Cognitive, Affective, & Behavioral Neuroscience

, Volume 14, Issue 3, pp 996–1008 | Cite as

Environmental enrichment eliminates the anxiety phenotypes in a triple transgenic mouse model of Alzheimer’s disease

  • Susanna PietropaoloEmail author
  • Joram Feldon
  • Benjamin K. YeeEmail author


Although the impacts of environmental enrichment (EE) in several genetic models of Alzheimer’s disease (AD) have been documented, the focus has remained predominantly on cognition. Few have investigated the expression of emotional phenotypes that mimic the notable affective features in AD. Here, we studied the interaction between EE and the coexpression of three genetic risk factors (mutations) for AD. In a longitudinal design, 3×Tg-AD mutants and wild type controls were compared at 6–7 months and subsequently at 12–13 months of age. Under standard housing, phenotypes of heightened anxiety levels were identified in the 3×Tg-AD mice in the elevated plus maze and open-field tests. Such trait differences between genotypes were substantially diminished under EE housing, which was attributable to the anxiolytic impact of EE on the mutant mice as much as the anxiogenic impact of EE on the wild type mice. In contrast, the phenotypes in learned fear were not significantly modified by EE in the tests of Pavlovian freezing and conditioned active avoidance conducted at either age. Rearing under EE thus has uncovered a novel distinction between innate and acquired expressions of fear response in the 3×Tg-AD mouse model that might be relevant to the mental health management of AD.


Animal models Anxiety Emotion 


Author note

The present study was supported by the Swiss National Science Foundation (Grant No. NSF 3100A0-100309), ETH Zurich, and the National Centre for Competence in Research (NCCR): Neural Plasticity and Repair. Frank M. Laferla (University of California, Irvine, USA) kindly provided us with breeders of the 3×Tg-AD line for generating the experimental subjects used in this study. The authors also thank the ETH animal husbandry staff and Frank Bootz for his veterinary supervision.


