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.

Huntington disease (HD) is a fatal neurodegenerative disease with no effective treatment. In the R6/1 mouse model of HD, environmental enrichment delays the neurologic phenotype onset and prevents cerebral volume loss by unknown molecular mechanisms. We examined the effects of environmental enrichment on well-characterized neuropathological parameters in a mouse model of HD. We found a trend toward preservation of downregulated neurotransmitter receptors in striatum of environmentally enriched mice and assessed possible enrichment-related modifications in gene expression using microarrays. We observed similar gene expression changes in R6/1 and R6/2 transgenic mice but found no specific changes in enrichment-related microarray expression profiles in either transgenic or wild-type mice. Furthermore, specific corrections in transprotein-induced transcriptional dysregulation in R6/1 mice were not detected by microarray profiling. However, gene-specific analyses suggested that long-term environmental enrichment may beneficially modulate gene expression dysregulation. Finally, environmental enrichment significantly decreased neuronal intranuclear inclusion load, despite unaffected transgene expression levels. Thus, the therapeutic effects of environmental enrichment likely contribute to decreasing aggregated polyglutamine protein levels without exerting strong effects on gene expression.

BACKGROUND:Huntington's disease (HD) is a neurodegenerative disorder predominantly affecting the cerebral cortex and striatum. Transgenic mice (R6/1 line), expressing a CAG repeat encoding an expanded polyglutamine tract in the N-terminus of the huntingtin protein, closely model HD. We have previously shown that environmental enrichment of these HD mice delays the onset of motor deficits. Furthermore, wheel running initiated in adulthood ameliorates the rear-paw clasping motor sign, but not an accelerating rotarod deficit.RESULTS:We have now examined the effects of enhanced physical activity via wheel running, commenced at a juvenile age (4 weeks), with respect to the onset of various behavioral deficits and their neuropathological correlates in R6/1 HD mice. HD mice housed post-weaning with running wheels only, to enhance voluntary physical exercise, have delayed onset of a motor co-ordination deficit on the static horizontal rod, as well as rear-paw clasping, although the accelerating rotarod deficit remains unaffected. Both wheel running and environmental enrichment rescued HD-induced abnormal habituation of locomotor activity and exploratory behavior in the open field. We have found that neither environment enrichment nor wheel running ameliorates the shrinkage of the striatum and anterior cingulate cortex (ACC) in HD mice, nor the overall decrease in brain weight, measured at 9 months of age. At this age, the density of ubiquitinated protein aggregates in the striatum and ACC is also not significantly ameliorated by environmental enrichment or wheel running.CONCLUSION:These results indicate that enhanced voluntary physical activity, commenced at an early presymptomatic stage, contributes to the positive effects of environmental enrichment. However, sensory and cognitive stimulation, as well as motor stimulation not associated with running, may constitute major components of the therapeutic benefits associated with enrichment. Comparison of different environmental manipulations, performed in specific time windows, can identify critical periods for the induction of neuroprotective 'brain reserve' in animal models of HD and related neurodegenerative diseases.

Reduced neuronal plasticity in the striatum, hippocampus, and neocortex is a common feature of transgenic mouse models of Huntington’s disease (HD). Doublecortin (DCX) and polysialylated neural cell adhesion molecule (PSA-NCAM) are associated with structural plasticity in the adult mammalian brain, are markers of newly formed neurons in the dentate gyrus of the adult hippocampus, and are highly expressed in primary olfactory (piriform) cortex. Animal studies have demonstrated that a reduction in plasticity in the piriform cortex is associated with a selective impairment in odour discrimination. Therefore, the number of DCX and PSA-NCAM immunoreactive cells in the piriform cortex were quantified as measures of plasticity in early stage (fifteen week old) R6/1 transgenic HD mice. The transgenic mice had a large reduction in the number of DCX and PSA-NCAM immunoreactive cells in the piriform cortex, similar to that previously reported in the R6/2 mice. We also tested whether odour discrimination, as well as identification and detection, were impaired in HD patients and found that patients (at a similar disease stage as the mice) had an impairment in odour discrimination and identification, but not odour detection. These results suggest that olfactory impairments observed in HD patients may be the result of reduced plasticity in the primary olfactory cortex.

Nektarios K. Mazarakis,1 Anita Cybulska-Klosowicz,2 Helen Grote,1 Terence Pang,3 Anton Van Dellen,1 Malgorzata Kossut,1 Colin Blakemore,1 and Anthony J. Hannan1,3 1University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom, 2Laboratory of Cortical Plasticity, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland, and 3Howard Florey Institute, University of Melbourne, Parkville, 3010 Victoria, Australia

SUMMARY1. Huntington's disease (HD) is a fatal autosomal dominant disorder in which there is progressive neurodegeneration producing motor, cognitive and psychiatric symptoms. The dynamic mutation that causes the disease is common to numerous other brain disorders, which may share similar pathogenic mechanisms.2. Much progress has been made in the past decade in understanding how a trinucleotide (CAG) repeat expansion, encoding an expanded polyglutamine tract in the huntingtin protein, induces dysfunction at molecular and cellular levels. The present review integrates various lines of experimental evidence in an attempt to move towards a unifying mechanistic framework, which may explain the pathogenesis of HD, from molecular through to neuronal network and behavioural levels.3. Recent evidence, using transgenic mouse models, also suggests that environmental factors can modify the onset and progression of HD. The effects of specific environmental manipulations are discussed in the context of gene–environment interactions and experience‐dependent plasticity in the healthy and diseased brain, particularly the cerebral cortex.

Huntington's disease is a fatal inherited disorder in which there is progressive neurodegeneration in specific brain areas, mainly the striatum and cerebral cortex, producing motor, cognitive, and psychiatric symptoms. The trinucleotide repeat mutation involved is common to many other brain diseases, which may therefore involve similar mechanisms of pathogenesis. We are beginning to understand how a CAG trinucleotide repeat expansion in the disease gene, encoding an expanded polyglutamine tract, induces neuronal dysfunction and symptomatology in Huntington's disease. Recent evidence that environmental factors modify the onset and progression of neurodegeneration has shed new light on Huntington's disease and other devastating brain diseases. This review focuses on genetic mediators, environmental modulators, and associated gene-environment interactions in the pathogenesis of Huntington's disease.

This unremitting disease develops later in animals stimulated by their environment.

Vanitha Subramaniam gives a regional perspective on the impact of globalization on women's overall health and well-being, particularly in light of the recent financial crisis in the Asian region.