Submitted by Marsha Miller Ph.D. on Thu, 04/10/2008
Dr Anthony J. Hannan and his colleagues have continued their work with the effects of environmental changes on the HD mice. They have previously shown that environmental enrichment, introduced at four weeks of age, delays the onset and progression of motor deficits and reverses the reduction of BDNF in the striatum and hippocampus at five months. To enrich the environment, an object such as a small cardboard box open at one end or a plastic cone was placed in in the cage and changed for another every two days.
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In the new study, the exercise wheels were introduced much earlier, when the mice were only four weeks old. This time the effect was much larger. The onset of a number of motor deficits was significantly delayed, although performance on the accelerating rotarod, a standard measure, was not improved with voluntary exercise as it is with environmental enrichment.
We already know, based on extensive analysis of data collected from HD families in Venezuela (2004), that there are environment effects on the age of onset of the disease. The number of CAG repeats is associated with the age of onset at the aggregate level. In general, those with a higher number will become symptomatic sooner than those with a lower number. However, it is not possible to predict age of onset for individuals because the age of onset for two people with the same CAG count often varies considerably. Some of the variation is genetic; there is good evidence that there are modifying genes.
However, other evidence points to environmental factors as another major influence. The age of onset can vary even with identical twins. The work of Dr. Hannan and colleagues suggests that positive environmental factors may include enhanced cognitive and sensory stimulation along with exercise and physical activities.This is as far as the research pipeline will go on exercise and environmental enrichment. Allthough there may be more mouse studies, there will be no human study with a control group of bored couch potatoes! But there's a clear take home message for young people at risk and anyone who has tested positive. Don't wait, start a healthy exercise program now. Keep learning, develop new skills, and seek new experiences to broaden your intellectual and cultural horizons.
References:
T.Y.C. Pang, N.C. Stam, J. Nithianantharajah, M.L. Howard, and A.J. Hannan, "Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington's disease transgenic mice." Behavioral Neuroscience 2006; 141(2): 569-584.
Tara L. Spires, Helen E. Grote, Neelash K. Varshney, Patricia M. Cordery, Anton van Dellen, Colin Blakemore, and Anthony J. Hannan, "Environmental Enrichment Rescues Protein Deficits in a Mouse Model of Huntington's Disease, Indicating a Possible Disease Mechanism." The Journal of Neuroscience, 2004 March 3; 24(9): 2270-2276.
The U.S.-Venezuela Collaborative Research Project and Nancy S. Wexler, "Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset." Proc Natl Acad Sci U S A. 2004 March 9; 101(10): 3498-3503.
The simple act of running in an exercise wheel delays the onset of some symptoms of Huntington’s disease in a mouse model of the fatal human disorder according to research published in the open-access journal BMC Neuroscience. These findings add insights into the pathogenesis of the disease and suggest possible preventive therapeutic targets.
Huntington’s disease affects up to one person in every 10 000, but clusters in families and certain populations. Affected people develop clusters of a defective protein in their neurons and shrinkage of brain areas associated with movement. The disorder causes disability and eventually death, but does not normally manifest until after people have had children, allowing the disease gene to be passed on.
“Although Huntington’s disease is considered the epitome of genetic determinism, environmental factors are increasingly recognised to influence the disease progress”, the researchers write.
The research team from the University of Oxford and the Howard Florey Institute, University of Melbourne, report findings of a study in mice with the genetic mutation that causes Huntington’s in humans. Just as mentally stimulating these mice by enriching their environment had previously been shown to delay onset and progression of motor symptoms, so does the simple physical activity of running in a wheel.
“Of particular interest was the fact that the wheel exercise was started in juvenile mice, much earlier than in a previous study that showed more limited protective effects of physical activity”, explains Anthony Hannan of the Howard Florey Institute. This finding suggests that the protective effect has a specific time window.
Hannan notes “Physical activity did not postpone all the motor symptoms delayed by environmental enrichment, which suggests that sensory stimulation, mental exercise, and physical activity could all be used for the benefit of human sufferers”. Early intervention is also possible in people who will develop Huntington’s, because genetic diagnosis is possible.
Density of protein aggregates in neurons and shrinkage in brain regions in mice that had benefited from physical activity were as advanced as in those raised without wheels, the authors suggest therefore that benefits stem from stimulation of neuronal receptors and other molecules that prolongs normal function and delays motor deficits.
The Journal Abstract
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.
Conclusions
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.