Advertisement

Applying the Attribute Model to Develop Behavioral Tasks that Phenocopy Human Clinical Phenotypes Using Mouse Disease Models: An Endophenotyping Approach

  • Michael R. HunsakerEmail author
Chapter

Abstract

With the increasing sophistication of the genetic techniques used to develop mouse models of genetic disorders, it is imperative that the techniques used to elucidate the behavioral phenotypes of these models evolve just as rapidly. At present, mouse models developed to study neurodevelopmental disorders either demonstrate inconsistent phenotypes or lack behavioral phenotypes when tested using the standard battery of behavioral tasks. In this chapter, I describe a behavioral endophenotyping approach that allows researchers to explicitly model in mice the clinical phenotypes reported in human genetic disease. This approach facilitates a comprehensive approach to studying the effects of genetic mutations on behavior by individually evaluating each of the different domains/attributes of memory (e.g., time, space, sensory/perceptual, response, affect, and language), as well as social behaviors and executive function. The data obtained from this approach can be translated back to the clinical population on a per attribute basis, allowing for a dialogue between the clinic and basic science to facilitate the generation of testable hypotheses. A reciprocal interaction across levels of analysis also results in efficient development of outcome measures that can be used to evaluate the efficacy of treatment or interventional studies in the mouse model that potentially show predictive validity with later clinical trials. Examples of standardizing the behavioral phenotyping process for human disease using the NIH Toolbox, a collection of cognitive assessments, as well as a proposed murine analog of the NIH Toolbox are provided to illustrate the power of applying the attribute model to behavioral phenotyping.

Keywords

Endophenotype Attribute model NIH Toolbox Mouse model Learning and memory Task design 

References

  1. Allen, E. G., Hunter, J. E., Rusin, M., Juncos, J., Novak, G., Hamilton, D., et al. (2011). Neuropsychological findings from older premutation carrier males and their noncarrier siblings from families with fragile X syndrome. Neuropsychology, 25(3), 404–411.PubMedCentralCrossRefPubMedGoogle Scholar
  2. Amann, L. C., Gandal, M. J., Halene, T. B., Ehrlichman, R. S., White, S. L., McCarren, H. S., & Siegel, S. J. (2010). Mouse behavioral endophenotypes for schizophrenia. Brain Research Bulletin, 83(3–4), 147–161.CrossRefPubMedGoogle Scholar
  3. Baker, K. B., Wray, S. P., Ritter, R., Mason, S., Lanthorn, T. H., & Savelieva, K. V. (2010). Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments. Genes, Brain, and Behavior, 9(6), 562–574.PubMedGoogle Scholar
  4. Banik, A., & Anand, A. (2011). Loss of learning in mice when exposed to rat odor: A water maze study. Behavioural Brain Research, 216(1), 466–471.CrossRefPubMedGoogle Scholar
  5. Barkus, C., McHugh, S. B., Sprengel, R., Seeburg, P. H., Rawlins, J. N., & Bannerman, D. M. (2010). Hippocampal NMDA receptors and anxiety: At the interface between cognition and emotion. European Journal of Pharmacology, 626(1), 49–56.PubMedCentralCrossRefPubMedGoogle Scholar
  6. Berge, O. G. (2011). Predictive validity of behavioral animal models for chronic pain. British Journal of Pharmacology, 164(4), 1195–1206.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Bohlen, M., Cameron, A., Metten, P., Crabbe, J. C., & Wahlsten, D. (2009). Calibration of rotational acceleration for the rotarod test of rodent motor coordination. Journal of Neuroscience Methods, 178, 10–14.PubMedCentralCrossRefPubMedGoogle Scholar
  8. Borthwell, R. M., Hunsaker, M. R., Willemsen, R., & Berman, R. F. (2012). Spatiotemporal processing deficits in female CGG KI mice modeling the fragile X premutation. Behavioural Brain Research, 233(1), 29–34.PubMedCentralCrossRefPubMedGoogle Scholar
  9. Cannon, T. D., & Keller, M. C. (2006). Endophenotypes in the genetic analyses of mental disorders. Annual Review of Clinical Psychology, 2, 267–290.CrossRefPubMedGoogle Scholar
  10. Chonchaiya, W., Schneider, A., & Hagerman, R. J. (2009a). Fragile X: A family of disorders. Advances in Pediatrics, 56, 165–186.PubMedCentralCrossRefPubMedGoogle Scholar
  11. Chonchaiya, W., Utari, A., Pereira, G. M., Tassone, F., Hessl, D., & Hagerman, R. J. (2009b). Broad clinical involvement in a family affected by the fragile X premutation. Journal of Developmental and Behavioral Pediatrics, 30, 544–551.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Crabbe, J. C., & Wahlsten, D. (2003). Of mice and their environments. Science, 299, 1313–1314.CrossRefPubMedGoogle Scholar
  13. Crabbe, J. C., Wahlsten, D., & Dudek, B. C. (1999). Genetics of mouse behavior: Interactions with laboratory environment. Science, 284, 1670–1672.CrossRefPubMedGoogle Scholar
  14. Crawley, J. N. (2004). Designing mouse behavioral tasks relevant to autistic-like behaviors. Mental Retardation and Developmental Disabilities Research Reviews, 10, 248–258.CrossRefPubMedGoogle Scholar
  15. Devanand, D. P., Michaels-Marston, K. S., Liu, X., Pelton, G. H., Padilla, M., Marder, K., et al. (2000). Olfactory deficits in patients with mild cognitive impairment predict Alzheimer’s disease at follow-up. The American Journal of Psychiatry, 157, 1399–1405.CrossRefPubMedGoogle Scholar
  16. Diep, A. A., Hunsaker, M. R., Kwock, R., Kim, K. M., Willemsen, R., & Berman, R. F. (2012). Female CGG knock-in mice modeling the fragile X premutation are impaired on a skilled forelimb reaching task. Neurobiology of Learning and Memory, 97, 229–234.PubMedCentralCrossRefPubMedGoogle Scholar
  17. Frick, K. M., Stillner, E. T., & Berger-Sweeney, J. (2000). Mice are not little rats: Species differences in a one-day water maze task. Neuroreport, 11(16), 3461–3465.CrossRefPubMedGoogle Scholar
  18. Gershon, R. C. (2007). NIH Toolbox: Assessment of neurological and behavioral function. NIH (contract HHS-N-260-2006 00007-c) http://www.nihtoolbox.org.
  19. Gershon, R. C., Cella, D., Fox, N. A., Havlik, R. J., Hendrie, H. C., & Wagster, M. V. (2010). Assessment of neurological and behavioural function: The NIH Toolbox. Lancet Neurology, 9(2), 138–139.CrossRefPubMedGoogle Scholar
  20. Gilbert, P. E., & Murphy, C. (2004a). Differences between recognition memory and remote memory for olfactory and visual stimuli in nondemented elderly individuals genetically at risk for Alzheimer’s disease. Experimental Gerontology, 39, 433–441.CrossRefPubMedGoogle Scholar
  21. Gilbert, P. E., & Murphy, C. (2004b). The effect of the ApoE epsilon4 allele on recognition memory for olfactory and visual stimuli in patients with pathologically confirmed Alzheimer’s disease, probable Alzheimer’s disease & healthy elderly controls. Journal of Clinical and Experimental Neuropsychology, 26, 779–794.CrossRefPubMedGoogle Scholar
  22. Goodrich-Hunsaker, N. J., Wong, L. M., McLennan, Y., Srivastava, S., Tassone, F., Harvey, D., et al. (2011a). Young adult female fragile X premutation carriers show age- and genetically-modulated cognitive impairments. Brain and Cognition, 75, 255–260.PubMedCentralCrossRefPubMedGoogle Scholar
  23. Goodrich-Hunsaker, N. J., Wong, L. M., McLennan, Y., Tassone, F., Harvey, D., Rivera, S. M., & Simon, T. J. (2011b). Adult female fragile X premutation carriers exhibit age- and CGG repeat length-related impairments on an attentionally based enumeration task. Frontiers in Human Neuroscience, 5, 63.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Gottesman, I. I., & Gould, T. D. (2003). The endophenotype concept in psychiatry: Etymology and strategic intentions. The American Journal of Psychiatry, 160, 636–645.CrossRefPubMedGoogle Scholar
  25. Gould, T. D., & Einat, H. (2007). Animal models of bipolar disorder and mood stabilizer efficacy: A critical need for improvement. Neuroscience and Biobehavioral Reviews, 31, 825–831.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Gould, T. D., & Gottesman, I. I. (2006). Psychiatric endophenotypes and the development of valid animal models. Genes, Brain, and Behavior, 5, 113–119.CrossRefPubMedGoogle Scholar
  27. Greco, C. M., Berman, R. F., Martin, R. M., Tassone, F., Schwartz, P. H., Chang, A., et al. (2006). Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain: A Journal of Neurology, 129(1), 243–255.CrossRefGoogle Scholar
  28. Greene-Schloesser, D. M., Van der Zee, E. A., Sheppard, D. K., Castillo, M. R., Gregg, K. A., et al. (2011). Predictive validity of a non-induced mouse model of compulsive-like behavior. Behavioural Brain Research, 221, 55–62.PubMedCentralCrossRefPubMedGoogle Scholar
  29. Grigsby, J., Brega, A. G., Engle, K., Leehey, M. A., Hagerman, R. J., Tassone, F., et al. (2008). Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome. Neuropsychology, 22(1), 48–60.CrossRefPubMedGoogle Scholar
  30. Guion, R. M. (1977). Content validity-the source of my discontent. Applied Psychological Measurement, 1, 1–10.CrossRefGoogle Scholar
  31. Gur, R. E., Calkins, M. E., Gur, R. C., Horan, W. P., Nuechterlein, K. H., Seidman, L. J., & Stone, W. S. (2007). The consortium on the genetics of schizophrenia: Neurocognitive endophenotypes. Schizophrenia Bulletin, 33, 49–68.PubMedCentralCrossRefPubMedGoogle Scholar
  32. Gurkoff, G. G., Gahan, J. D., Ghiasvand, R. T., Hunsaker, M. R., Feng, J. F., Berman, R. F., et al. (2012). Moderate lateral fluid percussion injury results in the metric and temporal ordering but not topological working memory tasks. Journal of Neurotrauma.Google Scholar
  33. Hagerman, P. J., & Hagerman, R. J. (2004). The fragile-X premutation: A maturing perspective. American Journal of Human Genetics, 74(5), 805–816.PubMedCentralCrossRefPubMedGoogle Scholar
  34. Hasler, G., Drevets, W. C., Gould, T. D., Gottesman, I. I., & Manji, H. K. (2006). Toward constructing an endophenotype strategy for bipolar disorders. Biological Psychiatry, 60, 93–105.CrossRefPubMedGoogle Scholar
  35. Hatcher, J. P., Jones, D. N., Rogers, D. C., Hatcher, P. D., Reavill, C., Hagan, J. J., & Hunter, A. J. (2001). Development of SHIRPA to characterise the phenotype of gene-targeted mice. Behavioural Brain Research, 125, 43–47.CrossRefPubMedGoogle Scholar
  36. Hocking, D. R., Kogan, C. S., & Cornish, K. M. (2012). Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation. Brain and Cognition, 79(1), 39–44.CrossRefPubMedGoogle Scholar
  37. Hoffman, H. J., Cruickshanks, K. J., & Davis, B. (2009). Perspectives on population-based epidemiological studies of olfactory and taste impairment. Annals of the New York Academy of Sciences, 1170, 514–530.PubMedCentralCrossRefPubMedGoogle Scholar
  38. Hunsaker, M. R. (2012a). Comprehensive neurocognitive endophenotyping strategies for mouse models of genetic disorders. Progress in Neurobiology, 96(2), 220–241.PubMedCentralCrossRefPubMedGoogle Scholar
  39. Hunsaker, M. R. (2012b). The importance of considering all attributes of memory in behavioral endophenotyping of mouse models of genetic disease. Behavioral Neuroscience, 126(3), 371–380.PubMedCentralCrossRefPubMedGoogle Scholar
  40. Hunsaker, M. R., Fieldsted, P. M., Rosenberg, J. S., & Kesner, R. P. (2008a). Dissociating the roles of dorsal and ventral CA1 for the temporal processing of spatial locations, visual objects, and odors. Behavioral Neuroscience, 122(3), 643–650.CrossRefPubMedGoogle Scholar
  41. Hunsaker, M. R., Tran, G. T., & Kesner, R. P. (2008b). A double dissociation of subcortical hippocampal efferents for encoding and consolidation/retrieval of spatial information. Hippocampus, 18, 699–709.CrossRefPubMedGoogle Scholar
  42. Hunsaker, M. R., Wenzel, H. J., Willemsen, R., & Berman, R. F. (2009). Progressive spatial processing deficits in a mouse model of the fragile X premutation. Behavioral Neuroscience, 123(6), 1315–1324.PubMedCentralCrossRefPubMedGoogle Scholar
  43. Hunsaker, M. R., Goodrich-Hunsaker, N. J., Willemsen, R., & Berman, R. F. (2010). Temporal ordering deficits in female CGG KI mice heterozygous for the fragile X premutation. Behavioral Brain Research, 213(2), 263–268.CrossRefGoogle Scholar
  44. Hunsaker, M. R., Greco, C. M., Spath, M. A., Smits, A. P. T., Navarro, C. S., Tassone, F., et al. (2011a). Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice. Acta Neuropathologica, 122(4), 467–479.PubMedCentralCrossRefPubMedGoogle Scholar
  45. Hunsaker, M. R., von Leden, R. E., Ta, B. T., Goodrich-Hunsaker, N. J., Arque, G., Kim, K. M., et al. (2011b). Motor deficits on a ladder rung task in male and female adolescent CGG knock-in mice. Behavioural Brain Research, 222, 117–121.PubMedCentralCrossRefPubMedGoogle Scholar
  46. Hunsaker, M. R., Kim, K. M., Willemsen, R., & Berman, R. F. (2012). CGG Trinucleotide repeat length modulates neural plasticity and spatiotemporal processing in a mouse model of the fragile X premutation. Hippocampus, 22, 2260–2275.PubMedCentralCrossRefPubMedGoogle Scholar
  47. Jacquemont, S., Hagerman, R. J., Leehey, M. A., Hall, D. A., Levine, R. A., Brunberg, J. A., et al. (2004). Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA, 291(4), 460–469.CrossRefPubMedGoogle Scholar
  48. Jerman, T. S., Kesner, R. P., & Hunsaker, M. R. (2006). Disconnection analysis of CA3 and DG in mediating encoding but not retrieval in a spatial maze learning task. Learning and Memory (Hove, England), 13(4), 458–464.CrossRefGoogle Scholar
  49. Karayiorgou, M., Simon, T. J., & Gogos, J. A. (2010). 22q11.2 microdeletions: Linking DNA structural variation to brain dysfunction and schizophrenia. Nature Reviews Neuroscience, 11, 402–416.PubMedCentralCrossRefPubMedGoogle Scholar
  50. Kendler, K. S., & Neale, M. C. (2010). Endophenotype: A conceptual analysis. Molecular Psychiatry, 15, 789–797.PubMedCentralCrossRefPubMedGoogle Scholar
  51. Kesner, R. P., & Hunsaker, M. R. (2010). The temporal attributes of episodic memory. Behavioural Brain Research, 215(2), 299–309.CrossRefPubMedGoogle Scholar
  52. Kesner, R. P., & Rogers, J. R. (2004). An analysis of independence and interactions of brain substrates that subserve multiple attributes, memory systems & underlying processes. Neurobiology of Learning and Memory, 82(3), 199–215.CrossRefPubMedGoogle Scholar
  53. Kesner, R. P., Farnsworth, G., & DiMattia, B. V. (1989). Double dissociation of egocentric and allocentric space following medial prefrontal and parietal cortex lesions in the rat. Behavioral Neuroscience, 103(5), 956–961.CrossRefPubMedGoogle Scholar
  54. Kesner, R. P., Hopkins, R. O., & Fineman, B. (1994). Item and order dissociation in humans with prefrontal cortex damage. Neuropsychologia, 32(8), 881–891.CrossRefPubMedGoogle Scholar
  55. Long, J. M., LaPorte, P., Merscher, S., Funke, B., Saint-Jore, B., Puech, A., et al. (2006). Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. Neurogenetics, 7, 247–257.CrossRefPubMedGoogle Scholar
  56. Llano Lopez, L., Hauser, J., Feldon, J., Gargiulo, P. A., & Yee, B. K. (2010). Evaluating spatial memory function in mice: A within-subjects comparison between the water maze test and its adaptation to dry land. Behavioural Brain Research, 209, 85–92.CrossRefPubMedGoogle Scholar
  57. Manji, H. K., Gottesman, I. I., & Gould, T. D. (2003). Signal transduction and genes-to-behaviors pathways in psychiatric diseases. Science STKE, 2003, pe49.Google Scholar
  58. McClelland, M. M., & Cameron, C. E. (2011). Self-regulation and academic achievement in elementary school children. In R. M. Lerner, J. V. Lerner, E. P. Bowers, S. Lewin-Bizan, S. Gestsdottir, & J. B. Urban (Eds.), Thriving in childhood and adolescence: The role of self-regulation processes. New Directions for Child and Adolescent Development, 133, 29–44.Google Scholar
  59. Nakazawa, K., McHugh, T. J., Wilson, M. A., & Tonegawa, S. (2004). NMDA receptors, place cells and hippocampal spatial memory. Nature Reviews Neuroscience, 5, 361–372.CrossRefPubMedGoogle Scholar
  60. Olton, D. S., Becker, J. T., & Handelmann, G. E. (1979). Hippocampus, space & memory. Brain and Behavioral Science, 2, 313–365.CrossRefGoogle Scholar
  61. Paylor, R., & Lindsay, E. (2006). Mouse models of 22q11 deletion syndrome. Biological Psychiatry, 59, 1172–1179.CrossRefPubMedGoogle Scholar
  62. Pilkonis, P. A., Choi, S. W., Salsman, J. M., Butt, Z., Moore, T. L., Lawrence, S. M., et al. (2012). Assessment of self-reported negative affect in the NIH Toolbox. Psychiatry Research.Google Scholar
  63. Pirogovsky, E., Goldstein, J., Peavy, G., Jacobson, M. W., Corey-Bloom, J., & Gilbert, P. E. (2009). Temporal order memory deficits prior to clinical diagnosis in Huntington’s disease. Journal of the International Neuropsychological Society, 15, 662–670.CrossRefPubMedGoogle Scholar
  64. Quatrano, L. A., & Cruz, T. H. (2011). Future of outcomes measurement: Impact on research in medical rehabilitation and neurologic populations. Archives of Physical Medicine and Rehabilitation, 92(10 Suppl), S7–S11.CrossRefPubMedGoogle Scholar
  65. Rogers, D. C., Fisher, E. M., Brown, S. D., Peters, J., Hunter, A. J., & Martin, J. E. (1997). Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mammalian Genome, 8, 711–713.CrossRefPubMedGoogle Scholar
  66. Rogers, D. C., Jones, D. N., Nelson, P. R., Jones, C. M., Quilter, C. A., Robinson, T. L., & Hagan, J. J. (1999). Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains. Behavioural Brain Research, 105, 207–217.CrossRefPubMedGoogle Scholar
  67. Rogers, D. C., Peters, J., Martin, J. E., Ball, S., Nicholson, S. J., Witherden, A. S., et al. (2001). SHIRPA, a protocol for behavioral assessment: Validation for longitudinal study of neurological dysfunction in mice. Neuroscience Letters, 306, 89–92.CrossRefPubMedGoogle Scholar
  68. Rondi-Reig, L., Petit, G. H., Tobin, C., Tonegawa, S., Mariani, J., & Berthoz, A. (2006). Impaired sequential egocentric and allocentric memories in forebrain-specific NMDA receptor knock-out mice during a new task dissociating strategies of navigation. Journal of Neuroscience, 26(15), 4071–4081.CrossRefPubMedGoogle Scholar
  69. Rupp, J., Blekher, T., Jackson, J., Beristain, X., Marshall, J., Hui, S., et al. (2009). Progression in prediagnostic Huntington disease. Journal of Neurology, Neurosurgery, and Psychiatry, 81(4), 379–384.PubMedCentralCrossRefPubMedGoogle Scholar
  70. Rustay, N. R., Wahlsten, D., & Crabbe, J. C. (2003). Influence of task parameters on rotarod performance and sensitivity to ethanol in mice. Behavioural Brain Research, 141, 237–249.CrossRefPubMedGoogle Scholar
  71. Salomonczyk, D., Panzera, R., Pirogovosky, E., Goldstein, J., Corey-Bloom, J., Simmons, R., & Gilbert, P. E. (2010). Impaired postural stability as a marker of premanifest Huntington’s disease. Movement Disorders, 25(14), 2428–2433.CrossRefPubMedGoogle Scholar
  72. Schluter, E. W., Hunsaker, M. R., Greco, C. M., Willemsen, R., & Berman, R. F. (2012). Distribution and frequency of intranuclear inclusions in female CGG KI mice modeling the fragile X premutation. Brain Research, 1472, 124–137.PubMedCentralCrossRefPubMedGoogle Scholar
  73. Simon, T. J. (2007). Cognitive characteristics of children with genetic syndromes. Child and Adolescent Psychiatric Clinics of North America, 16, 599–616.PubMedCentralCrossRefPubMedGoogle Scholar
  74. Simon, T. J. (2008). A new account of the neurocognitive foundations of impairments in space, time and number processing in children with chromosome 22q11.2 deletion syndrome. Developmental Disabilities Research Reviews, 14, 52–58.PubMedCentralCrossRefPubMedGoogle Scholar
  75. Simon, T. J. (2011). Clues to the foundation of numerical cognitive impairments: Evidence from genetic disorders. Developmental Neuropsychology, 36(6), 788–805.PubMedCentralCrossRefPubMedGoogle Scholar
  76. Spencer, C. M., Alekseyenko, O., Hamilton, S. M., Thomas, A. M., Serysheva, E., Yuva-Paylor, L. A., & Paylor, R. (2011). Modifying behavioral phenotypes in Fmr1 KO mice: Genetic background differences reveal autistic-like responses. Autism Research, 4, 40–56.PubMedCentralCrossRefPubMedGoogle Scholar
  77. Tassone, F., Greco, C. M., Hunsaker, M. R., Berman, R. F., Seritan, A. L., Gane, L. W., et al. (2011). Neuropathological, clinical, and molecular pathology in female fragile X premutation carriers with and without FXTAS. Genes, Brain and Behavior, 11(5), 577–585.CrossRefGoogle Scholar
  78. Taylor, T. N., Greene, J. G., & Miller, G. W. (2010). Behavioral phenotyping of mouse models of Parkinson’s disease. Behavioural Brain Research, 211(1), 1–10.PubMedCentralCrossRefPubMedGoogle Scholar
  79. Van Dam, D., Errijgers, V., Kooy, R. F., Willemsen, R., Mientjes, E., Oostra, B. A., & De Deyn, P. P. (2005). Cognitive decline, neuromotor and behavioural disturbances in a mouse model for fragile-X-associated tremor/ataxia syndrome (FXTAS). Behavioural Brain Research, 162(2), 233–239.CrossRefPubMedGoogle Scholar
  80. Wahlsten, D. (1972). Genetic experiments with animal learning: A critical review. Behavioral Biology, 7, 143–182.CrossRefPubMedGoogle Scholar
  81. Wahlsten, D. (2001). Standardizing tests of mouse behavior: Reasons, recommendations & reality. Physiology and Behavior, 73, 695–704.CrossRefPubMedGoogle Scholar
  82. Wahlsten, D., Metten, P., Phillips, T. J., Boehm, S. L., Burkhart-Kasch, S., Dorow, J., et al. (2003a). Different data from different labs: Lessons from studies of gene-environment interaction. Journal of Neurobiology, 54, 283–311.CrossRefPubMedGoogle Scholar
  83. Wahlsten, D., Rustay, N. R., Metten, P., & Crabbe, J. C. (2003b). In search of a better mouse test. Trends in Neurosciences, 26, 132–136.CrossRefPubMedGoogle Scholar
  84. Wahlsten, D., Metten, P., & Crabbe, J. C. (2003c). Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissure and absent corpus callosum. Brain Research, 971, 47–54.CrossRefPubMedGoogle Scholar
  85. Wahlsten, D., Bachmanov, A., Finn, D. A., & Crabbe, J. C. (2006). Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades. Proceeding of the National Academy of Sciences of the United States of America, 103, 16364–16369.CrossRefGoogle Scholar
  86. Wang, Y. C., Magasi, S. R., Bohannon, R. W., Reuben, D. B., McCreath, H. E., Bubela, D. J., et al. (2011). Assessing dexterity function: A comparison of two alternatives for the NIH Toolbox. Journal of Hand Therapy, 24(4), 313–320.PubMedCentralCrossRefPubMedGoogle Scholar
  87. Wenzel, H. J., Hunsaker, M. R., Greco, C. M., Willemsen, R., & Berman, R. F. (2010). Ubiquitin positive intranuclear inclusions in neuronal and glial cells in a mouse model of the fragile X premutation. Brain Research, 1318, 155–166.PubMedCentralCrossRefPubMedGoogle Scholar
  88. Wesson, D. W., Nixon, R. A., Levy, E., & Wilson, D. A. (2011). Mechanisms of neural and behavioral dysfunction in Alzheimer’s disease. Molecular Neurobiology, 43(3), 163–179.PubMedCentralCrossRefPubMedGoogle Scholar
  89. Weiser, M., Van Os, J., & Davidson, M. (2005). Time for a shift in focus in schizophrenia: From narrow phenotypes to broad endophenotypes. The British Journal of Psychiatry, 187, 203–205.CrossRefPubMedGoogle Scholar
  90. Whishaw, I. Q., & Tomie, J. (1996). Of mice and mazes: Similarities between mice and rats on dry land but not water mazes. Physiology and Behavior, 60(5), 1191–1197.CrossRefPubMedGoogle Scholar
  91. White, N. M., & McDonald, R. J. (2002). Multiple parallel memory systems in the brain of the rat. Neurobiology of Learning and Memory, 77(2), 125–184.CrossRefPubMedGoogle Scholar
  92. Wong, L. M., Goodrich-Hunsaker, N. J., McLennan, Y. A., Tassone, F., Harvey, D., Rivera, S. M., & Simon, T. J. (2012). Young adult male carriers of the Fragile X premutation exhibit genetically modulated impairments in visuospatial tasks controlled for psychomotor speed. Journal of Neurodevelopmental Disorders, 4(1), 26.PubMedCentralCrossRefPubMedGoogle Scholar
  93. Xu, B., Karayiorgou, M., & Gogos, J. A. (2010). microRNAs in psychiatric and neurodevelopmental disorders. Brain Research, 1338, 78–88.CrossRefPubMedGoogle Scholar
  94. Yan, Q. J., Asafo-Adjei, P. K., Arnold, H. M., Brown, R. E., & Bauchwitz, R. P. (2004). A phenotypic and molecular characterization of the Fmr1-tm1Cgr fragile X mouse. Genes, Brain, and Behavior, 3, 337–359.CrossRefPubMedGoogle Scholar
  95. Yong-Kee, C. J., Salomonczyk, D., & Nash, J. E. (2010). Development and validation of a screening assay for the evaluation of putative neuroprotective agents in the treatment of Parkinson’s disease. Neurotoxicity Research, 19(4), 519–526.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Center for Integrative Neuroscience and Human BehaviorUniversity of UtahSalt Lake CityUSA
  2. 2.Department of Neurological SurgeryUniversity of California, DavisDavisUSA
  3. 3.Granite School DistrictSalt Lake CityUSA

Personalised recommendations