Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Enriched environments, experience-dependent plasticity and disorders of the nervous system

Key Points

  • Environmental enrichment has been shown to have various effects on wild-type mice and rats, from behavioural to cellular and molecular alterations. There is no consensus on which environmental enrichment paradigms are ideal with respect to beneficial effects on brain and behaviour. However, key aspects seem to be environmental complexity, novelty and the age at which enrichment commences, as well as the duration of exposure to enriched environments.

  • Genetic and pharmacological parameters that modulate brain function and dysfunction have been explored in detail, but environmental parameters have received far less attention. The large number of uncontrolled variables that impinge on human epidemiological studies, which limits their ability to demonstrate the involvement of specific environmental factors in particular brain disorders, has meant that animal models have proved crucial in exploring gene–environment interactions.

  • During the last decade, enrichment studies using mouse models of Huntington's disease and Alzheimer's disease have opened the way for the exploration of gene–environment interactions in neurodegeneration. In a transgenic mouse model of Huntington's disease, environmental enrichment has been shown to delay the onset and progression of motor symptoms.

  • Using transgenic models of Alzheimer's disease, studies have also shown that enrichment can enhance learning and memory. However, there are contradictory results regarding its effects on amyloid levels.

  • Effects of environmental enrichment have also recently been identified in other brain disorders such as Parkinson's disease, amyotrophic lateral sclerosis, fragile X syndrome, Down syndrome and various other forms of brain injury. Although enrichment experiments could provide novel insights into each disorder, common effects across disorders point towards general mechanisms of experience-dependent plasticity.

  • Studies on the effect of environmental factors, such as enrichment, on a wide range of CNS disorders have implications for clinical occupational therapies and related approaches. In addition, these environmental manipulations can provide powerful tools to dissect cause and effect among molecular and cellular correlates of pathogenesis, and so identify novel targets for the future development of therapeutics.

Abstract

Behavioural, cellular and molecular studies have revealed significant effects of enriched environments on rodents and other species, and provided new insights into mechanisms of experience-dependent plasticity, including adult neurogenesis and synaptic plasticity. The demonstration that the onset and progression of Huntington's disease in transgenic mice is delayed by environmental enrichment has emphasized the importance of understanding both genetic and environmental factors in nervous system disorders, including those with Mendelian inheritance patterns. A range of rodent models of other brain disorders, including Alzheimer's disease and Parkinson's disease, fragile X and Down syndrome, as well as various forms of brain injury, have now been compared under enriched and standard housing conditions. Here, we review these findings on the environmental modulators of pathogenesis and gene–environment interactions in CNS disorders, and discuss their therapeutic implications.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Environmental enrichment and the effects of enhanced sensory, cognitive and motor stimulation on different brain areas.
Figure 2: Gene–environment interactions in Huntington's disease.
Figure 3: Gene–environment interactions in Alzheimer's disease.
Figure 4: Molecular mediators, environmental modulators and pharmacological modulators (enviromimetics).

References

  1. Mayeux, R. Epidemiology of neurodegeneration. Annu. Rev. Neurosci. 26, 81–104 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. van Dellen, A., Blakemore, C., Deacon, R., York, D. & Hannan, A. J. Delaying the onset of Huntington's in mice. Nature 404, 721–722 (2000). The first evidence that environmental enrichment can delay the onset of disease symptoms in a genetic model of a nervous system disorder.

    Article  CAS  PubMed  Google Scholar 

  3. Hockly, E. et al. Environmental enrichment slows disease progression in R6/2 Huntington's disease mice. Ann. Neurol. 51, 235–242 (2002).

    Article  PubMed  Google Scholar 

  4. Spires, T. L. et al. Environmental enrichment rescues protein deficits in a mouse model of Huntington's disease, indicating a possible disease mechanism. J. Neurosci. 24, 2270–2276 (2004). Showed that HD-induced downregulation of BDNF and DARPP-32 protein levels is ameliorated by enrichment, suggesting potential therapeutic targets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Arendash, G. W. et al. Environmental enrichment improves cognition in aged Alzheimer's transgenic mice despite stable β-amyloid deposition. Neuroreport 15, 1751–1754 (2004).

    Article  PubMed  Google Scholar 

  6. Jankowsky, J. L., Xu, G., Fromholt, D., Gonzales, V. & Borchelt, D. R. Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J. Neuropathol. Exp. Neurol. 62, 1220–1227 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Jankowsky, J. L. et al. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. J. Neurosci. 25, 5217–5224 (2005). Evidence that enrichment increases expression of neuritic plaques and Aβ levels, but also rescues a deficit in spatial memory.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lazarov, O. et al. Environmental enrichment reduces Aβ levels and amyloid deposition in transgenic mice. Cell 120, 701–713 (2005). Showed that enrichment results in decreased Aβ levels and amyloid deposits, in addition to increased activity of the Aβ-degrading protease neprilysin.

