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An approach to monitoring home-cage behavior in mice that facilitates data sharing

Nature Protocols volume 13, pages 1331–1347 (2018)Cite this article

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Abstract

Genetically modified mice are used as models for a variety of human behavioral conditions. However, behavioral phenotyping can be a major bottleneck in mouse genetics because many of the classic protocols are too long and/or are vulnerable to unaccountable sources of variance, leading to inconsistent results between centers. We developed a home-cage approach using a Chora feeder that is controlled by—and sends data to—software. In this approach, mice are tested in the standard cages in which they are held for husbandry, which removes confounding variables such as the stress induced by out-of-cage testing. This system increases the throughput of data gathering from individual animals and facilitates data mining by offering new opportunities for multimodal data comparisons. In this protocol, we use a simple work-for-food testing strategy as an example application, but the approach can be adapted for other experiments looking at, e.g., attention, decision-making or memory. The spontaneous behavioral activity of mice in performing the behavioral task can be monitored 24 h a day for several days, providing an integrated assessment of the circadian profiles of different behaviors. We developed a Python-based open-source analytical platform (Phenopy) that is accessible to scientists with no programming background and can be used to design and control such experiments, as well as to collect and share data. This approach is suitable for large-scale studies involving multiple laboratories.

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Figure 1: Schematic representation of Phenopy functionalities.
Figure 2: Phenopy and behavioral apparatus.
Figure 3: Example of analysis outputs.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Almasy, L. & Blangero, J. Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am. J. Med. Genet. 105, 42–44 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Gottesman, I.I. & Gould, T.D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160, 636–645 (2003).

    Article  PubMed  Google Scholar 

  4. Glahn, D.C. et al. Arguments for the sake of endophenotypes: examining common misconceptions about the use of endophenotypes in psychiatric genetics. Am. J. Med. Genet. B Neuropsychiatr. Genet. 165B, 122–130 (2014).

    Article  PubMed  CAS  Google Scholar 

  5. Kas, M.J. & Van Ree, J.M. Dissecting complex behaviours in the post-genomic era. Trends Neurosci. 27, 366–369 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Papaleo, F., Lipska, B.K. & Weinberger, D.R. Mouse models of genetic effects on cognition: relevance to schizophrenia. Neuropharmacology 62, 1204–1220 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Tucci, V., Lassi, G. & Kas, M.J. Current understanding of the interplay between catechol-O-methyltransferase genetic variants, sleep, brain development and cognitive performance in schizophrenia. CNS Neurol. Disord. Drug Targets 11, 292–298 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Papaleo, F., Burdick, M.C., Callicott, J.H. & Weinberger, D.R. Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans. Mol. Psychiatry 19, 311–316 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Flint, J. & Munafo, M.R. The endophenotype concept in psychiatric genetics. Psychol. Med. 37, 163–180 (2007).

    Article  PubMed  Google Scholar 

  10. Munafo, M.R., Bowes, L., Clark, T.G. & Flint, J. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol. Psychiatry 10, 765–770 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Bains, R.S. et al. Assessing mouse behaviour throughout the light/dark cycle using automated in-cage analysis tools. J. Neurosci. Methods 300, 37–47 (2017).

    Article  PubMed  Google Scholar 

  12. Lassi, G. et al. Loss of Gnas imprinting differentially affects REM/NREM sleep and cognition in mice. PLoS Genet. 8, e1002706 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Balzani, E. et al. The Zfhx3-mediated axis regulates sleep and interval timing in mice. Cell Rep. 16, 615–621 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tucci, V. et al. Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features. J. Clin. Invest. 124, 1468–1482 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lassi, G. et al. Working-for-food behaviors: a preclinical study in Prader-Willi mutant mice. Genetics 204, 1129–1138 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Maggi, S. et al. A cross-laboratory investigation of timing endophenotypes in mouse behavior. Timing Time Percept. 2, 35–50 (2014).

    Article  Google Scholar 

  17. Ward, R.D., Kellendonk, C., Kandel, E.R. & Balsam, P.D. Timing as a window on cognition in schizophrenia. Neuropharmacology 62, 1175–1181 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Teixeira, S. et al. Time perception distortion in neuropsychiatric and neurological disorders. CNS Neurol. Disord. Drug Targets 12, 567–582 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Hinton, S.C. et al. Motor timing variability increases in preclinical Huntington's disease patients as estimated onset of motor symptoms approaches. J. Int. Neuropsychol. Soc. 13, 539–543 (2007).

