Weber M, Fahrbach FO, Hombach S, Reischauer S, Huisken J (2014) High-resolution reconstruction of the beating zebrafish heart. Nat Methods 11:919–922
Milan DJ, Peterson TA, Ruskin JN, Peterson RT, MacRae CA (2003) Drugs that induce repolarization abnormalities cause bradycardia in zebrafish. Circulation 107:1355–1358
Miller S, Pollack J, Bradshaw J, Kumai Y, Perry SF (2014) Cardiac responses to hypercapnia in larval zebrafish (Danio rerio): the links between CO2 chemoreception, catecholamines and carbonic anhydrase. J Exp Biol 217:3569–3578
Mittelstadt SW, Hemenway CL, Craig MP, Hove JR (2008) Evaluation of zebrafish embryos as a model for assessing inhibition of hERG. J Pharmacol Toxicol Methods 57:100–105
Parker T, Libourel P-A, Hetheridge MJ, Cumming RI, Sutcliffe TP, Goonesinghe AC, Ball JS, Owen SF, Chomis Y, Winter MJ (2014a) A multi-endpoint in vivo larval zebrafish (Danio rerio) model for the assessment of integrated cardiovascular function. J Pharmacol Toxicol Methods 69:30–38
Peal DS, Mills RW, Lynch SN, Mosley JM, Lim E, Ellinor PT, January CT, Peterson RT, Milan DJ (2011a) Novel chemical suppressors of long QT syndrome identified by an in vivo functional screen. Circulation 123:23–30
Rana N, Moond M, Marthi A, Bapatla S, Sarvepalli T, Chatti K, Challa AK (2010) Caffeine-induced effects on heart rate in zebrafish embryos and possible mechanisms of action: an effective system for experiments in chemical biology. Zebrafish 7:69–81
Sabeh MK, Kekhia H, Macrae CA (2012) Optical mapping in the developing zebrafish heart. Pediatr Cardiol 33:916–922
Santoriello C, Zon LI (2012) Hooked! Modeling human disease in zebrafish. J Clin Invest 122:2337–2343
Yozzo KL, Isales GM, Raftery TD, Volz DC (2013a) High-content screening assay for identification of chemicals impacting cardiovascular function in zebrafish embryos. Environ Sci Technol 47:11302–11310
Circulation and Blood Vessel Formation
Han L, Yuan Y, Zhao L, He Q, Li Y, Chen X, Liu X, Liu K (2012) Tracking antiangiogenic components from Glycyrrhiza uralensis Fisch. based on zebrafish assays using high-speed countercurrent chromatography. J Sep Sci 35:1167–1172
Lawson ND, Weinstein BM (2002) In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248:307–318
Leet JK, Lindberg CD, Bassett LA, Isales GM, Yozzo KL, Raftery TD, Volz DC (2014) High-content screening in zebrafish embryos identifies butafenacil as a potent inducer of anemia. PLoS One 9:e104190
Parker T, Libourel P-A, Hetheridge MJ, Cumming RI, Sutcliffe TP, Goonesinghe AC, Ball JS, Owen SF, Chomis Y, Winter MJ (2014b) A multi-endpoint in vivo larval zebrafish (Danio rerio) model for the assessment of integrated cardiovascular function. J Pharmacol Toxicol Methods 69:30–38
Peterson RT, Shaw SY, Peterson TA, Milan DJ, Zhong TP, Schreiber SL, MacRae CA, Fishman MC (2004) Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat Biotechnol 22:595–599
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Watkins SC, Maniar S, Mosher M, Roman BL, Tsang M, St Croix CM (2012) High resolution imaging of vascular function in zebrafish. PLoS One 7:e44018
Watson O, Novodvorsky P, Gray C, Rothman AMK, Lawrie A, Crossman DC, Haase A, McMahon K, Gering M, Van Eeden FJM et al (2013) Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling. Cardiovasc Res 100:252–261
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Yozzo KL, Isales GM, Raftery TD, Volz DC (2013b) High-content screening assay for identification of chemicals impacting cardiovascular function in zebrafish embryos. Environ Sci Technol 47:11302–11310
