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The touchscreen operant platform for testing working memory and pattern separation in rats and mice

Nature Protocols volume 8, pages 2006–2021 (2013)Cite this article

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Abstract

The automated touchscreen operant chamber for rats and mice allows for the assessment of multiple cognitive domains within the same testing environment. This protocol presents the location discrimination (LD) task and the trial-unique delayed nonmatching-to-location (TUNL) task, which both assess memory for location. During these tasks, animals are trained to a predefined criterion during ∼20–40 daily sessions. In LD sessions, touching the same location on the screen is rewarded on consecutive trials, followed by a reversal of location-reward contingencies. TUNL, a working memory task, requires animals to 'nonmatch' to a sample location after a delay. In both the LD and TUNL tasks, spatial similarity can be varied, allowing assessment of pattern separation ability, a function that is thought to be performed by the dentate gyrus (DG). These tasks are therefore particularly useful in animal models of hippocampal, and specifically DG, function, but they additionally permit discernment of changes in pattern separation from those in working memory.

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Figure 1: Flowchart overview of the main features of the touchscreen TUNL task.
Figure 2: Flowchart overview of the intermediate training and performance probe phases of the location discrimination (LD) task.
Figure 3: Average performance of male Lister hooded rats on TUNL probe sessions for different delays and separations.
Figure 4: Average performance of Tnik−/− (n = 12, dashed line) and wild-type (WT) mice of the same background (C57BL/6 × 129S5, n = 8, solid line) on the LD task.

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References

  1. McTighe, S.M., Mar, A.C., Romberg, C., Bussey, T.J. & Saksida, L.M. A new touchscreen test of pattern separation: effect of hippocampal lesions. Neuroreport 20, 881–885 (2009).

    Article  Google Scholar 

  2. Talpos, J.C., Dias, R., Bussey, T.J. & Saksida, L.M. Hippocampal lesions in rats impair learning and memory for locations on a touch-sensitive computer screen: the 'ASAT' task. Behav. Brain Res. 192, 216–225 (2008).

    Article  CAS  Google Scholar 

  3. Talpos, J.C., McTighe, S.M., Dias, R., Saksida, L.M. & Bussey, T.J. Trial-unique, delayed nonmatching-to-location (TUNL): a novel, highly hippocampus-dependent automated touchscreen test of location memory and pattern separation. Neurobiol. Learn. Mem. 94, 341–352 (2010).

    Article  CAS  Google Scholar 

  4. Talpos, J.C., Winters, B.D., Dias, R., Saksida, L.M. & Bussey, T.J. A novel touchscreen-automated paired-associate learning (PAL) task sensitive to pharmacological manipulation of the hippocampus: a translational rodent model of cognitive impairments in neurodegenerative disease. Psychopharmacology 205, 157–168 (2009).

    Article  CAS  Google Scholar 

  5. Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47–60 (1984).

    Article  CAS  Google Scholar 

  6. Barnes, C.A. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J. Comp. Physiol. Psychol. 93, 74–104 (1979).

    Article  CAS  Google Scholar 

  7. Olton, D.S. The radial arm maze as a tool in behavioral pharmacology. Physiol. Behav. 40, 793–797 (1987).

    Article  CAS  Google Scholar 

  8. Olton, D.S. Mazes, maps, and memory. Am. Psychol. 34, 583–596 (1979).

    Article  CAS  Google Scholar 

  9. Dunnett, S.B. Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats. Psychopharmacology 87, 357–363 (1985).

    Article  CAS  Google Scholar 

  10. Bierley, R.A. & Kesner, R.P. Short-term memory: the role of the midbrain reticular formation. J. Comp. Physiol. Psychol. 94, 519–529 (1980).

    Article  CAS  Google Scholar 

  11. Aggleton, J.P., Keith, A.B., Rawlins, J.N., Hunt, P.R. & Sahgal, A. Removal of the hippocampus and transection of the fornix produce comparable deficits on delayed non-matching to position by rats. Behav. Brain Res. 52, 61–71 (1992).

    Article  CAS  Google Scholar 

  12. Deadwyler, S.A., Bunn, T. & Hampson, R.E. Hippocampal ensemble activity during spatial delayed-nonmatch-to-sample performance in rats. J. Neurosci. 16, 354–372 (1996).

    Article  CAS  Google Scholar 

  13. Hampson, R.E. & Deadwyler, S.A. Ensemble codes involving hippocampal neurons are at risk during delayed performance tests. Proc. Natl. Acad. Sci. USA 93, 13487–13493 (1996).

    Article  CAS  Google Scholar 

  14. Bussey, T.J. et al. New translational assays for preclinical modelling of cognition in schizophrenia: the touchscreen testing method for mice and rats. Neuropharmacology 62, 1191–1203 (2012).

