Behavioral Neurogenetics pp 3-24

Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 12) | Cite as

Using Zebrafish to Unravel the Genetics of Complex Brain Disorders



The zebrafish has been prominently utilized in developmental biology for the past three decades and numerous genetic tools have been developed for it. Due to the accumulated genetic knowledge the zebrafish has now been considered an excellent research tool in other disciplines of biology too, including behavioral neuroscience and behavior genetics. Given the complexity of the vertebrate brain in general and the large number of human brain disorders whose mechanisms remain mainly unmapped in particular, there is a substantial need for appropriate laboratory research organisms that may be utilized to model such diseases and facilitate the analysis of their mechanisms. The zebrafish may have a bright future in this research field. It offers a compromise between system complexity (it is a vertebrate similar in many ways to our own species) and practical simplicity (it is small, easy to keep, and it is prolific). These features have made zebrafish an excellent choice, for example, for large scale mutation and drug screening. Such approaches may have a chance to tackle the potentially large number of molecular targets and mechanisms involved in complex brain disorders. However, although promising, the zebrafish is admittedly a novel research tool and only few empirical examples exist to support this claim. In this chapter, first I briefly review some of the rapidly evolving genetic methods available for zebrafish. Second, I discuss some promising examples for how zebrafish have been used to model and analyze molecular mechanisms of complex brain disorders. Last, I present some recently developed zebrafish behavioral paradigms that may have relevance for a spectrum of complex human brain disorders including those associated with abnormalities of learning and memory, fear and anxiety, and social behavior. Although at this point co-application of the genetics and behavioral approaches is rare with zebrafish, I argue that the rapid accumulation of knowledge in both of these disciplines will make zebrafish a prominent research tool for the genetic analysis of complex brain disorders.


Zebrafish High throughput behavioral screening Fetal alcohol syndrome Alcoholism Learning and memory Fear and anxiety 