  1. Aalten, P., de Vugt, M. E., Lousberg, R., Korten, E., Jaspers, N., Senden, B., & Verhey, F. R. (2003). Behavioral problems in dementia: A factor analysis of the neuropsychiatric inventory. Dementia and Geriatric Cognitive Disorders, 15, 99–105.PubMedCrossRefGoogle Scholar
  2. Abramov, U., Puussaar, T., Raud, S., Kurrikoff, K., & Vasar, E. (2008). Behavioural differences between C57BL/6 and 129S6/SvEv strains are reinforced by environmental enrichment. Neuroscience Letters, 443, 223–227.PubMedCrossRefGoogle Scholar
  3. Akillioglu, K., Babar Melik, E., Melik, E., & Kocahan, S. (2012). The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice. Pharmacology Biochemistry and Behavior, 102, 407–414.CrossRefGoogle Scholar
  4. Almeida, S. S., Garcia, R. A., & de Oliveira, L. M. (1993). Effects of early protein malnutrition and repeated testing upon locomotor and exploratory behaviors in the elevated plus-maze. Physiology & Behavior, 54, 749–752.CrossRefGoogle Scholar
  5. Andel, R., Crowe, M., Pedersen, N. L., Mortimer, J., Crimmins, E., Johansson, B., & Gatz, M. (2005). Complexity of work and risk of Alzheimer’s disease: A population-based study of Swedish twins. Journals of Gerontology B, 60, 251–258.CrossRefGoogle Scholar
  6. Billings, L. M., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2007). Learning decreases A beta*56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice. Journal of Neuroscience, 27, 751–761.PubMedCrossRefGoogle Scholar
  7. Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2005). Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron, 45, 675–688.PubMedCrossRefGoogle Scholar
  8. Bishop, S. J. (2007). Neurocognitive mechanisms of anxiety: An integrative account. Trends in Cognitive Sciences, 11, 307–316.PubMedCrossRefGoogle Scholar
  9. Brown, J., Cooper-Kuhn, C. M., Kempermann, G., Van Praag, H., Winkler, J., Gage, F. H., & Kuhn, H. G. (2003). Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. European Journal of Neuroscience, 17, 2042–2046.PubMedCrossRefGoogle Scholar
  10. Butler, S. M., Ashford, J. W., & Snowdon, D. A. (1996). Age, education, and changes in the Mini-Mental State Exam scores of older women: Findings from the Nun Study. Journal of the American Geriatric Society, 44, 675–681.Google Scholar
  11. Chapillon, P., Manneche, C., Belzung, C., & Caston, J. (1999). Rearing environmental enrichment in two inbred strains of mice: 1. Effects on emotional reactivity. Behavioral Genetics, 29, 41–46.CrossRefGoogle Scholar
  12. Chapillon, P., Patin, V., Roy, V., Vincent, A., & Caston, J. (2002). Effects of pre- and postnatal stimulation on developmental, emotional, and cognitive aspects in rodents: A review. Developmental Psychobiology, 41, 373–387.PubMedCrossRefGoogle Scholar
  13. Connor, B., Young, D., Yan, Q., Faull, R. L., Synek, B., & Dragunow, M. (1997). Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Molecular Brain Research, 49, 71–81.PubMedCrossRefGoogle Scholar
  14. Corona, C., Masciopinto, F., Silvestri, E., Viscovo, A. D., Lattanzio, R., Sorda, R. L., & Sensi, S. L. (2010). Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction. Cell Death & Disease, 1, e91.CrossRefGoogle Scholar
  15. Crowe, M., Andel, R., Pedersen, N. L., Johansson, B., & Gatz, M. (2003). Does participation in leisure activities lead to reduced risk of Alzheimer’s disease? A prospective study of Swedish twins. Journals of Gerontology B, 58, 249–255.CrossRefGoogle Scholar
  16. Davis, K. E., Easton, A., Eacott, M. J., & Gigg, J. (2013). Episodic-like memory for what–where–which occasion is selectively impaired in the 3xTgAD mouse model of Alzheimer’s disease. Journal of Alzheimer's Disease, 33, 681–698.PubMedGoogle Scholar
  17. Diamond, M. C. (2001). Response of the brain to enrichment. Anais da Academia Brasileira de Ciências, 73, 211–220.PubMedCrossRefGoogle Scholar
  18. Donovick, P. J., Burright, R. G., Fuller, J. L., & Branson, P. R. (1975). Septal lesions and behavior: Effects of presurgical rearing and strain of mouse. Journal of Comparative and Physiological Psychology, 89, 859–867.PubMedCrossRefGoogle Scholar
  19. Espana, J., Gimenez-Llort, L., Valero, J., Minano, A., Rabano, A., Rodriguez-Alvarez, J., & Saura, C. A. (2010). Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice. Biological Psychiatry, 67, 513–521.PubMedCrossRefGoogle Scholar
  20. Fleming, K., Kim, S. H., Doo, M., Maguire, G., & Potkin, S. G. (2003). Memory for emotional stimuli in patients with Alzheimer’s disease. American Journal of Alzheimer's Disease and Other Dementias, 18, 340–342.PubMedCrossRefGoogle Scholar
  21. Frisoni, G. B., Rozzini, L., Gozzetti, A., Binetti, G., Zanetti, O., Bianchetti, A., & Cummings, J. L. (1999). Behavioral syndromes in Alzheimer’s disease: Description and correlates. Dementia and Geriatric Cognitive Disorders, 10, 130–138.PubMedCrossRefGoogle Scholar
  22. Garcia-Mesa, Y., Gimenez-Llort, L., Lopez, L. C., Venegas, C., Cristofol, R., Escames, G., & Sanfeliu, C. (2012). Melatonin plus physical exercise are highly neuroprotective in the 3xTg-AD mouse. Neurobiology of Aging, 33(1124), e1113–1129.Google Scholar
  23. Garcia-Mesa, Y., Lopez-Ramos, J. C., Gimenez-Llort, L., Revilla, S., Guerra, R., Gruart, A., & Sanfeliu, C. (2011). Physical exercise protects against Alzheimer’s disease in 3xTg-AD mice. Journal of Alzheimer's Disease, 24, 421–454.PubMedGoogle Scholar
  24. Gimenez-Llort, L., Blazquez, G., Canete, T., Johansson, B., Oddo, S., Tobena, A., & Fernandez-Teruel, A. (2007). Modeling behavioral and neuronal symptoms of Alzheimer’s disease in mice: A role for intraneuronal amyloid. Neuroscience & Biobehavioral Reviews, 31, 125–147.CrossRefGoogle Scholar
  25. Gotz, J., Streffer, J. R., David, D., Schild, A., Hoerndli, F., Pennanen, L., & Chen, F. (2004). Transgenic animal models of Alzheimer’s disease and related disorders: Histopathology, behavior and therapy. Molecular Psychiatry, 9, 664–683.PubMedGoogle Scholar
  26. Gray, J. A., & McNaughton, N. (1983). Comparison between the behavioural effects of septal and hippocampal lesions: A review. Neuroscience & Biobehavioral Reviews, 7, 119–188.CrossRefGoogle Scholar
  27. Haemisch, A., & Gartner, K. (1994). The cage design affects intermale aggression in small groups of male laboratory mice: Strain specific consequences on social organization, and endocrine activations in two inbred strains (DBA/2J and CBA/J). Journal of Experimental Animal Science, 36, 101–116.PubMedGoogle Scholar
  28. Haemisch, A., Voss, T., & Gartner, K. (1994). Effects of environmental enrichment on aggressive behavior, dominance hierarchies, and endocrine states in male DBA/2J mice. Physiology & Behavior, 56, 1041–1048.CrossRefGoogle Scholar
  29. Hebb, D. (1947). The effects of early experience on problem solving at maturity. American Psychologist, 2, 306–307.Google Scholar
  30. Hirata-Fukae, C., Li, H. F., Hoe, H. S., Gray, A. J., Minami, S. S., Hamada, K., & Matsuoka, Y. (2008). Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Research, 1216, 92–103.PubMedCrossRefGoogle Scholar
  31. Hope, T., Keene, J., Fairburn, C., McShane, R., & Jacoby, R. (1997). Behaviour changes in dementia. 2: Are there behavioural syndromes? International Journal of Geriatric Psychiatry, 12, 1074–1078.PubMedCrossRefGoogle Scholar
  32. Janus, C., & Westaway, D. (2001). Transgenic mouse models of Alzheimer’s disease. Physiology & Behavior, 73, 873–886.CrossRefGoogle Scholar
  33. Katzman, R. (1993). Education and the prevalence of dementia and Alzheimer’s disease. Neurology, 43, 13–20.PubMedCrossRefGoogle Scholar
  34. Kohl, Z., Kuhn, H. G., Cooper-Kuhn, C. M., Winkler, J., Aigner, L., & Kempermann, G. (2002). Preweaning enrichment has no lasting effects on adult hippocampal neurogenesis in four-month-old mice. Genes, Brain and Behavior, 1, 46–54.CrossRefGoogle Scholar
  35. LaFerla, F. M., Green, K. N., & Oddo, S. (2007). Intracellular amyloid-beta in Alzheimer’s disease. Nature Reviews Neuroscience, 8, 499–509.PubMedCrossRefGoogle Scholar
  36. Lawlor, B., & Bhriain, S. N. (2001). Psychosis and behavioural symptoms of dementia: Defining the role of neuroleptic interventions. International Journal of Geriatric Psychiatry, 16, S2–S6.PubMedCrossRefGoogle Scholar
  37. Marchese, M., Cowan, D., Head, E., Ma, D., Karimi, K., Ashthorpe, V., & Sakic, B. (2014). Autoimmune manifestations in the 3xTg-AD model of Alzheimer’s disease. Journal of Alzheimer's Disease, 39, 191–210. doi: 10.3233/JAD-131490 PubMedGoogle Scholar
  38. McNaughton, N., & Gray, J. A. (2000). Anxiolytic action on the behavioural inhibition system implies multiple types of arousal contribute to anxiety. Journal of Affective Disorders, 61, 161–176.PubMedCrossRefGoogle Scholar
  39. Mortimer, J. A., Borenstein, A. R., Gosche, K. M., & Snowdon, D. A. (2005). Very early detection of Alzheimer neuropathology and the role of brain reserve in modifying its clinical expression. Journal of Geriatric Psychiatry and Neurology, 18, 218–223.PubMedCentralPubMedCrossRefGoogle Scholar
  40. Nithianantharajah, J., & Hannan, A. J. (2009). The neurobiology of brain and cognitive reserve: Mental and physical activity as modulators of brain disorders. Progress in Neurobiology, 89, 369–382.PubMedCrossRefGoogle Scholar
  41. Nithianantharajah, J., & Hannan, A. J. (2011). Mechanisms mediating brain and cognitive reserve: Experience-dependent neuroprotection and functional compensation in animal models of neurodegenerative diseases. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 35, 331–339.CrossRefGoogle Scholar
  42. Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., & LaFerla, F. M. (2004). Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron, 43, 321–332.PubMedCrossRefGoogle Scholar
  43. Oddo, S., Caccamo, A., Cheng, D., Jouleh, B., Torp, R., & LaFerla, F. M. (2007). Genetically augmenting tau levels does not modulate the onset or progression of Abeta pathology in transgenic mice. Journal of Neurochemistry, 102, 1053–1063. doi: 10.1111/j.1471-4159.2007.04607.x PubMedCrossRefGoogle Scholar
  44. Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., & LaFerla, F. M. (2003). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron, 39, 409–421.PubMedCrossRefGoogle Scholar
  45. Palleschi, L., Vetta, F., De Gennaro, E., Idone, G., Sottosanti, G., & Gianni, W. (1996). Effect of aerobic training on the cognitive performance of elderly patients with senile dementia of Alzheimer type. Archives of Gerontology and Geriatrics, 5, 47–50.CrossRefGoogle Scholar
  46. Peng, S., Wuu, J., Mufson, E. J., & Fahnestock, M. (2005). Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. Journal of Neurochemistry, 93, 1412–1421. doi: 10.1111/j.1471-4159.2005.03135.x PubMedCrossRefGoogle Scholar
  47. Phillips, H. S., Hains, J. M., Armanini, M., Laramee, G. R., Johnson, S. A., & Winslow, J. W. (1991). BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron, 7, 695–702.PubMedCrossRefGoogle Scholar
  48. Pietropaolo, S., Branchi, I., Cirulli, F., Chiarotti, F., Aloe, L., & Alleva, E. (2004). Long-term effects of the periadolescent environment on exploratory activity and aggressive behaviour in mice: Social versus physical enrichment. Physiology & Behavior, 81, 443–453.CrossRefGoogle Scholar
  49. Pietropaolo, S., Feldon, J., Alleva, E., Cirulli, F., & Yee, B. K. (2006). The role of voluntary exercise in enriched rearing: A behavioral analysis. Behavioral Neuroscience, 120, 787–803.PubMedCrossRefGoogle Scholar
  50. Pietropaolo, S., Feldon, J., & Yee, B. K. (2008a). Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease. Behavioral Neuroscience, 122, 733–747.PubMedCrossRefGoogle Scholar
  51. Pietropaolo, S., Sun, Y., Li, R., Brana, C., Feldon, J., & Yee, B. K. (2008b). The impact of voluntary exercise on mental health in rodents: A neuroplasticity perspective. Behavioural Brain Research, 192, 42–60.PubMedCrossRefGoogle Scholar
  52. Pietropaolo, S., Sun, Y., Li, R., Brana, C., Feldon, J., & Yee, B. K. (2009). Limited impact of social isolation on Alzheimer-like symptoms in a triple transgenic mouse model. Behavioral Neuroscience, 123, 181–195.PubMedCrossRefGoogle Scholar
  53. Pigliucci, M. (2001). Phenotypic plasticity: Beyond nature and nurture. Baltimore: Johns Hopkins University Press.Google Scholar
  54. Prut, L., & Belzung, C. (2003). The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. European Journal of Pharmacology, 463, 3–33.PubMedCrossRefGoogle Scholar
  55. Renner, M. J., & Rosenzweig, M. R. (1987). Enriched and impoverished environments. New York: Springer.CrossRefGoogle Scholar
  56. Rhodes, J. S., van Praag, H., Jeffrey, S., Girard, I., Mitchell, G. S., Garland, T., Jr., & Gage, F. H. (2003). Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behavioral Neuroscience, 117, 1006–1016.PubMedCrossRefGoogle Scholar
  57. Richmond, M. A., Murphy, C. A., Pouzet, B., Schmid, P., Rawlins, J. N., & Feldon, J. (1998). A computer controlled analysis of freezing behaviour. Journal of Neuroscience Methods, 86, 91–99.PubMedCrossRefGoogle Scholar
  58. Rosenberg, R. N. (2000). The molecular and genetic basis of AD: The end of the beginning. The. (2000). Wartenberg lecture. Neurology, 54, 2045–2054.CrossRefGoogle Scholar
  59. Rosenzweig, M. R., & Bennett, E. L. (1996). Psychobiology of plasticity: Effects of training and experience on brain and behavior. Behavioural Brain Research, 78, 57–65.PubMedCrossRefGoogle Scholar
  60. Rovio, S., Kareholt, I., Helkala, E. L., Viitanen, M., Winblad, B., Tuomilehto, J., & Kivipelto, M. (2005). Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurology, 4, 705–711.PubMedCrossRefGoogle Scholar
  61. Roy, V., Belzung, C., Delarue, C., & Chapillon, P. (2001). Environmental enrichment in BALB/c mice: Effects in classical tests of anxiety and exposure to a predatory odor. Physiology & Behavior, 74, 313–320.CrossRefGoogle Scholar
  62. Spalletta, G., Baldinetti, F., Buccione, I., Fadda, L., Perri, R., Scalmana, S., & Caltagirone, C. (2004). Cognition and behaviour are independent and heterogeneous dimensions in Alzheimer’s disease. Journal of Neurology, 251, 688–695.PubMedCrossRefGoogle Scholar
  63. Sterniczuk, R., Antle, M. C., LaFerla, F. M., & Dyck, R. H. (2010). Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes. Brain Research, 1348, 149–155.PubMedCrossRefGoogle Scholar
  64. van de Weerd, H. A., Baumans, V., Koolhaas, J. M., & van Zutphen, L. F. (1994). Strain specific behavioural response to environmental enrichment in the mouse. Journal of Experimental Animal Science, 36, 117–127.PubMedGoogle Scholar
  65. van Praag, H., Kempermann, G., & Gage, F. H. (2000). Neural consequences of environmental enrichment. Nature Reviews Neuroscience, 1, 191–198.PubMedCrossRefGoogle Scholar
  66. Vespa, A., Gori, G., & Spazzafumo, L. (2002). Evaluation of non-pharmacological intervention on antisocial behavior in patients suffering from Alzheimer’s disease in a day care center. Archives of Gerontology and Geriatrics, 34, 1–8.PubMedCrossRefGoogle Scholar
  67. Waddington, C. H. (1957). The strategy of the genes. London: George Allen & Unwin.Google Scholar
  68. Will, B., Galani, R., Kelche, C., & Rosenzweig, M. R. (2004). Recovery from brain injury in animals: Relative efficacy of environmental enrichment, physical exercise or formal training (1990–2002). Progress in Neurobiology, 72, 167–182.PubMedCrossRefGoogle Scholar
  69. Wilson, R. S., Bennett, D. A., Bienias, J. L., Aggarwal, N. T., Mendes De Leon, C. F., Morris, M. C., & Evans, D. A. (2002). Cognitive activity and incident AD in a population-based sample of older persons. Neurology, 59, 1910–1914.PubMedCrossRefGoogle Scholar
  70. Yee, B. K., Zhu, S. W., Mohammed, A. H., & Feldon, J. (2007). Levels of neurotrophic factors in the hippocampus and amygdala correlate with anxiety- and fear-related behaviour in C57BL6 mice. Journal of Neural Transmission, 114, 431–444.PubMedCrossRefGoogle Scholar
  71. Zhu, S. W., Yee, B. K., Nyffeler, M., Winblad, B., Feldon, J., & Mohammed, A. H. (2006). Influence of differential housing on emotional behaviour and neurotrophin levels in mice. Behavioural Brain Research, 169, 10–20.PubMedCrossRefGoogle Scholar
  72. Zorrilla, E. P. (1997). Multiparous species present problems (and possibilities) to developmentalists. Developmental Psychobiology, 30, 141–150.PubMedCrossRefGoogle Scholar

Copyright information

© Psychonomic Society, Inc. 2014

Authors and Affiliations

  1. 1.Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology ZurichSchwerzenbachSwitzerland
  2. 2.Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS UMR5287Talence CedexFrance
  3. 3.Legacy Research InstitutePortlandOregon

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