    Article  CAS  Google Scholar 

  15. Bussey, T.J. et al. The touchscreen cognitive testing method for rodents: how to get the best out of your rat. Learn. Mem. 15, 516–523 (2008).

    Article  Google Scholar 

  16. Horner, A.E. et al. The touchscreen operant platform for testing learning and memory in rats and mice. Nat. Protoc. 8, 1961–1984 (2013).

    Article  CAS  Google Scholar 

  17. Nithianantharajah, J. et al. Synaptic scaffold evolution generated components of vertebrate cognitive complexity. Nat. Neurosci. 16, 16–24 (2013).

    Article  CAS  Google Scholar 

  18. Mar, A. et al. The touchscreen operant platform for testing executive function in rats and mice. Nat. Protoc. 8, 1985–2005 (2013).

    Article  CAS  Google Scholar 

  19. Wong, A.A. & Brown, R.E. Visual detection, pattern discrimination and visual acuity in 14 strains of mice. Genes Brain Behav. 5, 389–403 (2006).

    Article  CAS  Google Scholar 

  20. Prusky, G.T., Harker, K.T., Douglas, R.M. & Whishaw, I.Q. Variation in visual acuity within pigmented, and between pigmented and albino rat strains. Behav. Brain Res. 136, 339–348 (2002).

    Article  Google Scholar 

  21. Treves, A. & Rolls, E.T. Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network. Hippocampus 2, 189–199 (1992).

    Article  CAS  Google Scholar 

  22. Treves, A., Tashiro, A., Witter, M.P. & Moser, E.I. What is the mammalian dentate gyrus good for? Neuroscience 154, 1155–1172 (2008).

    Article  CAS  Google Scholar 

  23. Leutgeb, J.K., Leutgeb, S., Moser, M.B. & Moser, E.I. Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science 315, 961–966 (2007).

    Article  CAS  Google Scholar 

  24. Gilbert, P.E., Kesner, R.P. & Lee, I. Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1. Hippocampus 11, 626–636 (2001).

    Article  CAS  Google Scholar 

  25. Yassa, M.A. & Stark, C.E. Pattern separation in the hippocampus. Trends Neurosci. 34, 515–525 (2011).

    Article  CAS  Google Scholar 

  26. Gilbert, P.E., Kesner, R.P. & DeCoteau, W.E. Memory for spatial location: role of the hippocampus in mediating spatial pattern separation. J. Neurosci. 18, 804–810 (1998).

    Article  CAS  Google Scholar 

  27. McHugh, T.J. et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94–99 (2007).

    Article  CAS  Google Scholar 

  28. Clelland, C.D. et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213 (2009).

    Article  CAS  Google Scholar 

  29. DeCarolis, N.A. & Eisch, A.J. Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology 58, 884–893 (2010).

    Article  CAS  Google Scholar 

  30. Eisch, A.J. et al. Adult neurogenesis, mental health, and mental illness: hope or hype? J. Neurosci. 28, 11785–11791 (2008).

    Article  CAS  Google Scholar 

  31. Sahay, A. & Hen, R. Adult hippocampal neurogenesis in depression. Nat. Neurosci. 10, 1110–1115 (2007).

    Article  CAS  Google Scholar 

  32. Lucassen, P.J. et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. Eur. Neuropsychopharmacol. 20, 1–17 (2010).

    Article  CAS  Google Scholar 

  33. Reif, A. et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol. Psychiatry 11, 514–522 (2006).

    Article  CAS  Google Scholar 

  34. Toro, C.T. & Deakin, J.F. Adult neurogenesis and schizophrenia: a window on abnormal early brain development? Schizophr. Res. 90, 1–14 (2007).

    Article  CAS  Google Scholar 

  35. Jin, K. et al. Increased hippocampal neurogenesis in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 101, 343–347 (2004).

    Article  CAS  Google Scholar 

  36. Donovan, M.H. et al. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease. J. Comp. Neurol. 495, 70–83 (2006).

    Article  Google Scholar 

  37. Wen, P.H. et al. The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp. Neurol. 188, 224–237 (2004).

    Article  CAS  Google Scholar 

  38. Thompson, A., Boekhoorn, K., Van Dam, A.M. & Lucassen, P.J. Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence? Genes Brain Behav. 7 (suppl. 1), 28–42 (2008).

    Article  Google Scholar 

  39. Cameron, H.A. & Gould, E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61, 203–209 (1994).

    Article  CAS  Google Scholar 

  40. Heine, V.M., Maslam, S., Zareno, J., Joels, M. & Lucassen, P.J. Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible. Eur. J. Neurosci. 19, 131–144 (2004).

    Article  Google Scholar 

  41. Mirescu, C., Peters, J.D. & Gould, E. Early life experience alters response of adult neurogenesis to stress. Nat. Neurosci. 7, 841–846 (2004).

    Article  CAS  Google Scholar 

  42. Oomen, C.A. et al. Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J. Neurosci. 30, 6635–6645 (2010).

    Article  CAS  Google Scholar 

  43. Snyder, J.S., Soumier, A., Brewer, M., Pickel, J. & Cameron, H.A. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461 (2011).

    Article  CAS  Google Scholar 

  44. Seki, T. & Arai, Y. Age-related production of new granule cells in the adult dentate gyrus. Neuroreport 6, 2479–2482 (1995).

    Article  CAS  Google Scholar 

  45. Kuhn, H.G., Dickinson-Anson, H. & Gage, F.H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 (1996).

    Article  CAS  Google Scholar 

  46. van Praag, H., Christie, B.R., Sejnowski, T.J. & Gage, F.H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. USA 96, 13427–13431 (1999).

    Article  CAS  Google Scholar 

  47. Galea, L.A. Gonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents. Brain Res. Rev. 57, 332–341 (2008).

    Article  CAS  Google Scholar 

  48. Tanapat, P., Hastings, N.B., Reeves, A.J. & Gould, E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J. Neurosci. 19, 5792–5801 (1999).

    Article  CAS  Google Scholar 

  49. Shors, T.J. et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372–376 (2001).

    Article  CAS  Google Scholar 

  50. Leuner, B., Gould, E. & Shors, T.J. Is there a link between adult neurogenesis and learning? Hippocampus 16, 216–224 (2006).

    Article  Google Scholar 

  51. Deng, W., Aimone, J.B. & Gage, F.H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339–350 (2010).

    Article  CAS  Google Scholar 

  52. Bekinschtein, P., Oomen, C.A., Saksida, L.M. & Bussey, T.J. Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Semin. Cell Dev. Biol. 22, 536–542 (2011).

    Article  CAS  Google Scholar 

  53. Dunnett, S.B., Wareham, A.T. & Torres, E.M. Cholinergic blockade in prefrontal cortex and hippocampus disrupts short-term memory in rats. Neuroreport 1, 61–64 (1990).

    Article  CAS  Google Scholar 

  54. Granon, S., Vidal, C., Thinus-Blanc, C., Changeux, J.P. & Poucet, B. Working memory, response selection, and effortful processing in rats with medial prefrontal lesions. Behav. Neurosci. 108, 883–891 (1994).

    Article  CAS  Google Scholar 

  55. Sloan, H.L., Good, M. & Dunnett, S.B. Double dissociation between hippocampal and prefrontal lesions on an operant delayed matching task and a water maze reference memory task. Behav. Brain Res. 171, 116–126 (2006).

    Article  Google Scholar 

  56. Chudasama, Y. & Muir, J.L. A behavioural analysis of the delayed non-matching to position task: the effects of scopolamine, lesions of the fornix and of the prelimbic region on mediating behaviours by rats. Psychopharmacology 134, 73–82 (1997).

    Article  CAS  Google Scholar 

  57. Dudchenko, P. & Sarter, M. Behavioral microanalysis of spatial delayed alternation performance: rehearsal through overt behavior, and effects of scopolamine and chlordiazepoxide. Psychopharmacology 107, 263–270 (1992).

    Article  CAS  Google Scholar 

  58. Hearst, E. Delayed alternation in the pigeon. J. Exp. Anal. Behav. 5, 225–228 (1962).

    Article  CAS  Google Scholar 

  59. Herremans, A.H., Hijzen, T.H., Welborn, P.F., Olivier, B. & Slangen, J.L. Effects of infusion of cholinergic drugs into the prefrontal cortex area on delayed matching to position performance in the rat. Brain Res. 711, 102–111 (1996).

    Article  CAS  Google Scholar 

  60. McAllister, K.A.L., Saksida, L.M. & Bussey, T.J. Dissociation between memory retention across a delay and pattern separation following medial prefrontal cortex lesions in the touchscreen TUNL task. Neurobiol. Learn. Mem. 101, 120–126 (2013).

    Article  Google Scholar 

  61. Postman, L. & Underwood, B. Critical issues in interference theory. Mem. Cogn. 1, 19–40 (1973).

    Article  CAS  Google Scholar 

  62. Dale, R.H.I. & Roberts, W.A. Variations in radial maze performance under different levels of food and water-deprivation. Animal Learn. Behav. 14, 60–64 (1986).

    Article  Google Scholar 

  63. Roberts, W.A. & Dale, R.H.I. Remembrance of places lasts-proactive-inhibition and patterns of choice in rat spatial memory. Learn. Motiv. 12, 261–281 (1981).

    Article  Google Scholar 

  64. Grant, D.S. Intertrial interference in rat short-term memory. J. Exp. Psychol. Animal Behav. Processes 7, 217–227 (1981).

    Article  Google Scholar 

  65. Nuechterlein, K.H. et al. The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity. Am. J. Psychiatry 165, 203–213 (2008).

    Article  Google Scholar 

  66. Barch, D.M. et al. CNTRICS final task selection: working memory. Schizophr. Bull. 35, 136–152 (2009).

    Article  Google Scholar 

  67. Harrison, P.J. & Weinberger, D.R. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry 10, 40–68 (2005).

    Article  CAS  Google Scholar 

  68. Harrison, P.J. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology 174, 151–162 (2004).

    Article  CAS  Google Scholar 

  69. Meyer-Lindenberg, A.S. et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch. Gen. Psychiatry 62, 379–386 (2005).

    Article  Google Scholar 

  70. Carter, C.S. et al. Functional hypofrontality and working memory dysfunction in schizophrenia. Am. J. Psychiatry 155, 1285–1287 (1998).

    Article  CAS  Google Scholar 

  71. Creer, D.J., Romberg, C., Saksida, L.M., van Praag, H. & Bussey, T.J. Running enhances spatial pattern separation in mice. Proc. Natl. Acad. Sci. USA 107, 2367–2372 (2010).

    Article  CAS  Google Scholar 

  72. Coba, M.P. et al. TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. J. Neurosci. 32, 13987–13999 (2012).

    Article  CAS  Google Scholar 

  73. Chaudhury, D. & Colwell, C.S. Circadian modulation of learning and memory in fear-conditioned mice. Behav. Brain Res. 133, 95–108 (2002).

    Article  Google Scholar 

  74. Beeler, J.A., Prendergast, B. & Zhuang, X. Low amplitude entrainment of mice and the impact of circadian phase on behavior tests. Physiol. Behav 87, 870–880 (2006).

    Article  CAS  Google Scholar 

  75. Roedel, A., Storch, C., Holsboer, F. & Ohl, F. Effects of light or dark phase testing on behavioural and cognitive performance in DBA mice. Lab. Anim. 40, 371–381 (2006).

    Article  CAS  Google Scholar 

  76. Satoh, Y., Kawai, H., Kudo, N., Kawashima, Y. & Mitsumoto, A. Temperature rhythm reentrains faster than locomotor rhythm after a light phase shift. Physiol. Behav. 88, 404–410 (2006).

    Article  CAS  Google Scholar 

  77. Bussey, T.J., Muir, J.L. & Robbins, T.W. A novel automated touchscreen procedure for assessing learning in the rat using computer graphic stimuli. Neurosci. Res. Commun. 15, 103–110 (1994).

    Google Scholar 

  78. Cardinal, R.N. & Aitken, M.R. Whisker: a client-server high-performance multimedia research control system. Behav. Res. Methods 42, 1059–1071 (2010).

    Article  Google Scholar 

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Acknowledgements

The protocols described here are those used in our laboratory at present, and were written by current members of the group. However, many researchers have contributed to the development of touchscreen tasks and we would like to gratefully acknowledge their contribution. They include S. Bartko, J. Brigman, S. Forwood, C. Graybeal, A. Izquierdo, L. Lyon, A. Marti, K. McAllister, S. McTighe, J. Nithianantharajah, C. Romberg, J. Talpos and B. Winters. The research leading to these results has received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008, of which resources are composed of a European Federation of Pharmaceutical Industries and Associations in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013); and the Wellcome Trust/Medical Research Council (089703/Z/09/Z) and Alzheimer's Research UK (ART/PG2006/5). A.E.H. receives funding from the European Union Seventh Framework Programme under grant agreement nos. 241995 (Project 'GENCODYS') and 242167 (Project 'SYNSYS').

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Authors and Affiliations

  1. Department of Psychology, University of Cambridge, Cambridge, UK

    Charlotte A Oomen, Martha Hvoslef-Eide, Christopher J Heath, Adam C Mar, Alexa E Horner, Timothy J Bussey & Lisa M Saksida

  2. Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK

    Charlotte A Oomen, Martha Hvoslef-Eide, Christopher J Heath, Adam C Mar, Alexa E Horner, Timothy J Bussey & Lisa M Saksida

  3. Synome Ltd., Babraham Research Campus, Cambridge, UK

    Alexa E Horner

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All authors contributed to the writing of this manuscript. C.A.O. coordinated this effort.

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L.M.S. and T.J.B. consult for Campden Instruments, Ltd. A.E.H. is an employee of Synome, Ltd.

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Oomen, C., Hvoslef-Eide, M., Heath, C. et al. The touchscreen operant platform for testing working memory and pattern separation in rats and mice. Nat Protoc 8, 2006–2021 (2013). https://doi.org/10.1038/nprot.2013.124

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