Larval Electrocardiogram
Arnaout R, Ferrer T, Huisken J, Spitzer K, Stainier DYR, Tristani-Firouzi M, Chi NC (2007a) Zebrafish model for human long QT syndrome. Proc Natl Acad Sci U S A 104:11316–11321
Dhillon SS, Dóró E, Magyary I, Egginton S, Sík A, Müller F (2013) Optimisation of embryonic and larval ECG measurement in zebrafish for quantifying the effect of QT prolonging drugs. PLoS One 8:e60552
Huttner IG, Trivedi G, Jacoby A, Mann SA, Vandenberg JI, Fatkin D (2013) A transgenic zebrafish model of a human cardiac sodium channel mutation exhibits bradycardia, conduction-system abnormalities and early death. J Mol Cell Cardiol 61:123–132
Yu F, Huang J, Adlerz K, Jadvar H, Hamdan MH, Chi N, Chen J-N, Hsiai TK (2010a) Evolving cardiac conduction phenotypes in developing zebrafish larvae: implications to drug sensitivity. Zebrafish 7:325–331
Adult Electrocardiogram
Arnaout R, Ferrer T, Huisken J, Spitzer K, Stainier DYR, Tristani-Firouzi M, Chi NC (2007b) Zebrafish model for human long QT syndrome. Proc Natl Acad Sci U S A 104:11316–11321
Chaudhari GH, Chennubhotla KS, Chatti K, Kulkarni P (2013) Optimization of the adult zebrafish ECG method for assessment of drug-induced QTc prolongation. J Pharmacol Toxicol Methods 67:115–120
Milan DJ, Jones IL, Ellinor PT, MacRae CA (2006) In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation. Am J Physiol Heart Circ Physiol 291:H269–H273
Sun P, Zhang Y, Yu F, Parks E, Lyman A, Wu Q, Ai L, Hu C-H, Zhou Q, Shung K et al (2009) Micro-electrocardiograms to study post-ventricular amputation of zebrafish heart. Ann Biomed Eng 37:890–901
Yu F, Li R, Parks E, Takabe W, Hsiai TK (2010b) Electrocardiogram signals to assess zebrafish heart regeneration: implication of long QT intervals. Ann Biomed Eng 38:2346–2357
Action Potential Recording
Alday A, Alonso H, Gallego M, Urrutia J, Letamendia A, Callol C, Casis O (2014) Ionic channels underlying the ventricular action potential in zebrafish embryo. Pharmacol Res 84:26–31
Arnaout R, Ferrer T, Huisken J, Spitzer K, Stainier DYR, Tristani-Firouzi M, Chi NC (2007c) Zebrafish model for human long QT syndrome. Proc Natl Acad Sci U S A 104:11316–11321
Bazett H (1920) An analysis of the time-relations of electrocardiograms. Heart 7:353–370
Brette F, Luxan G, Cros C, Dixey H, Wilson C, Shiels HA (2008) Characterization of isolated ventricular myocytes from adult zebrafish (Danio rerio). Biochem Biophys Res Commun 374:143–146
Jou CJ, Spitzer KW, Tristani-Firouzi M (2010) Blebbistatin effectively uncouples the excitation-contraction process in zebrafish embryonic heart. Cell Physiol Biochem 25:419–424
Kovács M, Tóth J, Hetényi C, Málnási-Csizmadia A, Sellers JR (2004a) Mechanism of blebbistatin inhibition of myosin II. J Biol Chem 279:35557–35563
Nemtsas P, Wettwer E, Christ T, Weidinger G, Ravens U (2010) Adult zebrafish heart as a model for human heart? An electrophysiological study. J Mol Cell Cardiol 48:161–171
Tsai C-T, Wu C-K, Chiang F-T, Tseng C-D, Lee J-K, Yu C-C, Wang Y-C, Lai L-P, Lin J-L, Hwang J-J (2011) In-vitro recording of adult zebrafish heart electrocardiogram – a platform for pharmacological testing. Clin Chim Acta 412:1963–1967
Optical Mapping
Kovács M, Tóth J, Hetényi C, Málnási-Csizmadia A, Sellers JR (2004b) Mechanism of blebbistatin inhibition of myosin II. J Biol Chem 279:35557–35563