    Article  CAS  PubMed  Google Scholar 

  9. van Praag, H., Kempermann, G. & Gage, F. H. Neural consequences of environmental enrichment. Nature Rev. Neurosci. 1, 191–198 (2000). A comprehensive review on the known effects of environmental enrichment on the wild-type rodent brain.

    Article  CAS  Google Scholar 

  10. Hebb, D. O. The effects of early experience on problem-solving at maturity. Am. Psychol. 2, 306–307 (1947).

    Google Scholar 

  11. Bennett, E. L., Rosenzweig, M. R. & Diamond, M. C. Rat brain: effects of environmental enrichment on wet and dry weights. Science 163, 825–826 (1969).

    Article  CAS  PubMed  Google Scholar 

  12. Diamond, M. C., Ingham, C. A., Johnson, R. E., Bennett, E. L. & Rosenzweig, M. R. Effects of environment on morphology of rat cerebral cortex and hippocampus. J. Neurobiol. 7, 75–85 (1976).

    Article  CAS  PubMed  Google Scholar 

  13. Diamond, M. C., Rosenzweig, M. R., Bennett, E. L., Lindner, B. & Lyon, L. Effects of environmental enrichment and impoverishment on rat cerebral cortex. J. Neurobiol. 3, 47–64 (1972).

    Article  CAS  PubMed  Google Scholar 

  14. Greenough, W. T. & Volkmar, F. R. Pattern of dendritic branching in occipital cortex of rats reared in complex environments. Exp. Neurol. 40, 491–504 (1973).

    Article  CAS  PubMed  Google Scholar 

  15. Greenough, W. T., Volkmar, F. R. & Juraska, J. M. Effects of rearing complexity on dendritic branching in frontolateral and temporal cortex of the rat. Exp. Neurol. 41, 371–378 (1973).

    Article  CAS  PubMed  Google Scholar 

  16. Greenough, W. T., Hwang, H. M. & Gorman, C. Evidence for active synapse formation or altered postsynaptic metabolism in visual cortex of rats reared in complex environments. Proc. Natl Acad. Sci. USA 82, 4549–4552 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Connor, J. R., Wang, E. C. & Diamond, M. C. Increased length of terminal dendritic segments in old adult rats' somatosensory cortex: an environmentally induced response. Exp. Neurol. 78, 466–470 (1982).

    Article  CAS  PubMed  Google Scholar 

  18. Turner, A. M. & Greenough, W. T. Differential rearing effects on rat visual cortex synapses. I. Synaptic and neuronal density and synapses per neuron. Brain Res. 329, 195–203 (1985).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Faherty, C. J., Kerley, D. & Smeyne, R. J. A Golgi-Cox morphological analysis of neuronal changes induced by environmental enrichment. Brain Res. Dev. Brain Res. 141, 55–61 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Leggio, M. G. et al. Environmental enrichment promotes improved spatial abilities and enhanced dendritic growth in the rat. Behav. Brain Res. 163, 78–90 (2005).

    Article  PubMed  Google Scholar 

  22. Kempermann, G., Kuhn, H. G. & Gage, F. H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Kempermann, G., Kuhn, H. G. & Gage, F. H. Experience-induced neurogenesis in the senescent dentate gyrus. J. Neurosci. 18, 3206–3212 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kempermann, G., Brandon, E. P. & Gage, F. H. Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Curr. Biol. 8, 939–942 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Kempermann, G., Gast, D. & Gage, F. H. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann. Neurol. 52, 135–143 (2002).

    Article  PubMed  Google Scholar 

  26. Bruel-Jungerman, E., Laroche, S. & Rampon, C. New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur. J. Neurosci. 21, 513–521 (2005).

    Article  PubMed  Google Scholar 

  27. During, M. J. & Cao, L. VEGF, a mediator of the effect of experience on hippocampal neurogenesis. Curr. Alzheimer Res. 3, 29–33 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neurosci. 9, 268–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Rampon, C. et al. Effects of environmental enrichment on gene expression in the brain. Proc. Natl Acad. Sci. USA 97, 12880–12884 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Torasdotter, M., Metsis, M., Henriksson, B. G., Winblad, B. & Mohammed, A. H. Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus. Behav. Brain Res. 93, 83–90 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Pham, T. M. et al. Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year. Neuroscience 94, 279–286 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Ickes, B. R. et al. Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp. Neurol. 164, 45–52 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Frick, K. M. & Fernandez, S. M. Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiol. Aging 24, 615–626 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Nithianantharajah, J., Levis, H. & Murphy, M. Environmental enrichment results in cortical and subcortical changes in levels of synaptophysin and PSD-95 proteins. Neurobiol. Learn. Mem. 81, 200–210 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Lambert, T. J., Fernandez, S. M. & Frick, K. M. Different types of environmental enrichment have discrepant effects on spatial memory and synaptophysin levels in female mice. Neurobiol. Learn. Mem. 83, 206–216 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Tang, Y. P., Wang, H., Feng, R., Kyin, M. & Tsien, J. Z. Differential effects of enrichment on learning and memory function in NR2B transgenic mice. Neuropharmacology 41, 779–790 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Naka, F., Narita, N., Okado, N. & Narita, M. Modification of AMPA receptor properties following environmental enrichment. Brain Dev. 27, 275–278 (2005).

