Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The mouse: genetics meets behaviour

Key Points

  • The advantages of the mouse for behavioural studies are the extensive genetic technologies that are available for this species and its elaborate behavioural repertoire, which can be used to create models of human disease.

  • The ability to manipulate the mouse genome allows researchers to investigate the cellular and molecular bases of behaviour by using electrophysiological, biochemical and/or cellular approaches to study mice with behavioural phenotypes.

  • Defining causal relationships between specific behaviours and the electrophysiological, biochemical, cellular and/or neuropathological mechanisms that underlie them is hampered by several important factors, such as pleiotropy, genetic background and environmental effects, and by issues of experimental design.

  • A combination of genetic approaches is needed to identify genes that underlie behaviour in the mouse. These include reverse genetic approaches — such as gene targeting, the conditional inactivation or activation of transgenes, and gene-trapping — and forward genetic approaches — such as ENU mutagenesis and quantitative trait analysis.

  • Mutant mice are phenotyped by testing them in different behavioural paradigms, which can reveal the presence or absence of specific behaviours and allow them to be quantified.

  • Many more mouse mutants with behavioural phenotypes will need to be isolated and more behavioural assays will need to be developed to determine whether genes exist that are dedicated to specific behaviours.

  • Mouse mutants have shed light on the molecular mechanisms that underlie human disorders, as exemplified by the study of human sleep disorders, such as narcolepsy and familial advanced sleep-phase syndrome. They have also been used to investigate the mechanisms of action of certain therapeutics, such as those of the antipsychotic medications that are used to treat schizophrenia.

Abstract

Genetic studies in the mouse are important in the elucidation of molecular pathways that underlie behaviour. The advantages of the mouse for behavioural studies include an extensive array of genetic technologies and an elaborate behavioural repertoire that can be used to create models of human disease. This review discusses the relative advantages of forward and reverse genetic approaches to studying the genetic basis of behaviour in the mouse, and the complexities that behavioural studies need to address, such as phenotypic variability, genetic background effects and pleiotropy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genetic approaches to generating new behavioural and neurological mutations.
Figure 2: Several neural systems of the mouse brain and their behavioural functions.

Similar content being viewed by others

References

  1. Freedman, R., Adler, L. E. & Leonard, S. Alternative phenotypes for the complex genetics of schizophrenia. Biol. Psychiatry 45, 551–558 (1999).

    CAS  PubMed  Google Scholar 

  2. Gershon, E. S. & Goldin, L. R. Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies. Acta Psychiatr. Scand. 74, 113–118 (1986).

    CAS  PubMed  Google Scholar 

  3. Leboyer, M. et al. Psychiatric genetics: search for phenotypes. Trends Neurosci. 21, 102–105 (1998).

    CAS  PubMed  Google Scholar 

  4. Tarantino, L. M. & Bucan, M. Dissection of behavior and psychiatric disorders using the mouse as a model. Hum. Mol. Genet. 9, 953–965 (2000).

    CAS  PubMed  Google Scholar 

  5. King, D. P. & Takahashi, J. S. Molecular genetics of circadian rhythms in mammals. Annu. Rev. Neurosci. 23, 713–742 (2000).

    CAS  PubMed  Google Scholar 

  6. Williams, J. A. & Sehgal, A. Molecular components of the circadian system in Drosophila. Annu. Rev. Physiol. 63, 729–755 (2001).

    CAS  PubMed  Google Scholar 

  7. Abel, T. & Kandel, E. Positive and negative regulatory mechanisms that mediate long-term memory storage. Brain Res. Rev. 26, 360–378 (1998).

    CAS  PubMed  Google Scholar 

  8. Dubnau, J. & Tully, T. Gene discovery in Drosophila: new insights for learning and memory. Annu. Rev. Neurosci. 21, 407–444 (1998).

    CAS  PubMed  Google Scholar 

  9. Fernandez-Funez, P. et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106 (2000).

    CAS  PubMed  Google Scholar 

  10. Fortini, M. E. & Bonini, N. M. Modeling human neurodegenerative diseases in Drosophila: on a wing and a prayer. Trends Genet. 16, 161–167 (2000).

    CAS  PubMed  Google Scholar 

  11. LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Waelti, P., Dickinson, A. & Schultz, W. Dopamine responses comply with basic assumptions of formal learning theory. Nature 412, 43–48 (2001).