Lin E, Ribeiro A, Ding W, Hove-Madsen L, Sarunic MV, Beg MF, Tibbits GF (2014) Optical mapping of the electrical activity of isolated adult zebrafish hearts: acute effects of temperature. Am J Physiol Regul Integr Comp Physiol 306:R823–R836
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Samson SC, Ferrer T, Jou CJ, Sachse FB, Shankaran SS, Shaw RM, Chi NC, Tristani-Firouzi M, Yost HJ (2013) 3-OST-7 regulates BMP-dependent cardiac contraction. PLoS Biol 11:e1001727
Sedmera D, Reckova M, deAlmeida A, Sedmerova M, Biermann M, Volejnik J, Sarre A, Raddatz E, McCarthy RA, Gourdie RG et al (2003) Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts. Am J Physiol Heart Circ Physiol 284:H1152–H1160
Tsutsui H, Higashijima S, Miyawaki A, Okamura Y (2010) Visualizing voltage dynamics in zebrafish heart. J Physiol 588:2017–2021
Flow Cytometry of Red Blood Cells
Brownlie A, Donovan A, Pratt SJ, Paw BH, Oates AC, Brugnara C, Witkowska HE, Sassa S, Zon LI (1998) Positional cloning of the zebrafish sauternes gene: a model for congenital sideroblastic anaemia. Nat Genet 20:244–250
Danilova N, Sakamoto KM, Lin S (2008) Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood 112:5228–5237
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Shafizadeh E, Peterson RT, Lin S (2004) Induction of reversible hemolytic anemia in living zebrafish using a novel small molecule. Comp Biochem Physiol C Toxicol Pharmacol 138:245–249
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Uechi T, Nakajima Y, Chakraborty A, Torihara H, Higa S, Kenmochi N (2008) Deficiency of ribosomal protein S19 during early embryogenesis leads to reduction of erythrocytes in a zebrafish model of Diamond-Blackfan anemia. Hum Mol Genet 17:3204–3211
Van Rooijen E, Voest EE, Logister I, Korving J, Schwerte T, Schulte-Merker S, Giles RH, van Eeden FJ (2009) Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. Blood 113:6449–6460
Video Analysis of Gut Motility
Berghmans S, Butler P, Goldsmith P, Waldron G, Gardner I, Golder Z, Richards FM, Kimber G, Roach A, Alderton W et al (2008b) Zebrafish based assays for the assessment of cardiac, visual and gut function–potential safety screens for early drug discovery. J Pharmacol Toxicol Methods 58:59–68
Burzynski G, Shepherd IT, Enomoto H (2009) Genetic model system studies of the development of the enteric nervous system, gut motility and Hirschsprung’s disease. Neurogastroenterol Motil 21:113–127
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Holmberg A, Olsson C, Holmgren S (2006) The effects of endogenous and exogenous nitric oxide on gut motility in zebrafish Danio rerio embryos and larvae. J Exp Biol 209:2472–2479
Holmberg A, Olsson C, Hennig GW (2007) TTX-sensitive and TTX-insensitive control of spontaneous gut motility in the developing zebrafish (Danio rerio) larvae. J Exp Biol 210:1084–1091
Kuhlman J, Eisen JS (2007) Genetic screen for mutations affecting development and function of the enteric nervous system. Dev Dyn 236:118–127
Rich A (2009) A new high-content model system for studies of gastrointestinal transit: the zebrafish. Neurogastroenterol Motil 21:225–228
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Intestinal Transit Assay
Abrams J, Davuluri G, Seiler C, Pack M (2012) Smooth muscle caldesmon modulates peristalsis in the wild type and non-innervated zebrafish intestine. Neurogastroenterol Motil 24:288–299
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Renal Function
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Models of Infection and Immunity
