title: 'Super-Enrichment' Reveals Dose-Dependent Therapeutic Effects of Environmental Stimulation in a Transgenic Mouse Model of Huntington's Disease.
abstract: BACKGROUND
  Huntington's disease (HD) is caused by a tandem repeat expansion and involves progressive cognitive decline, psychiatric abnormalities and motor deficits. Disease onset and progression in HD mice can be substantially delayed by a housing environment with enhanced sensorimotor and cognitive stimulation. However, the proposed benefits of environmental enrichment (EE) are always taken in the context of 'deprived' standard housing and investigation is warranted into the graded effects of enrichment.
  
  
  OBJECTIVE
  To assess if a higher level of environmental stimulation ('super-enrichment') has additional benefits compared to home-cage EE in HD mice.
  
  
  METHODS
  One group of R6/1 transgenic HD mice and wild-type (WT) littermates were home-cage enriched (EE group). A second group also had enriched home cages, but from 6 weeks of age were exposed to a large 'super-enrichment' arena (SuperE group) three times per week. A range of motor tests (open field, rotarod, clasping) were conducted from 8 weeks of age and, at the end of the experiment, grip strength was assessed and post-mortem measures were taken (brain weight, striatal volume, dopamine receptor activation and aggregate density).
  
  
  RESULTS
  SuperE improved the reduction of exploration in the open field, ameliorated impaired grip strength in home-cage enriched HD mice and delayed, but did not abolish, the onset of rear-paw clasping compared to EE. SuperE increased brain weight compared to EE in HD mice and reduced striatal dopamine D1 receptor agonist-induced c-fos expression, regardless of genotype. Body weight, rotarod performance, aggregate formation and striatal volume in SuperE groups were no different compared to EE groups.
  
  
  CONCLUSIONS
  The beneficial effects of sensorimotor and cognitive stimulation are graded and extend beyond merely compensating for the deprivation of standard home cages in specific motor-related phenotypes in HD. Our findings highlight the importance of environmental enrichment quality and quantity and the translational value of stimulating living conditions as experience-dependent modulators of pathogenesis in HD and other brain disorders.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Nektarios K
authors.initials: NK
authors.lastname: Mazarakis
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Mo
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Thibault
authors.initials: T
authors.lastname: Renoir
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Anton
authors.initials: A
authors.lastname: van Dellen
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Deacon
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Blakemore
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004777:Environment; D005260:Female; D006816:Huntington Disease / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009473:Neuronal Plasticity; D016896:Treatment Outcome
keywords: Cerebral cortex; cognitive stimulation; dopamine; environmental enrichment; experience-dependent plasticity; neurodegeneration; physical activity; polyglutamine; striatum; tandem repeat disorder