    Article  PubMed  Google Scholar 

  20. Tinazzi, M. et al. Impaired temporal processing of tactile and proprioceptive stimuli in cerebellar degeneration. PLoS One 8, e78628 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Henley, S.M. et al. Degradation of cognitive timing mechanisms in behavioural variant frontotemporal dementia. Neuropsychologia 65, 88–101 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Crawley, J.N. Behavioral phenotyping strategies for mutant mice. Neuron 57, 809–818 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Mandillo, S. et al. Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study. Physiol. Genomics 34, 243–255 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hart, P.C. et al. Experimental models of anxiety for drug discovery and brain research. Methods Mol. Biol. 602, 299–321 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Rosenthal, R. & Fode, K. The effect of experimenter bias on performance of the albino rat. Behav. Sci. 8, 183–189 (1963).

    Article  Google Scholar 

  26. Holman, L., Head, M.L., Lanfear, R. & Jennions, M.D. Evidence of experimental bias in the life sciences: why we need blind data recording. PLoS Biol. 13, e1002190 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Longordo, F., Fan, J., Steimer, T., Kopp, C. & Luthi, A. Do mice habituate to 'gentle handling?' A comparison of resting behavior, corticosterone levels and synaptic function in handled and undisturbed C57BL/6J mice. Sleep 34, 679–681 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Costa, R., Tamascia, M.L., Nogueira, M.D., Casarini, D.E. & Marcondes, F.K. Handling of adolescent rats improves learning and memory and decreases anxiety. J. Am. Assoc. Lab. Anim. Sci. 51, 548–553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Tucci, V., Hardy, A. & Nolan, P.M. A comparison of physiological and behavioural parameters in C57BL/6J mice undergoing food or water restriction regimes. Behav. Brain Res. 173, 22–29 (2006).

    Article  PubMed  Google Scholar 

  30. Tucci, V. et al. Gene-environment interactions differentially affect mouse strain behavioral parameters. Mamm. Genome 17, 1113–1120 (2006).

    Article  PubMed  Google Scholar 

  31. Frick, K.M., Stearns, N.A., Pan, J.Y. & Berger-Sweeney, J. Effects of environmental enrichment on spatial memory and neurochemistry in middle-aged mice. Learn. Mem. 10, 187–198 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jankowsky, J.L. et al. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. J. Neurosci. 25, 5217–5224 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rampon, C. et al. Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat. Neurosci. 3, 238–244 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. van Praag, H., Kempermann, G. & Gage, F.H. Neural consequences of environmental enrichment. Nat. Rev. Neurosci. 1, 191–198 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Tucci, V. et al. Reaching and grasping phenotypes in the mouse (Mus musculus): a characterization of inbred strains and mutant lines. Neuroscience 147, 573–582 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Balci, F., Freestone, D. & Gallistel, C.R. Risk assessment in man and mouse. Proc. Natl. Acad. Sci. USA 106, 2459–2463 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Balci, F. et al. High-throughput automated phenotyping of two genetic mouse models of Huntington's disease. PLoS Curr. 5 http://dx.doi.org/10.1371/currents.hd.124aa0d16753f88215776fba102ceb29 (2013).

  38. Gallistel, C.R., Balci, F., Freestone, D., Kheifets, A. & King, A. Automated, quantitative cognitive/behavioral screening of mice: for genetics, pharmacology, animal cognition and undergraduate instruction. J. Vis. Exp. (84)e51047 http://dx.doi.org/10.3791/51047 (2014).

  39. Cordes, S. & Gallistel, C.R. Intact interval timing in circadian CLOCK mutants. Brain Res. 1227, 120–127 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Perkel, J.M. Programming: pick up Python. Nature 518, 125–126 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Dunlap, J.C. Molecular bases for circadian clocks. Cell 96, 271–290 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Mohawk, J.A. & Takahashi, J.S. Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators. Trends Neurosci. 34, 349–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Balci, F. et al. Interval timing in genetically modified mice: a simple paradigm. Genes Brain Behav. 7, 373–384 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Cheng, K., Westwood, R. & Crystal, J.D. Memory variance in the peak procedure of timing in pigeons. J. Exp. Psychol. Anim. Behav. Process. 19, 68–76 (1993).

    Article  Google Scholar 

  45. Church, R.M., Meck, W.H. & Gibbon, J. Application of scalar timing theory to individual trials. J. Exp. Psychol. Anim. Behav. Process. 20, 135–155 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Balci, F. et al. Acquisition of peak responding: what is learned? Behav. Process. 80, 67–75 (2009).

    Article  Google Scholar 

  47. Feldmann, H.M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 9, 203–209 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Lassi, G. et al. Deletion of the Snord116/SNORD116 alters sleep in mice and patients with Prader-Willi syndrome. Sleep 39, 637–644 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Balzani, E. et al. The Zfhx3-mediated axis regulates sleep and interval timing in mice. Cell Rep. 16(3), 615–621 (2016).

    Article  CAS  Google Scholar 

  50. Tosun, T., Gür, F. & Balci, F. Mice plan decision strategies based on previously learned time intervals, locations, and probabilities. Proc. Natl. Acad. Sci. USA 113, 787–792 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rossi, M.A. & Yin, H.H. Methods for studying habitual behavior in mice. Curr. Protoc. Neurosci. Chap. 8, Unit 8.29 (2012).

  52. Aquili, L. et al. Behavioral flexibility is increased by optogenetic inhibition of neurons in the nucleus accumbens shell during specific time segments. Learn. Mem. 21(4), 223–231 (2014).

    Article  Google Scholar 

  53. Cottrell, J.R. et al. Working memory impairment in calcineurin knock-out mice is associated with alterations in synaptic vesicle cycling and disruption of high-frequency synaptic and network activity in prefrontal cortex. J. Neurosci. 33(27) 10938–10949 (2013).

    Article  CAS  Google Scholar 

  54. Bach, M.E. et al. Transient and selective overexpression of D2 receptors in the striatum causes persistent deficits in conditional associative learning. Proc. Natl. Acad. Sci. 105 16027–16032 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Papachristos, E.B. & Gallistel, C.R. Autoshaped head poking in the mouse: a quantitative analysis of the learning curve. J. Exp. Anal. Behav. 85, 293–308 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Gallistel, C.R. et al. Is matching innate? J. Exp. Anal. Behav. 87, 161–199 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pinkston, J.W. & Lamb, R.J. Delay discounting in C57BL/6J and DBA/2J mice: adolescent-limited and life-persistent patterns of impulsivity. Behav. Neurosci. 125, 194–201 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Young, J.W., Light, G.A., Marston, H.M., Sharp, R. & Geyer, M.A. The 5-choice continuous performance test: evidence for a translational test of vigilance for mice. PLoS One 4 e4227 (2009).

  59. Gourley, S.L. et al. Dissociable regulation of instrumental action within mouse prefrontal cortex. Eur. J. Neurosci. 32, 1726–1734 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the IT group at the IIT for technical support. This study was supported by the European Commission FP7 Programme under project 223263 (PhenoScale).

Author information

Author notes

  1. Edoardo Balzani and Matteo Falappa: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy

    Edoardo Balzani, Matteo Falappa & Valter Tucci

  2. Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, Genova, Italy

    Matteo Falappa

  3. Department of Psychology, Koç University, Istanbul, Turkey

    Fuat Balci

  4. Research Center for Translational Medicine, Koç University, Istanbul, Turkey

    Fuat Balci

Authors
  1. Edoardo Balzani
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Contributions

E.B. and M.F. wrote Phenopy and performed the experiments and the analyses. F.B. designed the original timing analyses. V.T. conceived, planned and supervised the project, and wrote the manuscript with the help of all co-authors.

Corresponding author

Correspondence to Valter Tucci.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Top view of CHORA feeders

This picture shows the top panel of the CHORA feeders. The power lever and the operational mode lever are indicated by a red arrow. The lever of the operational state is set in via cable modality. Switch the lever for wireless mode. Once the feeder is turned on, the communication modality cannot be changed. To change the communication modality, first switch off the feeder and then change the communication modality.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1, Supplementary Methods and Supplementary Tables 1 and 2. (PDF 763 kb)

Supplementary Data

Recorded data and Python example scripts. (ZIP 117880 kb)

Running Phenopy.

This video shows how to set up a behavioral experimental protocol using Chora feeders and Phenopy. (MP4 4370 kb)

Data analysis example.

This video shows how to import, export, edit and analyze data using Phenopy. (MOV 4714 kb)

Importing functions.

This video shows how to upload a new importation function into Phenopy. (MOV 2841 kb)

Importing a new analysis.

This video shows how to upload a new analysis function into Phenopy. (MOV 4635 kb)

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Balzani, E., Falappa, M., Balci, F. et al. An approach to monitoring home-cage behavior in mice that facilitates data sharing. Nat Protoc 13, 1331–1347 (2018). https://doi.org/10.1038/nprot.2018.031

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