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Issue 98, September 2007

Research Report

Does Environmental Enrichment
Have A Future As A HD Treatment?

By a volunteer science writer, Alana Shepherd

The manifestation of the Huntington's Disease (HD) gene mutation occurs primarily in the cortical and striatal regions of the brain, interrupting the transmission of both cognitive and motor information from the cortex. The late stages of the disease are characterised by cortical and striatal degradation, however the early symptoms are more likely to be attributed to neuron (nerve Cell) dysfunction rather than death.

A number of potential targets for disease treatment in humans have been identified for further study through the use of mouse models. R6 transgenic HD mice provide one of the most clinically accurate animal models for the disease: essentially they develop similar symptoms at a correspondingly progressive rate. (1, 5, 6.)

One theory that has been gaining a great deal of support is the idea of environmental enrichment for the treatment of both motor and cognitive HD symptoms. Environmental enrichment is essentially the use of sensory, cognitive and motor stimuli to actively engage the parts of the brain affected by HD. In mice, sensory stimulation includes visual, auditory and olfactory stimuli while cognitive stimulation relates to spatial maps and object recognition. Motor stimuli include both fine and gross motor skills (4). The finding indicated by environmental enrichment studies have many potential applications in clinical therapy.

Manipulation of the environment can be used to identify cause-and-effect relationships between factors influencing the onset and progression of the disease, contributing to the growing list of potential therapeutic targets for treatment.

Tested in mice, environmental enrichment has been shown to relieve symptoms such as motor deficits; loss of spatial memory; reduced cortical volume; and decreased neurogenesis: in the bigger picture, working to delay the overall onset and progression of HD (1-6).

A noteworthy area of potential is that of 'enviromimetics': the idea that drugs can be administered to emulate the effects of environmental stimulation.

Evidence supports one such drug, fluoxetine, a selective serotonin reuptake inhibitor (SRI) currently used as an antidepressant. Several of the psychiatric symptoms of HD have been linked to the hippocampus, in particular the dentate gyrus, as HD mice show decreased cell proliferation in this area. Both environmental enrichment and fluoxetine have been shown to increase neurogenesis (neuron growth) in the dentate gyrus, thus improving cognitive function, behavioural symptoms and psychiatric symptoms, particularly depression, in mice (1).

Before any conclusions can be made with respect to potential therapeutic benefit for humans, a great deal more study is needed with mouse models to answer the multitude of questions that have arisen from the currents studies. It is clear that, in mice, provision of a complex environment provides the optimal conditions for delaying onset and slowing disease progression. However, exactly how the environment elicits changes to molecular disease mechanisms is still largely a mystery, the resolution of which will provide both understanding into HD pathogenesis as well as potential targets for treatment.

The standardisation of the complex environment also needs to be addressed. Although many studies have examined the effect of stimulating surroundings, there is limited consistency between these studies. Lack of standardisation means most studies have differed in the components of an enriched (with stimulation) and a standard (unenriched comparison) environment, as well as having a great deal of variation in both the age and the duration of exposure. All studies have in common key aspects of an enriched environment (novelty and complexity with motor, sensory and cognitive components) however there is no consensus on which aspects of the environment provide maximum benefit. Moreover, the differential effect of age needs to be examined: whether exposure during development or after maturation exerts distinct degrees of effect (4).

Furthermore, extensive research is needed to examine the individual effects of each component of the environment. Studies so far have indicated that the maximum benefit is to be obtained from application of a complex environment combining motor, sensory and cognitive stimulus. However, examination of each component individually could illustrate the discrete effects and the molecular mechanisms behind each.

Although the studies into environmental enrichment have shown great promise, the benefit for humans with HD has not been conclusively supported. There is evidence to suggest HD is affected by environmental factors, including studies of monozygotic twins with HD where each twin has an identical CAG length but elicits different clinical symptoms and behavioural abilities. The absence of genetic difference clearly indicates an environmental role (2). There have also been studies involving small numbers of human HD patients that have demonstrated improved physical and cognitive functioning in a proportion of the patients (4), however larger scale trials are required before any therapy can be recommended as clinically beneficial. Environmental enrichment has already shown to be effective in preventing aspects of other neurodegenerative disease (6), including Parkinson's disease and Alzheimer's disease.

Many questions need to be answered before this practice has therapeutic viability, most significantly the issue of relevance to humans: does a demonstrated effect in mice validate human testing? Although HD mice proved an anatomical model for the disease, there is enormous difference in natural environmental complexity between mice and humans (4).

If the relevance for humans can be justified by further research, the use of environmental enrichment as a therapy for the treatment of HD could have enormous implications for both sufferers of the disease and their families and carers, not only in terms of life expectancy, but also for quality of life.


1. Grote, H.E., Bull, N.D., Howard, M.L., van Dellen, A., Blakemore, C., Bartlett, P.F., Hannan, AJ. (2005). Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine. European Journal of Neuroscience. pp 1-8.

2. Hannan, A. (2004) Use It or Lose it. Australasian Science p 31-33.

3. Hannan, A. (2005). Novel therapeutic targets for Huntington's Disease. Expert Opinion. 9 (4): 1-12.

4. Nithianantharajah, J., Hannan, A. (2006). Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nature Reviews Neuroscience, 7: 697-709.

5. Pang, T.C., Stam, N.C., Nithianantharajah, J., Howard, M.L., Hannan, A.). (2006). Differential effects of voluntary physical exercise on behavioural and brain-derived neurotrophic factor expression deficits in Huntington's Disease transgenic mice. Neuroscience 10: 1016

6. Spires, T.L., Grote, H.E., Varshney, N.K., Cordery, P.M., van Dellen, A., Blakemore, C. Hannan, A. (2004). Environmental enrichment rescues protein deficits in a mouse model of Huntington's Disease, indication a possible disease mechanism. Journal of Neuroscience. 24(9): 2270-2276.

Acknowledgement: Gateway - Newsletter of AHDA (NSW) Inc - Summer/Autumn 2007

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