  1. Al-Imari L, Gerlai R (2008) Conspecifics as reward in associative learning tasks for zebrafish (Danio rerio). Behav Brain Res 189:216–219 Google Scholar
  2. Alsop D, Vijayan MM (2008) Development of the corticosteroid stress axis and receptor expression in zebrafish. Am J Physiol Regul Integr Comp Physiol 294:R711–R719PubMedCrossRefGoogle Scholar
  3. Amsterdam A, Hopkins N (2006) Mutagenesis strategies in zebrafish for identifying genes involved in development and disease. Trends Genet 22:473–478PubMedCrossRefGoogle Scholar
  4. Bailey CH, Kandel ER (2008) Synaptic remodeling, synaptic growth and the storage of long-term memory in Aplysia. Prog Brain Res 169:179–198PubMedCrossRefGoogle Scholar
  5. Bandmann O, Burton EA (2010) Genetic zebrafish models of neurodegenerative diseases. Neurobiol Dis 40:58–65PubMedCrossRefGoogle Scholar
  6. Bass SLS, Gerlai R (2008) Zebrafish (Danio rerio) responds differentially to stimulus fish: the effects of sympatric and allopatric predators and harmless fish. Behav Brain Res 186:107–117PubMedCrossRefGoogle Scholar
  7. Bill BR, Petzold AM, Clark KJ, Schimmenti LA, Ekker SC (2009) A primer for morpholino use in zebrafish. Zebrafish 6:69–77PubMedCrossRefGoogle Scholar
  8. Blaser R, Gerlai R (2006) Behavioral phenotyping in zebrafish: comparison of three behavioral quantification methods. Behav Res Meth 38:456–469CrossRefGoogle Scholar
  9. Braff DL, Geyer MA, Light GA, Sprock J, Perry W, Cadenhead KS et al (2001) Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia. Schizophr Res 49:171–178PubMedCrossRefGoogle Scholar
  10. Burgess HA, Granato M (2007) Sensorimotor gating in larval zebrafish. J Neurosci 27:4984–4994PubMedCrossRefGoogle Scholar
  11. Capecchi MR (1989) Altering the genome by homologous recombination. Science 244:1288–1292PubMedCrossRefGoogle Scholar
  12. Chatterjee D, Gerlai R (2009) High precision liquid chromatography analysis of dopaminergic and serotoninergic responses to acute alcohol exposure in zebrafish. Behav Brain Res 200:208–213PubMedCrossRefGoogle Scholar
  13. Chen E, Ekker SC (2004) Zebrafish as a genomics research model. Curr Pharm Biotechnol 5:409–413PubMedCrossRefGoogle Scholar
  14. Cohen NJ, Poldrack RA, Eichenbaum H (1997) Memory for items and memory for relations in the procedural/declarative memory framework. Memory 5:131–178Google Scholar
  15. Denver RJ (2009) Structural and functional evolution of vertebrate neuroendocrine stress systems. Ann N Y Acad Sci 1163:1–16PubMedCrossRefGoogle Scholar
  16. Drerup CM, Wiora HM, Topczewski J, Morris JA (2009) Disc1 regulates foxd3 and sox10 expression, affecting neural crest migration and differentiation. Development 136:2623–2632PubMedCrossRefGoogle Scholar
  17. Driever W, Solnica-Krezel L, Schier AF, Neuhauss, SCF, Malicki J, Stemple DL, Stainier DYR, Zwartkruis F, Abdelilah S, Rangini Z, Belak J, Boggs C (1996) A genetic screen for mutations affecting embryogenesis in zebrafish. Development 123:37–46PubMedGoogle Scholar
  18. Ekker SC (2008) Zinc finger-based knockout punches for zebrafish genes. Zebrafish 5:121–123PubMedCrossRefGoogle Scholar
  19. Engeszer RE, Patterson LB, Rao AA, Parichy DM (2007) Zebrafish in the wild: a review of natural history and new notes from the field. Zebrafish 4:21–40Google Scholar
  20. Fan L, Collodi P (2006) Zebrafish embryonic stem cells. Methods Enzymol 418:64–77PubMedCrossRefGoogle Scholar
  21. Gauthier J, Champagne N, Lafreniere RG, Xiong L, Spiegelman D, Brustein E et al (2010) De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci USA 107:7863–7868PubMedCrossRefGoogle Scholar
  22. Gerlai R (2010) Zebrafish antipredatory responses: a future for translational research? Behav Brain Res (in press)Google Scholar
  23. Gerlai R (2002) Phenomics: fiction or the future? Trends Neurosci 25:506–509PubMedCrossRefGoogle Scholar
  24. Gerlai J, Gerlai R (2003) Autism: a large unmet medical need and a complex research problem. Physiol Behav 79:461–470PubMedCrossRefGoogle Scholar