    CAS  PubMed  Google Scholar 

  13. Baker, B. S., Taylor, B. J. & Hall, J. C. Are complex behaviors specified by dedicated regulatory genes? Reasoning from Drosophila. Cell 105, 13–24 (2001).

    CAS  PubMed  Google Scholar 

  14. Greenspan, R. J. The flexible genome. Nature Rev. Genet. 2, 383–387 (2001).

    CAS  PubMed  Google Scholar 

  15. Sokolowski, M. B. Drosophila: genetics meets behaviour. Nature Rev. Genet. 2, 879–890 (2001).

    CAS  PubMed  Google Scholar 

  16. Nadeau, J. H. & Frankel, W. N. The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nature Genet. 25, 381–384 (2000).

    CAS  PubMed  Google Scholar 

  17. Grant, S. G. N. et al. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258, 1903–1910 (1992).

    CAS  PubMed  Google Scholar 

  18. Silva, A. J., Paylor, R., Wehner, J. M. & Tonegawa, S. Impaired spatial learning in α-calcium–calmodulin kinase II mutant mice. Science 257, 206–211 (1992). References 17 and 18 were the first to describe learning and memory phenotypes in knockout mice and to relate these behavioural alterations to changes in synaptic plasticity at the cellular level.

    CAS  PubMed  Google Scholar 

  19. Tsien, J. Z., Huerta, P. T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996). This paper describes the use of Cre recombinase to delete a gene in a specific hippocampal subregion, therefore firmly establishing the role of the NMDA receptor in synaptic plasticity, learning and memory.

    CAS  PubMed  Google Scholar 

  20. Mayford, M. et al. Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678–1683 (1996). This paper describes the use of the tetracycline system to regulate gene expression in adult transgenic mice — an approach that allows the effects of a mutation on development to be dissociated from its effects on neuronal function in the adult.

    CAS  PubMed  Google Scholar 

  21. Scearce-Levie, K., Chen, J. P., Gardner, E. & Hen, R. 5-HT receptor knockout mice: pharmacological tools or models of psychiatric disorders. Ann. NY Acad. Sci. 868, 701–715 (1999).

    CAS  PubMed  Google Scholar 

  22. Ralph, R. J. et al. The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J. Neurosci. 19, 4627–4633 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Holmes, A. et al. Behavioral characterization of dopamine D5 receptor null mutant mice. Behav. Neurosci. 115, 1129–1144 (2001).

    CAS  PubMed  Google Scholar 

  24. Mayford, M. & Kandel, E. R. Genetic approaches to memory storage. Trends Genet. 15, 463–470 (1999).

    CAS  PubMed  Google Scholar 

  25. Abel, T. & Lattal, K. M. Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr. Opin. Neurobiol. 11, 180–187 (2001).

    CAS  PubMed  Google Scholar 

  26. Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).

    CAS  PubMed  Google Scholar 

  27. Giese, K. P., Fedorov, N. B., Filipkowski, R. K. & Silva, A. J. Autophosphorylation at Thr286 of the α-calcium–calmodulin kinase II in LTP and learning. Science 279, 870–873 (1998).

    CAS  PubMed  Google Scholar 

  28. Nestler, E. J. Molecular basis of long-term plasticity underlying addiction. Nature Rev. Neurosci. 2, 119–128 (2001).

    CAS  Google Scholar 

  29. Nestler, E. J. & Aghajanian, G. K. Molecular and cellular basis of addiction. Science 278, 58–63 (1997).

    CAS  PubMed  Google Scholar 

  30. Kelz, M. B. et al. Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

    CAS  PubMed  Google Scholar 

  31. Kelz, M. B. & Nestler, E. J. ΔFosB: a molecular switch underlying long-term neural plasticity. Curr. Opin. Neurol. 13, 715–720 (2000).

    CAS  PubMed  Google Scholar 

  32. Pennacchio, L. A. & Rubin, E. M. Genomic strategies to identify mammalian regulatory sequences. Nature Rev. Genet. 2, 100–109 (2001).

    CAS  PubMed  Google Scholar 

  33. Copeland, N. G., Jenkins, N. A. & Court, D. L. Recombineering: a powerful new tool for mouse functional genomics. Nature Rev. Genet. 2, 769–779 (2001).

    CAS  PubMed  Google Scholar 

  34. Malleret, G. et al. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104, 675–686 (2001).

    CAS  PubMed  Google Scholar 

  35. Mansuy, I. M. & Bujard, H. Tetracycline-regulated gene expression in the brain. Curr. Opin. Neurobiol. 10, 593–596 (2000).