    Article  PubMed  Google Scholar 

  38. Green, E. J. & Greenough, W. T. Altered synaptic transmission in dentate gyrus of rats reared in complex environments: evidence from hippocampal slices maintained in vitro. J. Neurophysiol. 55, 739–750 (1986).

    Article  CAS  PubMed  Google Scholar 

  39. Foster, T. C., Gagne, J. & Massicotte, G. Mechanism of altered synaptic strength due to experience: relation to long-term potentiation. Brain Res. 736, 243–250 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Foster, T. C. & Dumas, T. C. Mechanism for increased hippocampal synaptic strength following differential experience. J. Neurophysiol. 85, 1377–1383 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Duffy, S. N., Craddock, K. J., Abel, T. & Nguyen, P. V. Environmental enrichment modifies the PKA-dependence of hippocampal LTP and improves hippocampus-dependent memory. Learn. Mem. 8, 26–34 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Artola, A. et al. Long-lasting modulation of the induction of LTD and LTP in rat hippocampal CA1 by behavioural stress and environmental enrichment. Eur. J. Neurosci. 23, 261–272 (2006).

    Article  PubMed  Google Scholar 

  43. Moser, M. B., Trommald, M., Egeland, T. & Andersen, P. Spatial training in a complex environment and isolation alter the spine distribution differently in rat CA1 pyramidal cells. J. Comp. Neurol. 380, 373–381 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Schrijver, N. C., Bahr, N. I., Weiss, I. C. & Wurbel, H. Dissociable effects of isolation rearing and environmental enrichment on exploration, spatial learning and HPA activity in adult rats. Pharmacol. Biochem. Behav. 73, 209–224 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Lee, E. H., Hsu, W. L., Ma, Y. L., Lee, P. J. & Chao, C. C. Enrichment enhances the expression of sgk, a glucocorticoid-induced gene, and facilitates spatial learning through glutamate AMPA receptor mediation. Eur. J. Neurosci. 18, 2842–2852 (2003).

    Article  PubMed  Google Scholar 

  46. Bennett, J. C., McRae, P. A., Levy, L. J. & Frick, K. M. Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice. Neurobiol. Learn. Mem. 85, 139–152 (2006).

    Article  PubMed  Google Scholar 

  47. Chapillon, P., Manneche, C., Belzung, C. & Caston, J. Rearing environmental enrichment in two inbred strains of mice: 1. Effects on emotional reactivity. Behav. Genet. 29, 41–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Roy, V., Belzung, C., Delarue, C. & Chapillon, P. Environmental enrichment in BALB/c mice: effects in classical tests of anxiety and exposure to a predatory odor. Physiol. Behav. 74, 313–320 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Benaroya-Milshtein, N. et al. Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. Eur. J. Neurosci. 20, 1341–1347 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Friske, J. E. & Gammie, S. C. Environmental enrichment alters plus maze, but not maternal defense performance in mice. Physiol. Behav. 85, 187–194 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Meshi, D. et al. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nature Neurosci. 9, 729–731 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Wolfer, D. P. et al. Laboratory animal welfare: cage enrichment and mouse behaviour. Nature 432, 821–822 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Neeper, S. A., Gomez-Pinilla, F., Choi, J. & Cotman, C. Exercise and brain neurotrophins. Nature 373, 109 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Tong, L., Shen, H., Perreau, V. M., Balazs, R. & Cotman, C. W. Effects of exercise on gene-expression profile in the rat hippocampus. Neurobiol. Dis. 8, 1046–1056 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Farmer, J. et al. Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience 124, 71–79 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Black, J. E., Isaacs, K. R., Anderson, B. J., Alcantara, A. A. & Greenough, W. T. Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc. Natl Acad. Sci. USA 87, 5568–5572 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Isaacs, K. R., Anderson, B. J., Alcantara, A. A., Black, J. E. & Greenough, W. T. Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning. J. Cereb. Blood Flow Metab. 12, 110–119 (1992).

    Article  CAS  PubMed  Google Scholar 

  58. Swain, R. A. et al. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 117, 1037–1046 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. van Praag, H., Kempermann, G. & Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2, 266–270 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Ehninger, D. & Kempermann, G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb. Cortex 13, 845–851 (2003).

    Article  PubMed  Google Scholar 

  61. Albeck, D. S., Sano, K., Prewitt, G. E. & Dalton, L. Mild forced treadmill exercise enhances spatial learning in the aged rat. Behav. Brain Res. 168, 345–348 (2006).