  25. Gerlai R, Clayton NS (1999) Analysing hippocampal function in transgenic mice: an ethological perspective. Trends Neurosci 22:47–51PubMedCrossRefGoogle Scholar
  26. Gerlai R, Chatterjee D, Pereira T, Sawashima T, Krishnannair R (2009a) Acute and chronic alcohol dose: population differences in behavior and neurochemistry of zebrafish. Genes Brain Behav 8:586–599PubMedCrossRefGoogle Scholar
  27. Gerlai R, Fernandes Y, Pereira T (2009b) Zebrafish (Danio rerio) responds to the animated image of a predator: towards the development of an automated aversive task. Behav Brain Res 201:318–324PubMedCrossRefGoogle Scholar
  28. Gerlai R, Wojtowicz JM, Marks A, Roder J (1995) Over-expression of a calcium binding protein, S100ß, in astrocytes alters synaptic plasticity and impairs spatial learning in transgenic mice. Learn Mem 2:26–39PubMedCrossRefGoogle Scholar
  29. Giles AC, Rankin CH (2009) Behavioral and genetic characterization of habituation using Caenorhabditis elegans. Neurobiol Learn Mem 92:139–146PubMedCrossRefGoogle Scholar
  30. Gómez-Laplaza LM, Gerlai R (2010) Latent Learning in Zebrafish (Danio rerio). Behav Brain Res 208:509–515 PubMedCrossRefGoogle Scholar
  31. Haffter P, Nüsslein-Volhard C (1996) Large scale genetics in a small vertebrate, the zebrafish. Int J Dev Biol 40:221–227PubMedGoogle Scholar
  32. Haffter P, Granato M, Brand M, Mullins MC, Hammerschmidt M, Kane DA, Odenthal J, Van Eeden FJM, Jiang YJ, Heisenberg CP, Kelsh RN, Furutaniseiki M, Vogelsang E, Beuchle D, Schach U, Fabian C, Nüsslein-Volhard C (1996) The identification of genes with unique and essential function in the development of the zebrafish, Danio rerio. Development 123:1–36PubMedGoogle Scholar
  33. Huang CJ, Jou TS, Ho YL, Lee WH, Jeng YT, Hsieh FJ, Tsai HJ (2005) Conditional expression of a myocardium-specific transgene in zebrafish transgenic lines. Dev Dyn 233:1294–1303PubMedCrossRefGoogle Scholar
  34. Joshi P, Liang JO, Dimonte K, Sullivan J, Pimplikar SW (2009) Amyloid precursor protein is required for convergent-extension movements during zebrafish development. Dev Biol 335:1–11PubMedCrossRefGoogle Scholar
  35. Kim S, Radhakrishnan UP, Rajpurohit SK, Kulkarni V, Jagadeeswaran P (2010) Vivo-Morpholino knockdown of alpha IIb: a novel approach to inhibit thrombocyte function in adult zebrafish. Blood Cells Mol Dis 44:169–174PubMedCrossRefGoogle Scholar
  36. Knapik EW (2000) ENU mutagenesis in zebrafish—from genes to complex diseases. Mamm Genome 11:511–519PubMedCrossRefGoogle Scholar
  37. Langenau DM, Feng H, Berghmans S, Kanki JP, Kutok JL, Look AT (2005) Cre/lox-regulated transgenic zebrafish model with conditional myc-induced T cell acute lymphoblastic leukemia. Proc Natl Acad Sci USA 102:6068–6073PubMedCrossRefGoogle Scholar
  38. Lee KY, Huang H, Ju B, Yang Z, Lin S (2002) Cloned zebrafish by nuclear transfer from long-term-cultured cells. Nat Biotech 20:795–799Google Scholar
  39. Lekven AC, Helde KA, Thorpe CJ, Rooke R, Moon RT (2000) Reverse genetics in zebrafish. Physiol Genomics 2:37–48PubMedGoogle Scholar
  40. Mathur P, Guo S (2010) Use of zebrafish as a model to understand mechanisms of addiction and complex neurobehavioral phenotypes. Neurobiol Dis 40:66–72PubMedCrossRefGoogle Scholar
  41. McEchron MD, Disterhoft JF (1999) Hippocampal encoding of non-spatial trace conditioning. Hippocampus 9:385–396PubMedCrossRefGoogle Scholar
  42. Miller N, Gerlai R (2008) Oscillations in shoal cohesion in zebrafish (Danio rerio). Behav. Brain Res 193:148–151Google Scholar
  43. Miller N, Gerlai R (2007) Quantification of shoaling behaviour in zebrafish (Danio rerio). Behav. Brain Res 184:157–166CrossRefGoogle Scholar
  44. Moens CB, Donn TM, Wolf-Saxon ER, Ma TP (2008) Reverse genetics in zebrafish by TILLING. Brief Funct Genomic Proteomic 7:454–459PubMedCrossRefGoogle Scholar
  45. Pan Y, Razak Z, Mo K, Westwood JT, Gerlai R (2010) Chronic alcohol exposure induced gene expression changes in the zebrafish brain. Genes Brain Behav (in press)Google Scholar
  46. Parra KV, Adrian JC Jr, Gerlai R (2009) The synthetic substance hypoxanthine 3-N-oxide elicits alarm reactions in zebrafish (Danio rerio). Behav. Brain Res 205:336–341Google Scholar
  47. Paquet D et al (2009) A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest 119:1382–1395PubMedCrossRefGoogle Scholar
  48. Pather S, Gerlai R (2009) Shuttle box learning in zebrafish. Behav Brain Res 196:323–327Google Scholar
  49. Patton EE, Zon LI (2001) The art and design of genetic screens: zebrafish. Nat Rev Genet 2:956–966PubMedCrossRefGoogle Scholar
  50. Pekhletski R, Gerlai R, Overstreet L, Huang X-P, Agopyan N, Slater NT, Roder J, Hampson DR (1996) Impaired motor learning and short-term synaptic plasticity in mice lacking mGluR4 metabotropic glutamate receptors. J Neurosci 16:6364–6373PubMedGoogle Scholar
  51. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344PubMedCrossRefGoogle Scholar
  52. Reimers MJ, Hahn ME, Tanguay RL (2004) Two zebrafi sh alcohol dehydrogenases share common ancestry with mammalian class I, II, IV, and V alcohol dehydrogenase genes but have distinct functional characteristics. J Biol Chem; 279:38303–38312PubMedCrossRefGoogle Scholar
  53. Renier C, Faraco JH, Bourgin P, Motley T, Bonaventure P, Rosa F, Mignot E (2007) Genomic and functional conservation of sedative-hypnotic targets in the zebrafish. Pharmacogen Genomics 17:237–253CrossRefGoogle Scholar
  54. Salas C, Rodríguez F, Vargas JP, Durán E, Torres B (1996) Spatial learning and memory deficits after telencephalic ablation in goldfish trained in place and turn maze procedures. Behav Neurosci 110:965–980PubMedCrossRefGoogle Scholar
  55. Scott EK, Mason L, Arrenberg AB, Ziv L, Gosse NJ, Xiao T, Chi NC, Asakawa K, Kawakami K, Baier H (2007) Targeting neural circuitry in zebrafish using GAL4 enhancer trapping. Nat Methods 4:323–326PubMedGoogle Scholar
  56. Sison M, Gerlai R (2010) Associative learning in zebrafish (Danio rerio) in the plus maze. Behav Brain Res 207:99–104PubMedCrossRefGoogle Scholar
  57. Sison M, Cawker J, Buske C, Gerlai R (2006) Fishing for genes of vertebrate behavior: zebra fish as an upcoming model system. Lab Animal 35:33–39PubMedCrossRefGoogle Scholar
  58. Sivasubbu S, Balciunas D, Davidson AE, Pickart MA, Hermanson SB, Wangensteen KJ, Wolbrink DC, Ekker SC (2006) Gene-breaking transposon mutagenesis reveals an essential role for histone H2afza in zebrafish larval development. Mech Dev 123:513–529PubMedCrossRefGoogle Scholar
  59. Skromne I, Prince VE (2008) Current perspectives in zebrafish reverse genetics: moving forward. Dev Dyn 237:861–882PubMedCrossRefGoogle Scholar
  60. Sokolowski MB (2001) Drosophila: genetics meets behaviour. Nat Rev Genet 2:879–890PubMedCrossRefGoogle Scholar
  61. Speedie N, Gerlai R (2008) Alarm substance induced behavioral responses in zebrafish (Danio rerio) Behav. Brain Res 188:168–177Google Scholar
  62. Sweatt JD (2010) Mechanisms of memory. 2nd edn, Elsevier, Amsterdam, p 343Google Scholar
  63. Tong C, Li P, Wu NL, Yan Y, Ying QL (2010) Production of p53 gene knockout rats by homologous recombination in embryonic stem cells. Nature 467:211–213PubMedCrossRefGoogle Scholar
  64. Tropepe V, Sive HL (2003) Can zebrafish be used as a model to study the neurodevelopmental causes of autism? Genes Brain Behav 2:268–281PubMedCrossRefGoogle Scholar
  65. Vargas JP, López JC, Portavella M (2009) What are the functions of fish brain pallium? Brain Res Bull 79:436–440PubMedCrossRefGoogle Scholar
  66. Weisberg RB (2009) Overview of generalized anxiety disorder: epidemiology, presentation, and course. J Clin Psychiatry 70(Suppl 2):4–9 PubMedCrossRefGoogle Scholar
  67. Xia W (2010) Exploring Alzheimer’s disease in zebrafish. J Alzheimer’s Dis 20:981–990Google Scholar

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© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Department of PsychologyUniversity of Toronto MississaugaMississaugaCanada

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