    CAS  PubMed  Google Scholar 

  36. Lewandoski, M. Conditional control of gene expression in the mouse. Nature Rev. Genet. 2, 743–755 (2001).

    CAS  PubMed  Google Scholar 

  37. Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999).

    CAS  PubMed  Google Scholar 

  38. McMahon, M. Steroid receptor fusion proteins for conditional activation of Raf–MEK–ERK signaling pathway. Methods Enzymol. 332, 401–417 (2001).

    CAS  PubMed  Google Scholar 

  39. Yamamoto, A., Lucas, J. J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57–66 (2000).

    CAS  PubMed  Google Scholar 

  40. Leighton, P. A. et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410, 174–179 (2001).

    CAS  PubMed  Google Scholar 

  41. Mitchell, K. J. et al. Functional analysis of secreted and transmembrane proteins critical to mouse development. Nature Genet. 28, 241–249 (2001). A phenotypic analysis of mice with gene-trap insertions in genes that encode secreted and transmembrane proteins. Out of 60 insertions that were analysed in vivo , one-third cause recessive-lethal phenotypes.

    CAS  PubMed  Google Scholar 

  42. Wiles, M. V. et al. Establishment of a gene-trap sequence tag library to generate mutant mice from embryonic stem cells. Nature Genet. 24, 13–14 (2000).

    CAS  PubMed  Google Scholar 

  43. Zambrowicz, B. P. et al. Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells. Nature 392, 608–611 (1998).

    CAS  PubMed  Google Scholar 

  44. Stanford, W. L., Cohn, J. B. & Cordes, S. P. Gene-trap mutagenesis: past, present and beyond. Nature Rev. Genet. 2, 756–768 (2001).

    CAS  PubMed  Google Scholar 

  45. Justice, M. J. Capitalizing on large-scale mouse mutagenesis screens. Nature Rev. Genet. 1, 109–115 (2000).

    CAS  PubMed  Google Scholar 

  46. Nolan, P. M. et al. A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nature Genet. 25, 440–443 (2000). This large-scale mutagenesis screen involved assessing the progeny of ENU-mutagenized mice using the SHIRPA protocol — a specialized screen tailored to investigate neurological and behavioural deficits.

    CAS  PubMed  Google Scholar 

  47. Nolan, P. M. et al. Implementation of a large-scale ENU mutagenesis program: towards increasing the mouse mutant resource. Mamm. Genome 11, 500–506 (2000).

    CAS  PubMed  Google Scholar 

  48. Sayah, D. M., Khan, A. H., Gasperoni, T. L. & Smith, D. J. A genetic screen for novel behavioral mutations in mice. Mol. Psychiatry 5, 369–377 (2000).

    CAS  PubMed  Google Scholar 

  49. Vitaterna, M. H. et al. Mutagenesis and mapping of a mouse gene, clock, essential for circadian behavior. Science 264, 719–725 (1994). The first use of ENU mutagenesis to identify behavioural mutations in the mouse. Although circadian rhythm mutants existed in several other species, clock was the first circadian mutation to be found in the mouse.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Moldin, S. O., Farmer, M. E., Chin, H. R. & Battey, J. F. Jr Trans-NIH neuroscience initiatives on mouse phenotyping and mutagenesis. Mamm. Genome 12, 575–581 (2001).

    CAS  PubMed  Google Scholar 

  51. Tsai, H. et al. The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti. Hum. Mol. Genet. 10, 507–512 (2001).

    CAS  PubMed  Google Scholar 

  52. Kiernan, A. et al. The Notch ligand Jagged1 is required for inner ear sensory development. Proc. Natl Acad. Sci. USA 98, 3873–3878 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Xue, Y. et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum. Mol. Genet. 8, 723–730 (1999).

    CAS  PubMed  Google Scholar 

  54. Underhill, P. A. et al. Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography. Genome Res. 7, 996–1005 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Gao, Q. & Yeung, E. High-throughput detection of unknown mutations by using multiplexed capillary electrophoresis with poly(vinylpyrrolidone) solution. Anal. Chem. 72, 2499–2506 (2000).

    CAS  PubMed  Google Scholar 

  56. Turri, M. G., Datta, S. R., DeFries, J., Henderson, N. D. & Flint, J. QTL analysis identifies multiple behavioral dimensions in ethological tests of anxiety in laboratory mice. Curr. Biol. 11, 725–734 (2001).

    CAS  PubMed  Google Scholar 

  57. Turri, M. G., Henderson, N. D., DeFries, J. C. & Flint, J. Quantitative trait locus mapping in laboratory mice derived from a replicated selection experiment for open-field activity. Genetics 158, 1217–1226 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Shimomura, K. et al. Genome-wide epistatic interaction analysis reveals complex genetic determinants of circadian behavior in mice. Genome Res. 11, 959–980 (2001). This comprehensive QTL analysis led to the identification of loci that influence five specific aspects of circadian rhythms and activity, and to the identification of additive and epistatic interactions between loci in the BALB/cJ and C57BL/6J genomes.

    CAS  PubMed  Google Scholar 

  59. Caldarone, B. et al. Quantitative trait loci analysis affecting contextual conditioning in mice. Nature Genet. 17, 335–337 (1997).

    CAS  PubMed  Google Scholar 

  60. Wehner, J. M. et al. Quantitative trait locus analysis of contextual fear conditioning in mice. Nature Genet. 17, 331–334 (1997).

    CAS  PubMed  Google Scholar 

  61. Bannerman, D. M., Good, M. A., Butcher, S. P., Ramsay, M. & Morris, R. G. Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature 378, 182–186 (1995).

    CAS  PubMed  Google Scholar 

  62. Thomas, S. A. & Palmiter, R. D. Impaired maternal behavior in mice lacking norepinephrine and epinephrine. Cell 91, 583–592 (1997).

    CAS  PubMed  Google Scholar 

  63. Ernfors, P., Lee, K. F. & Jaenisch, R. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368, 147–150 (1994).

    CAS  PubMed  Google Scholar 

  64. Linnarsson, S., Bjorklund, A. & Ernfors, P. Learning deficit in BDNF mutant mice. Eur. J. Neurosci. 9, 2581–2587 (1997).

    CAS  PubMed  Google Scholar 

  65. Lyons, W. E. et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc. Natl Acad. Sci. USA 96, 15239–15244 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Silva, A. J. et al. Mutant mice and neuroscience: recommendations concerning genetic background. Banbury Conference on genetic background in mice. Neuron 19, 755–759 (1997).

    Google Scholar 

  67. Bourtchouladze, R. et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 59–68 (1994).

    Google Scholar 

  68. Kogan, J. H. et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 7, 1–11 (1997).

    CAS  PubMed  Google Scholar 

  69. Gass, P. et al. Deficits in memory tasks of mice with CREB mutations depend on gene dosage. Learn. Mem. 5, 274–288 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Graves, L., Dalvi, A., Lucki, I., Blendy, J. & Abel, T. Behavioral analysis of the CREB αΔ mutation on a B6/129 F1 hybrid background. Hippocampus (in the press).

  71. Guzowski, J. F. & McGaugh, J. L. Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc. Natl Acad. Sci. USA 94, 2693–2698 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Josselyn, S. A. et al. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J. Neurosci. 21, 2404–2412 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Crabbe, J. C., Wahlsten, D. & Dudek, B. C. Genetics of mouse behavior: interactions with laboratory environment. Science 284, 1670–1672 (1999).

    CAS  PubMed  Google Scholar 

  74. Tarantino, L. M., Gould, T. J., Druhan, J. P. & Bucan, M. Behavior and mutagenesis screens: the importance of baseline analysis of inbred strains. Mamm. Genome 11, 555–564 (2000).

    CAS  PubMed  Google Scholar 

  75. Veasey, S. C. et al. An automated system for recording and analysis of sleep in mice. Sleep 23, 1025–1040 (2000).

    CAS  PubMed  Google Scholar 

  76. Reppert, S. M. & Weaver, D. R. Molecular analysis of mammalian circadian rhythms. Annu. Rev. Physiol. 63, 647–676 (2001).

    CAS  PubMed  Google Scholar 

  77. Blau, J. & Young, M. W. Cycling vrille expression is required for a functional Drosophila clock. Cell 99, 661–671 (1999).

    CAS  PubMed  Google Scholar 

  78. Martinek, S., Inonog, S., Manoukian, A. S. & Young, M. W. A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105, 769–779 (2001).

    CAS  PubMed  Google Scholar 

  79. Zilian, O. et al. double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs. Development 126, 5409–5420 (1999).

    CAS  PubMed  Google Scholar 

  80. Gailey, D. A., Villella, A. & Tully, T. Reassessment of the effect of biological rhythm mutations on learning in Drosophila melanogaster. J. Comp. Physiol. A 169, 685–697 (1991).

    CAS  Google Scholar 

  81. Belvin, M. P., Zhou, H. & Yin, J. C. The Drosophila dCREB2 gene affects the circadian clock. Neuron 22, 777–787 (1999).

    CAS  PubMed  Google Scholar 

  82. Hendricks, J. C. et al. A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis. Nature Neurosci. 4, 1108–1115 (2001).

    CAS  PubMed  Google Scholar 

  83. Moore, M. S. et al. Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway. Cell 93, 997–1007 (1998).

    CAS  PubMed  Google Scholar 

  84. Wand, G., Levine, M., Zweifel, L., Schwindinger, W. & Abel, T. The cAMP-protein kinase. A signal transduction pathway modulates ethanol consumption and sedative effects of ethanol. J. Neurosci. 21, 5297–5303 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Brown, W. & Hagland, K. Bringing behavioral genes to light. J. NIH Res. 6, 66–73 (1994).

    Google Scholar 

  86. Chelly, J. & Mandel, J. L. Monogenic causes of X-linked mental retardation. Nature Rev. Genet. 2, 669–680 (2001).

    CAS  PubMed  Google Scholar 

  87. Chapman, P. F., Falinska, A. M., Knevett, S. G. & Ramsay, M. F. Genes, models and Alzheimer's disease. Trends Genet. 17, 254–261 (2001).

    CAS  PubMed  Google Scholar 

  88. Chen, G. et al. A learning deficit related to age and ß-amyloid plaques in a mouse model of Alzheimer's disease. Nature 408, 975–979 (2000).

    CAS  PubMed  Google Scholar 

  89. Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001). The first report of a mutation in a core circadian rhythm gene in humans. Linkage analysis of a large kindred in which affected family members have advanced sleep-phase led to the identification of a mutation in PER2 , a human orthologue of the Drosophila gene period.

    CAS  PubMed  Google Scholar 

  90. Jones, C. R. et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nature Med. 5, 1062–1065 (1999).

    CAS  PubMed  Google Scholar 

  91. Zheng, B. et al. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400, 169–173 (1999).

    CAS  PubMed  Google Scholar 

  92. Bae, K. et al. Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30, 525–536 (2001).

    CAS  PubMed  Google Scholar 

  93. Willie, J. T., Chemelli, R. M., Sinton, C. M. & Yanagisawa, M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu. Rev. Neurosci. 24, 429–458 (2001).

    CAS  PubMed  Google Scholar 

  94. Hungs, M. & Mignot, E. Hypocretin/orexin, sleep and narcolepsy. Bioessays 23, 397–408 (2001).

    CAS  PubMed  Google Scholar 

  95. Thannickal, T. C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Nishino, S., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39–40 (2000).

    CAS  PubMed  Google Scholar 

  97. Peyron, C. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Med. 6, 991–997 (2000).

    CAS  PubMed  Google Scholar 

  98. Koch, M. The neurobiology of startle. Prog. Neurobiol. 59, 107–128 (1999).

    CAS  PubMed  Google Scholar 

  99. Swerdlow, N. R. & Geyer, M. A. Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr. Bull. 24, 285–301 (1998).

    CAS  PubMed  Google Scholar 

  100. Crawley, J. N. & Paylor, R. A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm. Behav. 31, 197–211 (1997).

    CAS  PubMed  Google Scholar 

  101. Crawley, J. N. in What's Wrong with my Mouse? 329 (John Wiley & Sons, Inc., New York, 2000).

    Google Scholar 

  102. Bolivar, V., Cook, M. & Flaherty, L. List of transgenic and knockout mice: behavioral profiles. Mamm. Genome 11, 260–274 (2000).

    CAS  PubMed  Google Scholar 

  103. Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376 (1999).

    CAS  PubMed  Google Scholar 

  104. Hungs, M. et al. Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines. Genome Res. 11, 531–539 (2001).

    CAS  PubMed  Google Scholar 

  105. Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999). References 103 and 105 describe work that linked the orexin/hypocretin pathway to narcolepsy. Reference 103 describes the positional cloning of spontaneous mutations in dogs, whereas reference 105 describes the narcolepsy-like phenotype of mice with a targeted mutation in Hcrt.

