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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.

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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).

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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).

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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.

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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

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