    Article  PubMed  Google Scholar 

  62. Bick-Sander, A., Steiner, B., Wolf, S. A., Babu, H. & Kempermann, G. Running in pregnancy transiently increases postnatal hippocampal neurogenesis in the offspring. Proc. Natl Acad. Sci. USA 103, 3852–3857 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

  64. Gatchel, J. R. & Zoghbi, H. Y. Diseases of unstable repeat expansion: mechanisms and common principles. Nature Rev. Genet. 6, 743–755 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. van Dellen, A. & Hannan, A. J. Genetic and environmental factors in the pathogenesis of Huntington's disease. Neurogenetics 5, 9–17 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. Turmaine, M. et al. Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease. Proc. Natl Acad. Sci. USA 97, 8093–8097 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nithianantharajah, J., Howard, M. L., Murphy, M. & Hannan, A. J. Environmental enrichment ameliorates a deficit in hippocampal dependent learning and induces synaptic plasticity in a transgenic mouse model of Huntington's disease. Soc. Neurosci. Abstr. 1009.11 (2005).

  69. Schilling, G. et al. Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice. Exp. Neurol. 187, 137–149 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Wexler, N. S. et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc. Natl Acad. Sci. USA 101, 3498–3503 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sullivan, F. R., Bird, E. D., Alpay, M. & Cha, J. H. Remotivation therapy and Huntington's disease. J. Neurosci. Nurs. 33, 136–142 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Pang, T. Y. C., Stam, N. C., Nithianantharajah, J., Howard, M. L. & Hannan, A. J. Differential effects of voluntary physical exercise on behavioral and BDNF expression deficits in Huntington's disease transgenic mice. Neuroscience 141, 569–584 (2006). Demonstrates that enhanced physical activity contributes to some of the beneficial effects of enrichment on HD mice, but that sensory and cognitive stimulation must also be important.

    Article  CAS  PubMed  Google Scholar 

  73. Lazic, S. E. et al. Decreased hippocampal cell proliferation in R6/1 Huntington's mice. Neuroreport 15, 811–813 (2004).

    Article  PubMed  Google Scholar 

  74. Grote, H. E. et al. Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine. Eur. J. Neurosci. 22, 2081–2088 (2005).

    Article  PubMed  Google Scholar 

  75. Lazic, S. E. et al. Neurogenesis in the R6/1 transgenic mouse model of Huntington's disease: effects of environmental enrichment. Eur. J. Neurosci. 23, 1829–1838 (2006).

    Article  PubMed  Google Scholar 

  76. Cha, J. H. et al. Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. Proc. Natl Acad. Sci. USA 95, 6480–6485 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Luthi-Carter, R. et al. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum. Mol. Genet. 9, 1259–1271 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. van Dellen, A. et al. N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice. Neuroreport 11, 3751–3757 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Murphy, K. P. et al. Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation. J. Neurosci. 20, 5115–5123 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mazarakis, N. K. et al. Deficits in experience-dependent cortical plasticity and sensory-discrimination learning in presymptomatic Huntington's disease mice. J. Neurosci. 25, 3059–3066 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Spires, T. L. et al. Effects of environmental enrichment on disease symptoms, gene expression and protein aggregation. Soc. Neurosci. Abstr. 388.13 (2002).

  82. Glass, M., van Dellen, A., Blakemore, C., Hannan, A. J. & Faull, R. L. Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience 123, 207–212 (2004). Examined gene–environment interactions in HD mice, and suggested that CB 1 receptors might represent a useful therapeutic target.

    Article  CAS  PubMed  Google Scholar 

  83. Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Benn, C. L. et al. Environmental enrichment reduces mRNA down-regulation and impedes neuronal intranuclear inclusion formation. Soc. Neurosci. Abstr. (2006).

  86. Glenner, G. G. & Wong, C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).

    Article  CAS  PubMed  Google Scholar 

  87. Masters, C. L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci. USA 82, 4245–4249 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kang, J. et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736 (1987).

    Article  CAS  PubMed  Google Scholar 

  89. Tanzi, R. E. et al. Amyloid β protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235, 880–884 (1987).

    Article  CAS  PubMed  Google Scholar 

  90. Binder, L. I., Guillozet-Bongaarts, A. L., Garcia-Sierra, F. & Berry, R. W. Tau, tangles, and Alzheimer's disease. Biochim. Biophys. Acta 1739, 216–223 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Selkoe, D. J. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399, A23–A31 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–933 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. Saunders, A. M. et al. Association of apolipoprotein E allele ε 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43, 1467–1472 (1993).

    Article  CAS  PubMed  Google Scholar 

  94. Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hyman, B. T. et al. Epidemiological, clinical, and neuropathological study of apolipoprotein E genotype in Alzheimer's disease. Ann. NY Acad. Sci. 802, 1–5 (1996).

    Article  CAS  PubMed  Google Scholar 

  96. Small, D. H., Mok, S. S. & Bornstein, J. C. Alzheimer's disease and Aβ toxicity: from top to bottom. Nature Rev. Neurosci. 2, 595–598 (2001).

    Article  CAS  Google Scholar 

  97. Spires, T. L. & Hyman, B. T. Transgenic models of Alzheimer's disease: learning from animals. NeuroRx 2, 423–437 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  98. DeKosky, S. T., Scheff, S. W. & Styren, S. D. Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5, 417–421 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Coleman, P. D. & Yao, P. J. Synaptic slaughter in Alzheimer's disease. Neurobiol. Aging 24, 1023–1027 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Stern, Y. et al. Influence of education and occupation on the incidence of Alzheimer's disease. JAMA 271, 1004–1010 (1994).

    Article  CAS  PubMed  Google Scholar 

  101. Friedland, R. P. et al. Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. Proc. Natl Acad. Sci. USA 98, 3440–3445 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Laurin, D., Verreault, R., Lindsay, J., MacPherson, K. & Rockwood, K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch. Neurol. 58, 498–504 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Wilson, R. S. et al. Cognitive activity and incident AD in a population-based sample of older persons. Neurology 59, 1910–1914 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Valenzuela, M. J. & Sachdev, P. Brain reserve and dementia: a systematic review. Psychol. Med. 36, 441–454 (2006).

    Article  PubMed  Google Scholar 

  105. Levi, O., Jongen-Relo, A. L., Feldon, J., Roses, A. D. & Michaelson, D. M. ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory. Neurobiol. Dis. 13, 273–282 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Nitsch, R. M., Farber, S. A., Growdon, J. H. & Wurtman, R. J. Release of amyloid β-protein precursor derivatives by electrical depolarization of rat hippocampal slices. Proc. Natl Acad. Sci. USA 90, 5191–5193 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kamenetz, F. et al. APP processing and synaptic function. Neuron 37, 925–937 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Karsten, S. L. & Geschwind, D. H. Exercise your amyloid. Cell 120, 572–574 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Marx, J. Neuroscience. Preventing Alzheimer's: a lifelong commitment? Science 309, 864–866 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Adlard, P. A., Perreau, V. M., Pop, V. & Cotman, C. W. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J. Neurosci. 25, 4217–4221 (2005). Suggests that enhanced physical activity might contribute to the observed beneficial effects of enrichment in AD mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Feng, R. et al. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32, 911–926 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. 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  PubMed  Google Scholar 

  113. Padovani, A., Costanzi, C., Gilberti, N. & Borroni, B. Parkinson's disease and dementia. Neurol. Sci. 27, S40–S43 (2006).

    Article  PubMed  Google Scholar 

  114. Abou-Sleiman, P. M., Muqit, M. M. & Wood, N. W. Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nature Rev. Neurosci. 7, 207–219 (2006).

    Article  CAS  Google Scholar 

  115. de Lau, L. M. & Breteler, M. M. Epidemiology of Parkinson's disease. Lancet Neurol. 5, 525–535 (2006).

    Article  PubMed  Google Scholar 

  116. Melrose, H. L., Lincoln, S. J., Tyndall, G. M. & Farrer, M. J. Parkinson's disease: a rethink of rodent models. Exp. Brain Res. Apr 26 2006 (doi:10.1007/s00221.006.0461.3).

  117. Bezard, E. et al. Enriched environment confers resistance to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors. J. Neurosci. 23, 10999–11007 (2003). The first study to show that animals exposed to an enriched environment exhibit resistance to an MPTP insult.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Faherty, C. J., Raviie Shepherd, K., Herasimtschuk, A. & Smeyne, R. J. Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism. Brain Res. Mol. Brain Res. 134, 170–179 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Jadavji, N. M., Kolb, B. & Metz, G. A. Enriched environment improves motor function in intact and unilateral dopamine-depleted rats. Neuroscience 140, 1127–1138 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Tillerson, J. L., Caudle, W. M., Reveron, M. E. & Miller, G. W. Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson's disease. Neuroscience 119, 899–911 (2003). Showed that enhanced physical exercise could contribute to the observed beneficial effects of enrichment on models of PD.

    Article  CAS  PubMed  Google Scholar 

  121. Granieri, E. et al. Motor neuron disease in the province of Ferrara, Italy, in 1964–1982. Neurology 38, 1604–1608 (1988).

    Article  CAS  PubMed  Google Scholar 

  122. Gregoire, N. & Serratrice, G. [Risk factors in amyotrophic lateral sclerosis. Initial results apropos of 35 cases]. Rev. Neurol. (Paris) 147, 706–713 (1991) (in French).

    CAS  Google Scholar 

  123. Strickland, D., Smith, S. A., Dolliff, G., Goldman, L. & Roelofs, R. I. Physical activity, trauma, and ALS: a case-control study. Acta Neurol. Scand. 94, 45–50 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Scarmeas, N., Shih, T., Stern, Y., Ottman, R. & Rowland, L. P. Premorbid weight, body mass, and varsity athletics in ALS. Neurology 59, 773–775 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Kurtzke, J. F. & Beebe, G. W. Epidemiology of amyotrophic lateral sclerosis: 1. A case-control comparison based on ALS deaths. Neurology 30, 453–462 (1980).

