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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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Volumetric measurement of neurodegeneration in the striatum and anterior cingulate cortex (ACC). The volumes of the striatum and ACC were calculated for non-enriched (NE), environmentally enriched (EE) and wheel running (RW) groups of wild-type (WT) and HD mice at 9 months of age for the striatum (A and C) and ACC (B and D). The presence of the transgene reduced all these brain volumes, reaching statistical significance for both striatum (P < 0.001) and anterior cingulate cortex (P < 0.05). No effect was seen on the striatum or anterior cingulate cortex by either environmental enrichment or wheel running.
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Figure 4: Volumetric measurement of neurodegeneration in the striatum and anterior cingulate cortex (ACC). The volumes of the striatum and ACC were calculated for non-enriched (NE), environmentally enriched (EE) and wheel running (RW) groups of wild-type (WT) and HD mice at 9 months of age for the striatum (A and C) and ACC (B and D). The presence of the transgene reduced all these brain volumes, reaching statistical significance for both striatum (P < 0.001) and anterior cingulate cortex (P < 0.05). No effect was seen on the striatum or anterior cingulate cortex by either environmental enrichment or wheel running.

Mentions: We analysed serial coronal sections to measure the volume of the striatum and the anterior cingulate cortex (ACC) in environmentally enriched (Fig. 4A,B) and wheel running (Fig. 4C,D) cohorts. Expression of the HD transgene reduced the volumes of both the striatum and the ACC (striatum: F [1, 12] = 39.74, P < 0.001; ACC: F [1, 12] = 5.24, P < 0.05; 2-way ANOVA).


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)

Volumetric measurement of neurodegeneration in the striatum and anterior cingulate cortex (ACC). The volumes of the striatum and ACC were calculated for non-enriched (NE), environmentally enriched (EE) and wheel running (RW) groups of wild-type (WT) and HD mice at 9 months of age for the striatum (A and C) and ACC (B and D). The presence of the transgene reduced all these brain volumes, reaching statistical significance for both striatum (P < 0.001) and anterior cingulate cortex (P < 0.05). No effect was seen on the striatum or anterior cingulate cortex by either environmental enrichment or wheel running.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Volumetric measurement of neurodegeneration in the striatum and anterior cingulate cortex (ACC). The volumes of the striatum and ACC were calculated for non-enriched (NE), environmentally enriched (EE) and wheel running (RW) groups of wild-type (WT) and HD mice at 9 months of age for the striatum (A and C) and ACC (B and D). The presence of the transgene reduced all these brain volumes, reaching statistical significance for both striatum (P < 0.001) and anterior cingulate cortex (P < 0.05). No effect was seen on the striatum or anterior cingulate cortex by either environmental enrichment or wheel running.
Mentions: We analysed serial coronal sections to measure the volume of the striatum and the anterior cingulate cortex (ACC) in environmentally enriched (Fig. 4A,B) and wheel running (Fig. 4C,D) cohorts. Expression of the HD transgene reduced the volumes of both the striatum and the ACC (striatum: F [1, 12] = 39.74, P < 0.001; ACC: F [1, 12] = 5.24, P < 0.05; 2-way ANOVA).

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