Burgos JS, Ripoll-Gomez J, Alfaro JM, Sastre I, Valdivieso F (2008) Zebrafish as a new model for herpes simplex virus type 1 infection. Zebrafish 5:323–333
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Ding C-B, Zhang J-P, Zhao Y, Peng Z-G, Song D-Q, Jiang J-D (2011) Zebrafish as a potential model organism for drug test against hepatitis C virus. PLoS One 6:e22921
Gabor KA, Goody MF, Mowel WK, Breitbach ME, Gratacap RL, Witten PE, Kim CH (2014) Influenza A virus infection in zebrafish recapitulates mammalian infection and sensitivity to anti-influenza drug treatment. Dis Model Mech 7:1227–1237
Goody MF, Sullivan C, Kim CH (2014) Studying the immune response to human viral infections using zebrafish. Dev Comp Immunol 46:84–95
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Harriff MJ, Bermudez LE, Kent ML (2007) Experimental exposure of zebrafish, Danio rerio (Hamilton), to Mycobacterium marinum and Mycobacterium peregrinum reveals the gastrointestinal tract as the primary route of infection: a potential model for environmental mycobacterial infection. J Fish Dis 30:587–600
Meijer AH, Spaink HP (2011) Host-pathogen interactions made transparent with the zebrafish model. Curr Drug Targets 12:1000–1017
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Robertson AL, Holmes GR, Bojarczuk AN, Burgon J, Loynes CA, Chimen M, Sawtell AK, Hamza B, Willson J, Walmsley SR et al (2014) A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism. Sci Transl Med 6:225ra29
Sullivan C, Kim CH (2008) Zebrafish as a model for infectious disease and immune function. Fish Shellfish Immunol 25:341–350
Van der Sar AM, Musters RJP, van Eeden FJM, Appelmelk BJ, Vandenbroucke-Grauls CMJE, Bitter W (2003) Zebrafish embryos as a model host for the real time analysis of Salmonella typhimurium infections. Cell Microbiol 5:601–611
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The Photomotor Response (PMR)
Fernandes AM, Fero K, Driever W, Burgess HA (2013) Enlightening the brain: linking deep brain photoreception with behavior and physiology. Bioessays 35:775–779
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Kokel D, Dunn TW, Ahrens MB, Alshut R, Cheung CYJ, Saint-Amant L, Bruni G, Mateus R, van Ham TJ, Shiraki T et al (2013a) Identification of nonvisual photomotor response cells in the vertebrate hindbrain. J Neurosci 33:3834–3843
Kokel D, Cheung CYJ, Mills R, Coutinho-Budd J, Huang L, Setola V, Sprague J, Jin S, Jin YN, Huang X-P et al (2013b) Photochemical activation of TRPA1 channels in neurons and animals. Nat Chem Biol 9:257–263
Rihel J, Schier AF (2012a) Behavioral screening for neuroactive drugs in zebrafish. Dev Neurobiol 72:373–385
Visual Motor Response (Light and Dark Photokinesis)
Akhtar MT, Ali S, Rashidi H, van der Kooy F, Verpoorte R, Richardson MK (2013) Developmental effects of cannabinoids on zebrafish larvae. Zebrafish 10:283–293
Ali S, van Mil HGJ, Richardson MK (2011b) Large-scale assessment of the zebrafish embryo as a possible predictive model in toxicity testing. PLoS One 6:e21076
Ali S, Champagne DL, Richardson MK (2012) Behavioral profiling of zebrafish embryos exposed to a panel of 60 water-soluble compounds. Behav Brain Res 228:272–283
Burgess HA, Granato M (2007a) Modulation of locomotor activity in larval zebrafish during light adaptation. J Exp Biol 210:2526–2539
Deeti S, O’Farrell S, Kennedy BN (2014a) Early safety assessment of human oculotoxic drugs using the zebrafish visualmotor response. J Pharmacol Toxicol Methods 69:1–8