    CAS  PubMed  Google Scholar 

  106. Kisanuki, Y. Y. et al. Behavioral and polysomnographic characterization of orexin-1 receptor and orexin-2 receptor double knockout mice. Sleep 24, A22 (2001).

    Google Scholar 

  107. Kilduff, T. S. & Peyron, C. The hypocretin/orexin ligand–receptor system: implications for sleep and sleep disorders. Trends Neurosci. 23, 359–365 (2000).

    CAS  PubMed  Google Scholar 

  108. Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 1 page following 696 (1998).

  109. De Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank our colleagues, members of our laboratories and especially S. Poethig for helpful discussions and comments on the manuscript. We thank L. Maltais for help with the nomenclature. These studies were supported by grants from the National Institutes of Health and the Whitehall Foundation. T.A. is a Packard Fellow and a John Merck Scholar.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maja Bućan.

Related links

Related links

DATABASES

LocusLink

double-time

Drd2

Drd3

Drd4

Fosb

huntingtin

Jag1

orexin/hypocretin

per

PER2

Per2

shaggy

vrille

MedScape DrugInfo

amphetamine

clozapine

OMIM

Alzheimer disease

FASPS

Huntington disease

narcolepsy

The Jackson Laboratory

Creb1 tm1Gsc

slalom

FURTHER INFORMATION

Encyclopedia of Life Sciences

Learning and memory

Memory in fruit flies and nematodes 

 Seymour Benzer

Stanford University Center for Narcolepsy

Glossary

LONG-TERM POTENTIATION

A long-lasting increase in the efficacy of synaptic transmission, which is commonly elicited by high-frequency neuronal stimulation.

ELECTROENCEPHALOGRAPHY

(EEG). This technique measures neural activity by monitoring electrical signals from the brain that reach the scalp. EEG has good temporal but relatively poor spatial resolution.

PLEIOTROPY

The phenomenon in which a single gene is responsible for several distinct and seemingly unrelated phenotypic effects.

REVERSE GENETICS

A genetic analysis that proceeds from genotype to phenotype by gene-manipulation techniques, such as homologous recombination in embryonic stem cells.

CRE/LOXP

A site-specific recombination system derived from the Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, which leads to the excision of the intervening sequence.

STEROID-HORMONE-REGULATED CRE

Cre recombinase that has been engineered to contain mutated progesterone or oestrogen ligand-binding domains that are specifically bound by synthetic steroids. This binding allows Cre to be translocated to the nucleus.

ALLELIC SERIES

An array of possible mutant forms of a gene, which usually causes multiple phenotypes.

ORGAN OF CORTI

The structure in the inner ear that contains receptor cells that are sensitive to sound vibrations.

AMPULLA

A swelling at the base of the semicircular canals, which contains sensory cells that detect the movement of fluid inside the canals.

QUANTITATIVE TRAIT

A measurable trait that depends on a single gene or on the cumulative action of many genes and the environment.

QUANTITATIVE TRAIT LOCUS

(QTL). A genetic locus that is identified through the statistical analysis of complex traits (such as height or body weight). These traits are typically affected by more than one gene and also by the environment.

ELECTROMYOGRAPHY

(EMG). A technique used to measure striated muscle activity by monitoring electrical signals from a surrounding group of muscles. In sleep studies, EMG activity, in combination with electroencephalography, determines behavioural states, wakefulness, rapid eye movement (REM) and non-REM sleep.

FORWARD GENETICS

A genetic analysis that proceeds from phenotype to genotype by positional cloning or candidate-gene analysis.

FEAR CONDITIONING

A test to measure the ability of a rodent to learn and remember an association between an aversive experience and environmental cues. Learning and memory are assessed by scoring freezing behaviour in the presence of the cue or context.

SENSORIMOTOR GATING

A behavioural trait in humans and animals that reflects the ability to filter out extraneous stimuli and to process information that comes in rapid succession.

PREPULSE INHIBITION OF THE STARTLE RESPONSE

A behavioural test for sensorimotor gating. This task measures the level of attenuation of a startle response on presentation of a non-startle-inducing prepulse.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bućan, M., Abel, T. The mouse: genetics meets behaviour. Nat Rev Genet 3, 114–123 (2002). https://doi.org/10.1038/nrg728

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg728

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing