A Cross-Laboratory Investigation of Timing Endophenotypes in Mouse Behavior

In: Timing & Time Perception
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  • 1 Department of Neuroscience and Brain Technologies-Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy
  • 2 Consiglio Nazionale delle Ricerche-Institute of Cell Biology and Neurobiology-EMMA-Infrafrontier-IMPC, Monterotondo, Italy
  • 3 MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK
  • 4 Department of Psychology, Koç University, Istanbul, Turkey

Phenotyping behavioral and cognitive processes is a critical practice in mouse research and reliable phenotypic assessment is an essential component of building well-defined links between genes and behavioral/cognitive functions.

The success of behavioral screens in neurobehavioral mouse genetics depends on the identification of reliable, reproducible, and high-throughput behavioral/cognitive measures from individual animals irrespective of the differences in opinions regarding how to tackle phenotyping in different behavioral domains. Furthermore, reliable behavioral assays must be resistant to inevitable environmental differences across laboratories since protocols can be replicated but not all the environmental conditions.

Here we present a cross-laboratory study of interval timing behaviors in mice. Two classically used mouse inbred substrains, C57BL/6J and C57BL/6N, were studied over several days in home-cages containing automated testing apparatus. Remarkably, all timing measures in mouse performance showed a robust reproducibility across centers and even small differences between the two substrains were comparable across laboratories. Moreover, we have observed a consistent increase in error rate during the light phase of the light–dark cycle, which suggests that mouse performance during this phase is compromised by a possible sleep inertia-like effect. Overall, our study demonstrates that analysis of mouse timing behavior can lead to robust and reliable endophenotypes in mouse behavioral genetic studies.

  • Agostino P. V., do Nascimento M., Bussi I. L., Eguia M. C., Golombek D. A. (2011). Circadian modulation of interval timing in mice. Brain Res., 1370, 154163.

    • Search Google Scholar
    • Export Citation
  • Agostino P. V., Golombek D. A., Meck W. H. (2011). Unwinding the molecular basis of interval and circadian timing. Front. Integr. Neurosci., 5, 64.

    • Search Google Scholar
    • Export Citation
  • Bailey D. W. (1978). Sources of subline divergence and their relative importance for sublines of six major inbred strains of mice. In Morse H. C. (Ed.), Origins of inbred mice (pp.  197215). New York: Academic Press.

    • Search Google Scholar
    • Export Citation
  • Balci F., Freestone D., Gallistel C. R. (2009). Risk assessment in man and mouse. Proc. Natl Acad. Sci. USA, 106, 24592463.

  • Balci F., Freestone D., Simen P., Desouza L., Cohen J. D., Holmes P. (2011). Optimal temporal risk assessment. Frontier. Integr. Neurosci., 5, 56.

  • Balci F., Gallistel C. R., Allen B. D., Frank K. M., Gibson J. M., Brunner D. (2009). Acquisition of peak responding: What is learned? Behav. Process., 80, 6775.

    • Search Google Scholar
    • Export Citation
  • Balci F., Papachristos E. B., Gallistel C. R., Brunner D., Gibson J., Shumyatsky G. P. (2008). Interval timing in genetically modified mice: A simple paradigm. Genes Brain Behav., 7, 373384.

    • Search Google Scholar
    • Export Citation
  • Balci F., Simen P., Niyogi R., Saxe A., Hughes J. A., Holmes P., Cohen J. D. (2011). Acquisition of decision making criteria: Reward rate ultimately beats accuracy. Atten. Percept. Psycho., 73, 640657.

    • Search Google Scholar
    • Export Citation
  • Barnard A. R., Nolan P. M. (2008). When clocks go bad: Neurobehavioural consequences of disrupted circadian timing. PLoS Genet., 4, e1000040.

    • Search Google Scholar
    • Export Citation
  • Blum K., Briggs A. H., DeLallo L., Elston S. F., Ochoa R. (1982). Whole brain methionine-enkephalin of ethanol-avoiding and ethanol-preferring c57BL mice. Experientia, 38, 14691470.

    • Search Google Scholar
    • Export Citation
  • Brown S. D., Chambon P., de Angelis M. H. (2005). EMPReSS: standardized phenotype screens for functional annotation of the mouse genome. Nat. Gen., 37, 1155.

    • Search Google Scholar
    • Export Citation
  • Buhusi C. V., Meck W. H. (2005). What makes us tick? Functional and neural mechanisms of interval timing. Nat. Rev. Neurosci., 6, 755765.

    • Search Google Scholar
    • Export Citation
  • Cheng K., Westwood R. (1993). Analysis of single trials in pigeons timing performance. J. Exp. Psychol.-Anim. Behav. Proc., 19, 5667.

  • Church R. M., Meck W. H., Gibbon J. (1994). Application of scalar timing theory to individual trials. J. Exp. Psychol.-Anim. Behav. Proc., 20, 135155.

    • Search Google Scholar
    • Export Citation
  • Crabbe J. C., Wahlsten D., Dudek B. C. (1999). Genetics of mouse behavior: Interactions with laboratory environment. Science, 284, 16701672.