    Article  CAS  PubMed  Google Scholar 

  126. Longstreth, W. T., McGuire, V., Koepsell, T. D., Wang, Y. & van Belle, G. Risk of amyotrophic lateral sclerosis and history of physical activity: a population-based case-control study. Arch. Neurol. 55, 201–206 (1998).

    Article  CAS  PubMed  Google Scholar 

  127. Veldink, J. H. et al. Physical activity and the association with sporadic ALS. Neurology 64, 241–245 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Liebetanz, D., Hagemann, K., von Lewinski, F., Kahler, E. & Paulus, W. Extensive exercise is not harmful in amyotrophic lateral sclerosis. Eur. J. Neurosci. 20, 3115–3120 (2004).

    Article  PubMed  Google Scholar 

  129. Veldink, J. H. et al. Sexual differences in onset of disease and response to exercise in a transgenic model of ALS. Neuromuscul. Disord. 13, 737–743 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Kirkinezos, I. G., Hernandez, D., Bradley, W. G. & Moraes, C. T. Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis. Ann. Neurol. 53, 804–807 (2003).

    Article  PubMed  Google Scholar 

  131. Stam, N. C. et al. Differential effects of environmental enrichment and wheel running in a transgenic mouse model of amyotrophic lateral sclerosis. Soc. Neurosci. Abstr. (2006).

  132. Mulley, J. C., Scheffer, I. E., Harkin, L. A., Berkovic, S. F. & Dibbens, L. M. Susceptibility genes for complex epilepsy. Hum. Mol. Genet. 14 Spec No. 2, R243–R249 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Young, D., Lawlor, P. A., Leone, P., Dragunow, M. & During, M. J. Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nature Med. 5, 448–453 (1999). The first evidence to show that enrichment has a beneficial effect in protecting against kainate-induced seizures and excitotoxic insult.

    Article  CAS  PubMed  Google Scholar 

  134. Auvergne, R. et al. Delayed kindling epileptogenesis and increased neurogenesis in adult rats housed in an enriched environment. Brain Res. 954, 277–285 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Koh, S., Chung, H., Xia, H., Mahadevia, A. & Song, Y. Environmental enrichment reverses the impaired exploratory behavior and altered gene expression induced by early-life seizures. J. Child Neurol. 20, 796–802 (2005).

    Article  PubMed  Google Scholar 

  136. Faverjon, S. et al. Beneficial effects of enriched environment following status epilepticus in immature rats. Neurology 59, 1356–1364 (2002).

    Article  CAS  PubMed  Google Scholar 

  137. Rutten, A. et al. Memory impairment following status epilepticus in immature rats: time-course and environmental effects. Eur. J. Neurosci. 16, 501–513 (2002).

    Article  PubMed  Google Scholar 

  138. Ohlsson, A. L. & Johansson, B. B. Environment influences functional outcome of cerebral infarction in rats. Stroke 26, 644–649 (1995).

    Article  CAS  PubMed  Google Scholar 

  139. Johansson, B. B. Functional outcome in rats transferred to an enriched environment 15 days after focal brain ischemia. Stroke 27, 324–326 (1996).

    Article  CAS  PubMed  Google Scholar 

  140. Risedal, A. et al. Environmental influences on functional outcome after a cortical infarct in the rat. Brain Res. Bull. 58, 315–321 (2002).

    Article  PubMed  Google Scholar 

  141. Komitova, M., Zhao, L. R., Gido, G., Johansson, B. B. & Eriksson, P. Postischemic exercise attenuates whereas enriched environment has certain enhancing effects on lesion-induced subventricular zone activation in the adult rat. Eur. J. Neurosci. 21, 2397–2405 (2005).

    Article  PubMed  Google Scholar 

  142. Farrell, R., Evans, S. & Corbett, D. Environmental enrichment enhances recovery of function but exacerbates ischemic cell death. Neuroscience 107, 585–592 (2001).

    Article  CAS  PubMed  Google Scholar 

  143. Hicks, R. R. et al. Environmental enrichment attenuates cognitive deficits, but does not alter neurotrophin gene expression in the hippocampus following lateral fluid percussion brain injury. Neuroscience 112, 631–637 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Dahlqvist, P., Ronnback, A., Bergstrom, S. A., Soderstrom, I. & Olsson, T. Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats. Eur. J. Neurosci. 19, 2288–2298 (2004).

    Article  PubMed  Google Scholar 

  145. Ronnback, A. et al. Gene expression profiling of the rat hippocampus one month after focal cerebral ischemia followed by enriched environment. Neurosci. Lett. 385, 173–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Schwartz, S. Effect of neonatal cortical lesions and early environmental factors on adult rat behavior. J. Comp. Physiol. Psychol. 57, 72–77 (1964).