Emran F, Rihel J, Adolph AR, Wong KY, Kraves S, Dowling JE (2007a) OFF ganglion cells cannot drive the optokinetic reflex in zebrafish. Proc Natl Acad Sci U S A 104:19126–19131
Emran F, Rihel J, Dowling JE (2008). A behavioral assay to measure responsiveness of zebrafish to changes in light intensities. J Vis Exp 20. pii: 923
Emran F, Rihel J, Adolph AR, Dowling JE (2010a) Zebrafish larvae lose vision at night. Proc Natl Acad Sci U S A 107:6034–6039
Fernandes AM, Fero K, Arrenberg AB, Bergeron SA, Driever W, Burgess HA (2012) Deep brain photoreceptors control light-seeking behavior in zebrafish larvae. Curr Biol 22:2042–2047
Fadool JM, Dowling JE (2008) Zebrafish: a model system for the study of eye genetics. Prog Retin Eye Res 27:89–110
Gao Y, Chan RHM, Chow TWS, Zhang L, Bonilla S, Pang C-P, Zhang M, Leung YF (2014) A high-throughput zebrafish screening method for visual mutants by light-induced locomotor response. IEEE/ACM Trans Comput Biol Bioinform 11:693–701
Long S-M, Liang F-Y, Wu Q, Lu X-L, Yao X-L, Li S-C, Li J, Su H, Pang J-Y, Pei Z (2014) Identification of marine neuroactive molecules in behaviour-based screens in the larval zebrafish. Mar Drugs 12:3307–3322
Spulber S, Kilian P, Wan Ibrahim WN, Onishchenko N, Ulhaq M, Norrgren L, Negri S, Di Tuccio M, Ceccatelli S (2014) PFOS induces behavioral alterations, including spontaneous hyperactivity that is corrected by dexamfetamine in zebrafish larvae. PLoS One 9:e94227
Optomotor Reflex (OMR)
Bilotta J, Saszik S, Givin CM, Hardesty HR, Sutherland SE (2002b) Effects of embryonic exposure to ethanol on zebrafish visual function. Neurotoxicol Teratol 24:759–766
Orger MB, Smear MC, Anstis SM, Baier H (2000) Perception of Fourier and non-Fourier motion by larval zebrafish. Nat Neurosci 3:1128–1133
Orger MB, Gahtan E, Muto A, Page-McCaw P, Smear MC, Baier H (2004) Behavioral screening assays in zebrafish. In: Westerfield M, Zon LI, Detrich WH (eds) Methods in cell biology, vol I. Academic, San Diego, pp 53–68
Richards FM, Alderton WK, Kimber GM, Liu Z, Strang I, Redfern WS, Valentin J-P, Winter MJ, Hutchinson TH (2008a) Validation of the use of zebrafish larvae in visual safety assessment. J Pharmacol Toxicol Methods 58:50–58
Zou SQ, Yin W, Zhang MJ, Hu CR, Huang YB, Hu B (2010) Using the optokinetic response to study visual function of zebrafish. J Vis Exp 36. pii: 1742
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Optokinetic Reflex (OKR)
Bilotta J, Saszik S, Givin CM, Hardesty HR, Sutherland SE (2002c) Effects of embryonic exposure to ethanol on zebrafish visual function. Neurotoxicol Teratol 24:759–766
Brockerhoff SE (2006) Measuring the optokinetic response of zebrafish larvae. Nat Protoc 1:2448–2451
Brockerhoff SE, Hurley JB, Janssen-Bienhold U, Neuhauss SC, Driever W, Dowling JE (1995a) A behavioral screen for isolating zebrafish mutants with visual system defects. Proc Natl Acad Sci U S A 92:10545–10549
Cameron DJ, Rassamdana F, Tam P, Dang K, Yanez C, Ghaemmaghami S, Dehkordi MI (2013) The optokinetic response as a quantitative measure of visual acuity in zebrafish. J Vis Exp 80
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Mueller KP, Neuhauss SCF (2010) Quantitative measurements of the optokinetic response in adult fish. J Neurosci Methods 186:29–34
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Electroretinogram (ERG)
