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Wheel running from a juvenile age delays onset of specific motor deficits but does not alter protein aggregate density in a mouse model of Huntington's disease.

van Dellen A, Cordery PM, Spires TL, Blakemore C, Hannan AJ - BMC Neurosci (2008)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK. anthony.hannan@florey.edu.au

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.

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.

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Effects of wheel running in delaying the onset of motor deficits, measured by tests of performance on the horizontal rod and rear-paw clasping. The cumulative percentage of mice consistently failing each test is plotted as a function of age. A) Wheel running from 4 weeks of age delays the onset of motor deficits revealed by the horizontal rod (P < 0.05). Wild-type mice, regardless of housing condition, always pass the horizontal rod test. B) Wheel running also delays onset of the rear-paw clasping motor deficit (P < 0.05). Triangles: non-enriched HD mice. Squares: wheel running HD mice. Circles: wild-type (WT) mice (enriched and non-enriched groups pooled: no failures).
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Figure 1: Effects of wheel running in delaying the onset of motor deficits, measured by tests of performance on the horizontal rod and rear-paw clasping. The cumulative percentage of mice consistently failing each test is plotted as a function of age. A) Wheel running from 4 weeks of age delays the onset of motor deficits revealed by the horizontal rod (P < 0.05). Wild-type mice, regardless of housing condition, always pass the horizontal rod test. B) Wheel running also delays onset of the rear-paw clasping motor deficit (P < 0.05). Triangles: non-enriched HD mice. Squares: wheel running HD mice. Circles: wild-type (WT) mice (enriched and non-enriched groups pooled: no failures).

Mentions: By approximately 5 months of age, all non-enriched (standard-housed) HD mice fail the static horizontal rod test of motor co-ordination (Fig. 1A). Environmental enrichment dramatically delays the onset of these deficits as previously demonstrated [6]. Wheel running alone also induces a delay in onset of this motor deficit on the static horizontal rod (Fig. 1A, P < 0.05; Chi2 Test). Furthermore, wheel running from 4 weeks also delays onset of rear-paw clasping (Fig. 1B, P < 0.05; Chi2 Test), a reflexive motor sign in HD mice [3,6].


Wheel running from a juvenile age delays onset of specific motor deficits but does not alter protein aggregate density in a mouse model of Huntington's disease.

van Dellen A, Cordery PM, Spires TL, Blakemore C, Hannan AJ - BMC Neurosci (2008)

Effects of wheel running in delaying the onset of motor deficits, measured by tests of performance on the horizontal rod and rear-paw clasping. The cumulative percentage of mice consistently failing each test is plotted as a function of age. A) Wheel running from 4 weeks of age delays the onset of motor deficits revealed by the horizontal rod (P < 0.05). Wild-type mice, regardless of housing condition, always pass the horizontal rod test. B) Wheel running also delays onset of the rear-paw clasping motor deficit (P < 0.05). Triangles: non-enriched HD mice. Squares: wheel running HD mice. Circles: wild-type (WT) mice (enriched and non-enriched groups pooled: no failures).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2335112&req=5

Figure 1: Effects of wheel running in delaying the onset of motor deficits, measured by tests of performance on the horizontal rod and rear-paw clasping. The cumulative percentage of mice consistently failing each test is plotted as a function of age. A) Wheel running from 4 weeks of age delays the onset of motor deficits revealed by the horizontal rod (P < 0.05). Wild-type mice, regardless of housing condition, always pass the horizontal rod test. B) Wheel running also delays onset of the rear-paw clasping motor deficit (P < 0.05). Triangles: non-enriched HD mice. Squares: wheel running HD mice. Circles: wild-type (WT) mice (enriched and non-enriched groups pooled: no failures).
Mentions: By approximately 5 months of age, all non-enriched (standard-housed) HD mice fail the static horizontal rod test of motor co-ordination (Fig. 1A). Environmental enrichment dramatically delays the onset of these deficits as previously demonstrated [6]. Wheel running alone also induces a delay in onset of this motor deficit on the static horizontal rod (Fig. 1A, P < 0.05; Chi2 Test). Furthermore, wheel running from 4 weeks also delays onset of rear-paw clasping (Fig. 1B, P < 0.05; Chi2 Test), a reflexive motor sign in HD mice [3,6].

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK. anthony.hannan@florey.edu.au

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.

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.

Show MeSH
Related in: MedlinePlus