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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 the HD mutation and environmental manipulations on the open field test. Spontaneous exploratory behavior was measured in terms of the horizontal activity (A) and vertical (rearing) activity (B) in the 3 min period of the open field test at 5 months of age. Interestingly, the decrease between the first and second days was highly significant for non-enriched HD mice (double asterisk: P < 0.001) for both the number of squares crossed (A) as well as the number of rears (B). This effect was not seen in the environmentally enriched or wheel running HD mice. This suggests that the habituation of activity seen during re-testing in HD mice is attenuated through environmental enrichment or wheel running. NE: non-enriched; EE: environmentally enriched; RW: running wheel; WT: wild-type; HD: Huntington's disease; 1st: first day of testing; 2nd: second day of testing.
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Figure 3: Effects of the HD mutation and environmental manipulations on the open field test. Spontaneous exploratory behavior was measured in terms of the horizontal activity (A) and vertical (rearing) activity (B) in the 3 min period of the open field test at 5 months of age. Interestingly, the decrease between the first and second days was highly significant for non-enriched HD mice (double asterisk: P < 0.001) for both the number of squares crossed (A) as well as the number of rears (B). This effect was not seen in the environmentally enriched or wheel running HD mice. This suggests that the habituation of activity seen during re-testing in HD mice is attenuated through environmental enrichment or wheel running. NE: non-enriched; EE: environmentally enriched; RW: running wheel; WT: wild-type; HD: Huntington's disease; 1st: first day of testing; 2nd: second day of testing.

Mentions: In a test of exploratory behavior in the open field, carried out at 5 months of age, there was a non-significant trend for HD mice to be less active than wild-type littermates (Fig. 3A) (HD: F [1, 38] = 3.71, P < 0.10, 2-way ANOVA). Although in some groups of mice exploratory activity was reduced on the second day of testing (2nd blocks in Fig. 3A), this reduction was highly significant only for non-enriched HD mice (HD: F[1,38] = 22.29, P < 0.001; 2-way ANOVA). This demonstrates that the abnormal habituation of locomotor activity in HD mice was rescued by both environmental enrichment and wheel running.


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 the HD mutation and environmental manipulations on the open field test. Spontaneous exploratory behavior was measured in terms of the horizontal activity (A) and vertical (rearing) activity (B) in the 3 min period of the open field test at 5 months of age. Interestingly, the decrease between the first and second days was highly significant for non-enriched HD mice (double asterisk: P < 0.001) for both the number of squares crossed (A) as well as the number of rears (B). This effect was not seen in the environmentally enriched or wheel running HD mice. This suggests that the habituation of activity seen during re-testing in HD mice is attenuated through environmental enrichment or wheel running. NE: non-enriched; EE: environmentally enriched; RW: running wheel; WT: wild-type; HD: Huntington's disease; 1st: first day of testing; 2nd: second day of testing.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Effects of the HD mutation and environmental manipulations on the open field test. Spontaneous exploratory behavior was measured in terms of the horizontal activity (A) and vertical (rearing) activity (B) in the 3 min period of the open field test at 5 months of age. Interestingly, the decrease between the first and second days was highly significant for non-enriched HD mice (double asterisk: P < 0.001) for both the number of squares crossed (A) as well as the number of rears (B). This effect was not seen in the environmentally enriched or wheel running HD mice. This suggests that the habituation of activity seen during re-testing in HD mice is attenuated through environmental enrichment or wheel running. NE: non-enriched; EE: environmentally enriched; RW: running wheel; WT: wild-type; HD: Huntington's disease; 1st: first day of testing; 2nd: second day of testing.
Mentions: In a test of exploratory behavior in the open field, carried out at 5 months of age, there was a non-significant trend for HD mice to be less active than wild-type littermates (Fig. 3A) (HD: F [1, 38] = 3.71, P < 0.10, 2-way ANOVA). Although in some groups of mice exploratory activity was reduced on the second day of testing (2nd blocks in Fig. 3A), this reduction was highly significant only for non-enriched HD mice (HD: F[1,38] = 22.29, P < 0.001; 2-way ANOVA). This demonstrates that the abnormal habituation of locomotor activity in HD mice was rescued by both environmental enrichment and wheel running.

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