Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington’s disease transgenic mice

doi:10.1016/j.neuroscience.2006.04.013

Neuroscience

Volume 141, Issue 2, 2006, Pages 569-584

https://doi.org/10.1016/j.neuroscience.2006.04.013 Get rights and content

Abstract

Huntington’s disease is a fatal neurodegenerative disorder caused by a mutation of the huntingtin gene and involves progressive motor abnormalities (including chorea), cognitive deficits (dementia) as well as psychiatric symptoms. We have previously demonstrated that environmental enrichment slows the onset and progression of Huntington’s disease in transgenic mice. Here, we investigated the effects of enhanced physical exercise on disease progression and brain-derived neurotrophic factor expression. Standard-housed Huntington’s disease mice developed phenotypic rear-paw clasping by 16 weeks of age, displayed abnormal rearing behavior, deficits in motor co-ordination and of spatial working memory. Huntington’s disease mice with access to running wheels exhibited delayed onset of rear-paw clasping, normalized levels of rearing behavior and amelioration of the cognitive deficits. However, in contrast to our previous environmental enrichment studies, there was no rescue of motor coordination deficits in wheel-running Huntington’s disease mice. An abnormal accumulation of brain-derived neurotrophic factor protein in the frontal cortex of Huntington’s disease mice was unaffected by running. Striatal and hippocampal brain-derived neurotrophic factor protein levels were unchanged. Brain-derived neurotrophic factor mRNA levels were reduced in the anterior cortex, striatum and hippocampus of Huntington’s disease mice, and only striatal deficits were ameliorated by running. Overall, we show that voluntary physical exercise delays the onset of Huntington’s disease and the decline in cognitive ability. In addition, our results reveal that some aspects of hippocampal dependent memory are not entirely reliant on sustained hippocampal brain-derived neurotrophic factor expression.

Section snippets

Animals

R6/1 hemizygote males were obtained from the Jackson Laboratory (Bar Harbor, ME, USA) and bred with CBB6 (CBA×C57/B6) F1 females to establish the R6/1 colony at the Howard Florey Institute. The offspring were PCR genotyped with genomic DNA obtained from toe biopsy. Ten week old R6/1 (HD) and WT mice were randomly allocated to undergo either housing under standard housing (SH) conditions (HD and WT SH) or provided with running wheels (HD and WT runners) for 10 weeks. Wheel-running mice were

HD mice exhibit abnormal rearing behavior that is rescued by running

A comparison of the distances moved by the mice during the first and last habituation sessions in the photobeam arenas was used as a measure of habituation. All four groups of mice showed a decrease in the distance moved indicating habituation to the photobeam arenas (Fig. 1). Only WT SH displayed a reduction in distance moved which was significant over the first 5 min (Fig. 1A) and over 30 min (Fig. 1B).

The environmental factor (enhanced physical activity) had a significant effect on the

Discussion

We report that the exploratory behaviors of R6/1 HD mice do not differ from WT mice up until the age of 20 weeks. That is in contrast to a previous study that reported hypoactivity in SH R6/1 HD mice from 6 to 14 weeks of age (Bolivar et al., 2004). However, that study had limitations because its conclusions were based on data pooling from different animals of different ages to chart out the progressive changes in exploratory behaviors of those mice as they aged. In general, running decreased

Acknowledgments

We thank H. Grote for assistance with real-time PCR and C. Hannan for comments on the manuscript. This work was supported by an NHMRC (Australia) RD Wright Career Development Award and Project Grant (A.J.H.), the Lord Mayor’s Charitable Fund (Eldon and Anne Foote Trust) and a University of Melbourne Research Scholarship (N.S.).

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Behavioural neuroscienceDifferential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington’s disease transgenic mice

Abstract

Section snippets

Animals

HD mice exhibit abnormal rearing behavior that is rescued by running

Discussion

Acknowledgments

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Behavioural neuroscience
Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington’s disease transgenic mice