    Article  CAS  PubMed  Google Scholar 

  147. Will, B. E., Rosenzweig, M. R. & Bennett, E. L. Effects of differential environments on recovery from neonatal brain lesions, measured by problem-solving scores and brain dimensions. Physiol. Behav. 16, 603–611 (1976).

    Article  CAS  PubMed  Google Scholar 

  148. Whishaw, I. Q., Zaborowski, J. A. & Kolb, B. Postsurgical enrichment aids adult hemidecorticate rats on a spatial navigation task. Behav. Neural Biol. 42, 183–190 (1984).

    Article  CAS  PubMed  Google Scholar 

  149. Kolb, B. & Gibb, R. Environmental enrichment and cortical injury: behavioral and anatomical consequences of frontal cortex lesions. Cereb. Cortex 1, 189–198 (1991).

    Article  CAS  PubMed  Google Scholar 

  150. Hamm, R. J., Temple, M. D., O'Dell, D. M., Pike, B. R. & Lyeth, B. G. Exposure to environmental complexity promotes recovery of cognitive function after traumatic brain injury. J. Neurotrauma 13, 41–47 (1996).

    Article  CAS  PubMed  Google Scholar 

  151. van Rijzingen, I. M., Gispen, W. H. & Spruijt, B. M. Postoperative environmental enrichment attenuates fimbria-fornix lesion-induced impairments in Morris maze performance. Neurobiol. Learn. Mem. 67, 21–28 (1997).

    Article  CAS  PubMed  Google Scholar 

  152. Passineau, M. J., Green, E. J. & Dietrich, W. D. Therapeutic effects of environmental enrichment on cognitive function and tissue integrity following severe traumatic brain injury in rats. Exp. Neurol. 168, 373–384 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Wagner, A. K. et al. Intervention with environmental enrichment after experimental brain trauma enhances cognitive recovery in male but not female rats. Neurosci. Lett. 334, 165–168 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Kozlowski, D. A., Nahed, B. V., Hovda, D. A. & Lee, S. M. Paradoxical effects of cortical impact injury on environmentally enriched rats. J. Neurotrauma 21, 513–519 (2004).

    Article  PubMed  Google Scholar 

  155. Maegele, M. et al. Multimodal early onset stimulation combined with enriched environment is associated with reduced CNS lesion volume and enhanced reversal of neuromotor dysfunction after traumatic brain injury in rats. Eur. J. Neurosci. 21, 2406–2418 (2005).

    Article  PubMed  Google Scholar 

  156. Biernaskie, J. & Corbett, D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J. Neurosci. 21, 5272–5280 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Johansson, B. B. & Belichenko, P. V. Neuronal plasticity and dendritic spines: effect of environmental enrichment on intact and postischemic rat brain. J. Cereb. Blood Flow Metab. 22, 89–96 (2002).

    Article  PubMed  Google Scholar 

  158. Gobbo, O. L. & O'Mara, S. M. Impact of enriched-environment housing on brain-derived neurotrophic factor and on cognitive performance after a transient global ischemia. Behav. Brain Res. 152, 231–241 (2004).

    Article  CAS  PubMed  Google Scholar 

  159. Dahlqvist, P. et al. Environmental enrichment alters nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression after middle cerebral artery occlusion in rats. Neuroscience 93, 527–535 (1999).

    Article  CAS  PubMed  Google Scholar 

  160. Dahlqvist, P. et al. Effects of postischemic environment on transcription factor and serotonin receptor expression after permanent focal cortical ischemia in rats. Neuroscience 119, 643–652 (2003).

    Article  CAS  PubMed  Google Scholar 

  161. Komitova, M., Perfilieva, E., Mattsson, B., Eriksson, P. S. & Johansson, B. B. Effects of cortical ischemia and postischemic environmental enrichment on hippocampal cell genesis and differentiation in the adult rat. J. Cereb. Blood Flow Metab. 22, 852–860 (2002).

    Article  PubMed  Google Scholar 

  162. Komitova, M., Mattsson, B., Johansson, B. B. & Eriksson, P. S. Enriched environment increases neural stem/progenitor cell proliferation and neurogenesis in the subventricular zone of stroke-lesioned adult rats. Stroke 36, 1278–1282 (2005).

    Article  PubMed  Google Scholar 

  163. Komitova, M., Perfilieva, E., Mattsson, B., Eriksson, P. S. & Johansson, B. B. Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex. Exp. Neurol. 199, 113–121 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Gaulke, L. J., Horner, P. J., Fink, A. J., McNamara, C. L. & Hicks, R. R. Environmental enrichment increases progenitor cell survival in the dentate gyrus following lateral fluid percussion injury. Brain Res. Mol. Brain Res. 141, 138–150 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chen, X. et al. Gender and environmental effects on regional brain-derived neurotrophic factor expression after experimental traumatic brain injury. Neuroscience 135, 11–17 (2005).