Brockerhoff SE, Hurley JB, Janssen-Bienhold U, Neuhauss SC, Driever W, Dowling JE (1995b) A behavioral screen for isolating zebrafish mutants with visual system defects. Proc Natl Acad Sci U S A 92:10545–10549
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Fleisch VC, Jametti T, Neuhauss SCF (2008) Electroretinogram (ERG) measurements in larval zebrafish. CSH Protoc 2008:pdb.prot4973
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Wong KY, Gray J, Hayward CJC, Adolph AR, Dowling JE (2004) Glutamatergic mechanisms in the outer retina of larval zebrafish: analysis of electroretinogram b- and d-waves using a novel preparation. Zebrafish 1:121–131
Acoustic Startle
Bergeron SA, Carrier N, Li GH, Ahn S, Burgess HA (2014) Gsx1 expression defines neurons required for prepulse inhibition. Mol Psychiatry. doi:10.1038/mp.2014.106
Best JD, Berghmans S, Hunt JJFG, Clarke SC, Fleming A, Goldsmith P, Roach AG (2008a) Non-associative learning in larval zebrafish. Neuropsychopharmacology 33:1206–1215
Bhandiwad AA, Zeddies DG, Raible DW, Rubel EW, Sisneros JA (2013) Auditory sensitivity of larval zebrafish (Danio rerio) measured using a behavioral prepulse inhibition assay. J Exp Biol 216:3504–3513
Burgess HA, Granato M (2007b) Sensorimotor gating in larval zebrafish. J Neurosci 27:4984–4994
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Roberts AC, Reichl J, Song MY, Dearinger AD, Moridzadeh N, Lu ED, Pearce K, Esdin J, Glanzman DL (2011a) Habituation of the C-start response in larval zebrafish exhibits several distinct phases and sensitivity to NMDA receptor blockade. PLoS One 6:e29132
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Olfactory Explants
Blumhagen F, Zhu P, Shum J, Schärer Y-PZ, Yaksi E, Deisseroth K, Friedrich RW (2011) Neuronal filtering of multiplexed odour representations. Nature 479:493–498
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Friedrich RW (2014) Calcium imaging in the intact olfactory system of zebrafish and mouse. Cold Spring Harb Protoc 2014:310–316
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Tabor R, Friedrich RW (2008) Pharmacological analysis of ionotropic glutamate receptor function in neuronal circuits of the zebrafish olfactory bulb. PLoS One 3:e1416
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Yaksi E, von Saint Paul F, Niessing J, Bundschuh ST, Friedrich RW (2009) Transformation of odor representations in target areas of the olfactory bulb. Nat Neurosci 12:474–482
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Larval Short Term Tracking
Bichara D, Calcaterra NB, Arranz S, Armas P, Simonetta SH (2014) Set-up of an infrared fast behavioral assay using zebrafish (Danio rerio) larvae, and its application in compound biotoxicity screening. J Appl Toxicol 34:214–219
Duan J, Yu Y, Shi H, Tian L, Guo C, Huang P, Zhou X, Peng S, Sun Z (2013) Toxic effects of silica nanoparticles on zebrafish embryos and larvae. PLoS One 8:e74606
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Irons TD, MacPhail RC, Hunter DL, Padilla S (2010) Acute neuroactive drug exposures alter locomotor activity in larval zebrafish. Neurotoxicol Teratol 32:84–90
Irons TD, Kelly PE, Hunter DL, Macphail RC, Padilla S (2013) Acute administration of dopaminergic drugs has differential effects on locomotion in larval zebrafish. Pharmacol Biochem Behav 103:792–813
MacPhail RC, Brooks J, Hunter DL, Padnos B, Irons TD, Padilla S (2009) Locomotion in larval zebrafish: influence of time of day, lighting and ethanol. Neurotoxicology 30:52–58
Mirat O, Sternberg JR, Severi KE, Wyart C (2013a) ZebraZoom: an automated program for high-throughput behavioral analysis and categorization. Front Neural Circ 7:107
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Head Embedded, Tail Free Swimming
Bianco IH, Kampff AR, Engert F (2011) Prey capture behavior evoked by simple visual stimuli in larval zebrafish. Front Syst Neurosci 5:101
Brustein E, Drapeau P (2005a) Serotoninergic modulation of chloride homeostasis during maturation of the locomotor network in zebrafish. J Neurosci 25:10607–10616
Brustein E, Chong M, Holmqvist B, Drapeau P (2003a) Serotonin patterns locomotor network activity in the developing zebrafish by modulating quiescent periods. J Neurobiol 57:303–322
Budick SA, O’Malley DM (2000) Locomotor repertoire of the larval zebrafish: swimming, turning and prey capture. J Exp Biol 203:2565–2579
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O’Malley DM, Sankrithi NS, Borla MA, Parker S, Banden S, Gahtan E, Detrich HW (2004) Optical physiology and locomotor behaviors of wild-type and nacre zebrafish. Methods Cell Biol 76:261–284
Portugues R, Engert F (2011) Adaptive locomotor behavior in larval zebrafish. Front Syst Neurosci 5:72
Portugues R, Feierstein CE, Engert F, Orger MB (2014) Whole-brain activity maps reveal stereotyped, distributed networks for visuomotor behavior. Neuron 81:1328–1343
Severi KE, Portugues R, Marques JC, O’Malley DM, Orger MB, Engert F (2014) Neural control and modulation of swimming speed in the larval zebrafish. Neuron 83:692–707
Wyart C, Bene FD, Warp E, Scott EK, Trauner D, Baier H, Isacoff EY (2009) Optogenetic dissection of a behavioral module in the vertebrate spinal cord. Nature 461:407–410
Larval Fictive Swimming
Ahrens MB, Li JM, Orger MB, Robson DN, Schier AF, Engert F, Portugues R (2012) Brain-wide neuronal dynamics during motor adaptation in zebrafish. Nature 485:471–477
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Buss RR, Drapeau P (2001) Synaptic drive to motoneurons during fictive swimming in the developing zebrafish. J Neurophysiol 86:197–210
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Knogler LD, Liao M, Drapeau P (2010) Synaptic scaling and the development of a motor network. J Neurosci 30:8871–8881
Knogler LD, Ryan J, Saint-Amant L, Drapeau P (2014) A hybrid electrical/chemical circuit in the spinal cord generates a transient embryonic motor behavior. J Neurosci 34:9644–9655
Masino MA, Fetcho JR (2005) Fictive swimming motor patterns in wild type and mutant larval zebrafish. J Neurophysiol 93:3177–3188
Trapani JG, Nicolson T (2010) Physiological recordings from zebrafish lateral-line hair cells and afferent neurons. Methods Cell Biol 100:219–231
Vladimirov N, Mu Y, Kawashima T, Bennett DV, Yang C-T, Looger LL, Keller PJ, Freeman J, Ahrens MB (2014) Light-sheet functional imaging in fictively behaving zebrafish. Nat Methods 11:883–884
Long Term Tracking: Sleep
Cahill GM, Hurd MW, Batchelor MM (1998) Circadian rhythmicity in the locomotor activity of larval zebrafish. Neuroreport 9:3445–3449
Gandhi AV, Mosser EA, Oikonomou G, Prober DA (2015) Melatonin is required for the circadian regulation of sleep. Neuron 85:1193–1199
Hurd MW, Cahill GM (2002) Entraining signals initiate behavioral circadian rhythmicity in larval zebrafish. J Biol Rhythms 17:307–314
Prober DA, Rihel J, Onah AA, Sung R-J, Schier AF (2006) Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish. J Neurosci 26:13400–13410
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Rihel J, Prober DA, Schier AF (2010a) Monitoring sleep and arousal in zebrafish. Methods Cell Biol 100:281–294
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Yokogawa T, Marin W, Faraco J, Pézeron G, Appelbaum L, Zhang J, Rosa F, Mourrain P, Mignot E (2007) Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants. PLoS Biol 5:e277
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Novel Tank and Anxiety
Ahmad F, Richardson MK (2013) Exploratory behaviour in the open field test adapted for larval zebrafish: impact of environmental complexity. Behav Processes 92:88–98
Amir-Zilberstein L, Blechman J, Sztainberg Y, Norton WHJ, Reuveny A, Borodovsky N, Tahor M, Bonkowsky JL, Bally-Cuif L, Chen A, Levkowitz G (2012) Homeodomain protein otp and activity-dependent splicing modulate neuronal adaptation to stress. Neuron 73(2):279–291
Bencan Z, Sledge D, Levin ED (2009) Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety. Pharmacol Biochem Behav 94(1):75–80
Blaser RE, Chadwick L, McGinnis GC (2010) Behavioral measures of anxiety in zebrafish (Danio rerio). Behav Brain Res 208(1):56–62
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Cachat J, Kyzar EJ, Collins C, Gaikwad S, Green J, Roth A, El-Ounsi M, Davis A, Pham M, Landsman S, Stewart AM, Kalueff AV (2013a) Unique and potent effects of acute ibogaine on zebrafish: the developing utility of novel aquatic models for hallucinogenic drug research. Behav Brain Res 236(1):258–269
Grossman L, Utterback E, Stewart A, Gaikwad S, Chung KM, Suciu C, Wong K, Elegante M, Elkhayat S, Tan J et al (2010a) Characterization of behavioral and endocrine effects of LSD on zebrafish. Behav Brain Res 214:277–284
Kyzar EJ, Collins C, Gaikwad S, Green J, Roth A, Monnig L, El-Ounsi M, Davis A, Freeman A, Capezio N, Stewart AM, Kalueff AV (2012b) Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior and physiology. Prog Neuropsychopharmacol Biol Psychiatry 37(1):194–202
Levin ED, Bencan Z, Cerutti DT (2007) Anxiolytic effects of nicotine in zebrafish. Physiol Behav 90(1):54–58
Maximino C, de Brito TM, Colmanetti R, Pontes AAA, de Castro HM, de Lacerda RIT, Morato S, Gouveia A (2010a) Parametric analyses of anxiety in zebrafish scototaxis. Behav Brain Res 210(1):1–7
Maximino C, Marques de Brito T, Dias CA, Gouveia G, Morato S (2010b) Scototaxis as anxiety-like behavior in fish. Nat Protoc 5(2):209–216
Schnörr SJ, Steenbergen PJ, Richardson MK, Champagne DL (2012) Measuring thigmotaxis in larval zebrafish. Behav Brain Res 228(2):367–374
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Electrophysiology
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Electroencephalogram
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Seizure Behavior
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Associative Learning-Classical Conditioning
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Aggression: Mirror
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Conspecific Aggression
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Competitive Spawning
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Social Preference
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Shoaling
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Rihel, J., Ghosh, M. (2015). Zebrafish. In: Hock, F. (eds) Drug Discovery and Evaluation: Pharmacological Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27728-3_135-1
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