    • Search Google Scholar
    • Export Citation
  • Ferrara M., De Gennaro L., Bertini M. (2000). Time-course of sleep inertia upon awakening from nighttime sleep with different sleep homeostasis conditions. Aviat. Space Envir. Md., 71, 225229.

    • Search Google Scholar
    • Export Citation
  • Gallistel C. R., King A. P., Daniel A. M., Freestone D., Papachristos E. B., Balci F., Kheifets A., Zhang J., Su X., Schiff G., Kourtev H. (2010). Screening for learning and memory mutations: A new approach. Xin Li Xue Bao, 42, 138158.

    • Search Google Scholar
    • Export Citation
  • Godinho S. I., Maywood E. S., Shaw L., Tucci V., Barnard A. R., Busino L., Pagano M., Kendall R., Quwailid M. M., Rosario Romero M., O’Neill J., Chesham J. E., Brooker D., Lalanne Z., Hastings M. H., Nolan P. M. (2007). The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science, 316, 897900.

    • Search Google Scholar
    • Export Citation
  • Kas M. J., Van Ree J. M. (2004). Dissecting complex behaviours in the post-genomic era. Tr. Neurosci., 27, 366369.

  • Khisti R. T., Wolstenholme J., Shelton K. L., Miles M. F. (2006). Characterization of the ethanol-deprivation effect in substrains of C57BL/6 mice. Alcohol, 40, 119126.

    • Search Google Scholar
    • Export Citation
  • Lassi G., Ball S. T., Maggi S., Colonna G., Nieus T., Cero C., Bartolomucci A., Peters J., Tucci V. (2012). Loss of Gnas imprinting differentially affects REM/NREM sleep and cognition in mice. PLoS Genet., 8, e1002706.

    • Search Google Scholar
    • Export Citation
  • Leise T. L., Indic P., Paul M. J., Schwartz W. J. (2013). Wavelet meets actogram. J. Biol. Rhythm., 28, 6268.

  • Mandillo S., Tucci V., Holter S. M., Meziane H., Banchaabouchi M. A., Kallnik M., Lad H. V., Nolan P. M., Ouagazzal A.-M., Coghill E. L., Gale K., Golini E., Jacquot S., Krezel W., Parker A., Riet F., Schneider I., Marazziti D., Auwerx J., Brown S. D. M., Chambon P., Rosenthal N., Tocchini-Valentini G., Wurst W. (2008). Reliability, robustness, and reproducibility in mouse behavioral phenotyping: A cross-laboratory study. Physiol. Genomics, 34, 243255.

    • Search Google Scholar
    • Export Citation
  • Matsuo N., Yamasaki N., Ohira K., Takao K., Toyama K., Eguchi M., Yamaguchi S., Miyakawa T. (2009). Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice. Front. Behav. Neurosci., 3.

    • Search Google Scholar
    • Export Citation
  • Mekada K., Abe K., Murakami A., Nakamura S., Nakata H., Moriwaki K., Obata Y., Yoshiki A. (2009). Genetic differences among C57BL/6 substrains. Exp. Anim. Tokyo, 58, 141149.

    • Search Google Scholar
    • Export Citation
  • Radulovic J., Kammermeier J., Spiess J. (1998). Generalization of fear responses in C57BL/6N mice subjected to one-trial foreground contextual fear conditioning. Behav. Brain Res., 95, 179189.

    • Search Google Scholar
    • Export Citation
  • Shurtleff D., Raslear T. G., Simmons L. (1990). Circadian variations in time perception in rats. Physiol. Behav., 47, 931939.

  • Stiedl O., Radulovic J., Lohmann R., Birkenfeld K., Palve M., Kammermeier J., Sananbenesi F., Spiess J. (1999). Strain and substrain differences in context- and tone-dependent fear conditioning of inbred mice. Behav. Brain Res., 104, 112.

    • Search Google Scholar
    • Export Citation
  • Tassi P., Muzet A. (2000). Sleep inertia. Sleep Med Rev., 4, 341353.

  • Tucci V. (2011). Sleep, circadian rhythms, and interval timing: Evolutionary strategies to time information. Front. Integr. Neurosci., 5, 92.

    • Search Google Scholar
    • Export Citation
  • Tucci V., Achilli F., Blanco G., Lad H. V., Wells S., Godinho S., Nolan P. M. (2007). Reaching and grasping phenotypes in the mouse (Mus musculus): A characterization of inbred strains and mutant lines. Neuroscience, 147, 573582.

    • Search Google Scholar
    • Export Citation
  • Tucci V., Lad H. V., Parker A., Polley S., Brown S. D., Nolan P. M. (2006). Gene-environment interactions differentially affect mouse strain behavioral parameters. Mamm. Genome, 17, 11131120.

    • Search Google Scholar
    • Export Citation
  • Urback Y. K., Bode F., Nguyen H. P., Riess O., van Horsten S. (2010). Neurobehavioral tests in rat models of degenerative brain diseases. In Anegon I. (Ed.), Rat genomics: methods and protocols. Methods in molecular biology ( Vol. 597, pp.  333356). New York, NY: Humana Press, Springer Science + Business Media, LLC.

    • Search Google Scholar
    • Export Citation

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