    Article  CAS  PubMed  Google Scholar 

  166. Wagner, A. K. et al. Gender and environmental enrichment impact dopamine transporter expression after experimental traumatic brain injury. Exp. Neurol. 195, 475–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  167. Restivo, L. et al. Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome. Proc. Natl Acad. Sci. USA 102, 11557–11562 (2005). The first study to show that enrichment results in beneficial effects on both brain and behaviour in a mouse model of fragile X syndrome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Martinez-Cue, C. et al. Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice, a model for Down syndrome. Behav. Brain Res. 134, 185–200 (2002). The first study to investigate the effects of environmental enrichment in a mouse model of Down syndrome.

    Article  PubMed  Google Scholar 

  169. Martinez-Cue, C. et al. Behavioral, cognitive and biochemical responses to different environmental conditions in male Ts65Dn mice, a model of Down syndrome. Behav. Brain Res. 163, 174–185 (2005).

    Article  CAS  PubMed  Google Scholar 

  170. Dierssen, M. et al. Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment. Cereb. Cortex 13, 758–764 (2003).

    Article  CAS  PubMed  Google Scholar 

  171. Berton, O. & Nestler, E. J. New approaches to antidepressant drug discovery: beyond monoamines. Nature Rev. Neurosci. 7, 137–151 (2006).

    Article  CAS  Google Scholar 

  172. Francis, D. D., Diorio, J., Plotsky, P. M. & Meaney, M. J. Environmental enrichment reverses the effects of maternal separation on stress reactivity. J. Neurosci. 22, 7840–7843 (2002). This study highlights that a combination of the enrichment paradigm and maternal separation are of relevance to understanding environmental modulation of affective disorders.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Morley-Fletcher, S., Rea, M., Maccari, S. & Laviola, G. Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats. Eur. J. Neurosci. 18, 3367–3374 (2003).

    Article  PubMed  Google Scholar 

  174. McOmish, C., Howard, M. L., van den Buuse, M. & Hannan, A. J. Behavioural analysis of PLC-β1 knockout mice: gene–environment interactions and experience-dependent plasticity. FENS Abstr. 3, A091.11 (2006).

  175. Magalhaes, A., Summavielle, T., Tavares, M. A. & de Sousa, L. Effects of postnatal cocaine exposure and environmental enrichment on rat behavior in a forced swim test. Ann. NY Acad. Sci. 1025, 619–629 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Bowling, S. L., Rowlett, J. K. & Bardo, M. T. The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release. Neuropharmacology 32, 885–893 (1993).

    Article  CAS  PubMed  Google Scholar 

  177. Bardo, M. T., Klebaur, J. E., Valone, J. M. & Deaton, C. Environmental enrichment decreases intravenous self-administration of amphetamine in female and male rats. Psychopharmacology (Berl) 155, 278–284 (2001).

    Article  CAS  Google Scholar 

  178. Hannan, A. J. Huntington's disease: which drugs might help patients? IDrugs 7, 351–358 (2004).

    CAS  PubMed  Google Scholar 

  179. Hannan, A. J. Novel therapeutic targets for Huntington's disease. Expert Opin. Ther. Targets 9, 639–650 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Stern, Y. What is cognitive reserve? Theory and research application of the reserve concept. J. Int. Neuropsychol. Soc. 8, 448–460 (2002).

    Article  PubMed  Google Scholar 

  181. Valenzuela, M. J. & Sachdev, P. Brain reserve and dementia: a systematic review. Psychol. Med. 36, 441–454 (2006).

    Article  PubMed  Google Scholar 

  182. Mortimer, J. A. Brain reserve and the clinical expression of Alzheimer's disease. Geriatrics 52, S50–S53 (1997).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of the Hannan laboratory, H. Grote, N. Mazarakis, S. Miller, T. Spires, A. van Dellen and C. Hannan for useful discussions and comments on earlier drafts of the manuscript. We also appreciate the constructive suggestions from the referees during peer review. A.J.H. is supported by an R. D. Wright award and project grants from the National Health and Medical Research Council (Australia).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anthony J. Hannan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

bipolar disorder

Down syndrome

fragile X syndrome

Huntington's disease

Parkinson's disease

schizophrenia

unipolar depression

FURTHER INFORMATION

Howard Florey Institute

Glossary

Microglia

Phagocytic immune cells in the brain that engulf and remove cells that have undergone apoptosis.

Long-term potentiation

(LTP). An enduring increase in amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic cell population spike. LTP is most frequently studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

Morris water maze

A task used to assess long-term spatial memory, most commonly in rodents. Animals use an array of extra-maze cues to locate a hidden escape platform that is submerged below the surface of the water. Learning in this task is hippocampus-dependent.

Endophenotype

A quantitative biological trait associated with a complex genetic disorder that is hoped to more directly index the underlying pathophysiology, facilitating efforts to find or characterize contributing genes.

Critical period

A strict time window during which experience provides information that is essential for normal development and permanently alters performance.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nithianantharajah, J., Hannan, A. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7, 697–709 (2006). https://doi.org/10.1038/nrn1970

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1970

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing