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Responses to environmental enrichment differ with sex and genotype in a transgenic mouse model of Huntington's disease.

ABSTRACT: BACKGROUND: Environmental enrichment (EE) in laboratory animals improves neurological function and motor/cognitive performance, and is proposed as a strategy for treating neurodegenerative diseases. EE has been investigated in the R6/2 mouse model of Huntington's disease (HD), where increased social interaction, sensory stimulation, exploration, and physical activity improved survival. We have also shown previously that HD patients and R6/2 mice have disrupted circadian rhythms, treatment of which may improve cognition, general health, and survival. METHODOLOGY/PRINCIPAL FINDINGS: We examined the effects of EE on the behavioral phenotype and circadian activity of R6/2 mice. Our mice are typically housed in an "enriched" environment, so the EE that the mice received was in addition to these enhanced housing conditions. Mice were either kept in their home cages or exposed daily to the EE (a large playground box containing running wheels and other toys). The "home cage" and "playground" groups were subdivided into "handling" (stimulated throughout the experimental period) and "no-handling" groups. All mice were assessed for survival, body weight, and cognitive performance in the Morris water maze (MWM). Mice in the playground groups were more active throughout the enrichment period than home cage mice. Furthermore, R6/2 mice in the EE/no-handling groups had better survival than those in the home cage/no-handling groups. Sex differences were seen in response to EE. Handling was detrimental to R6/2 female mice, but EE increased the body weight of male R6/2 and WT mice in the handling group. EE combined with handling significantly improved MWM performance in female, but not male, R6/2 mice. CONCLUSIONS/SIGNIFICANCE: We show that even when mice are living in an enriched home cage, further EE had beneficial effects. However, the improvements in cognition and survival vary with sex and genotype. These results indicate that EE may improve the quality of life of HD patients, but we suggest that EE as a therapy should be tailored to individuals.

SUBMITTER: Wood NI

PROVIDER: S-EPMC2820540 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Responses to environmental enrichment differ with sex and genotype in a transgenic mouse model of Huntington's disease.

Wood Nigel I NI Carta Valentina V Milde Stefan S Skillings Elizabeth A EA McAllister Catherine J CJ Ang Y L Mabel YL Duguid Alasdair A Wijesuriya Nadeev N Afzal Samira Mohd SM Fernandes Joe X JX Leong T W TW Morton A Jennifer AJ

PloS one 20100212 2

<h4>Background</h4>Environmental enrichment (EE) in laboratory animals improves neurological function and motor/cognitive performance, and is proposed as a strategy for treating neurodegenerative diseases. EE has been investigated in the R6/2 mouse model of Huntington's disease (HD), where increased social interaction, sensory stimulation, exploration, and physical activity improved survival. We have also shown previously that HD patients and R6/2 mice have disrupted circadian rhythms, treatment ...[more]

PMID: 20174443

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Project description:Huntington's disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein, Striatum atrophy in HD leads to a progressive disturbance of psychiatric, motor, and cognitive function. Recent studies of HD patients revealed that the degeneration of cerebellum is also observed independently from the striatal atrophy during early HD stage and may contribute to the motor impairment and ataxia observed in HD. Cerebellar Purkinje cells (PCs) are responsible for the proper cerebellar pathways functioning and motor control. Recent studies on mouse models of HD have shown that the abnormality of the biochemical functions of PCs are observed in HD, suggesting the contribution of PC dysfunction and death to the impaired movement coordination observed in HD. To investigate ataxic symptoms in HD we performed a series of experiments with the yeast artificial chromosome transgenic mouse model of HD (YAC128). Using extracellular single-unit recording method we found that the portion of the cerebellar PCs with bursting and irregular patterns of spontaneous activity drastically rises in aged YAC128 HD mice when compared with wild type littermates. Previous studies demonstrated that SK channels are responsible for the cerebellar PC pacemaker activity and that positive modulation of SK channel activity exerted beneficial effects in different ataxic mouse models. Here we studied effects of the SK channels modulator chlorzoxazone (CHZ) on the motor behavior of YAC128 HD mice and also on the electrophysiological activity and neuroanatomy of the cerebellar PCs from these mice. We determined that the long-term intraperitoneal injections of CHZ alleviated the progressive impairment in the firing pattern of YAC128 PCs. We also demonstrated that treatment with CHZ rescued age-dependent motor incoordination and improved the cerebellar morphology in YAC128 mice. We propose that abnormal changes in the PC firing patterns might be a one of the possible causes of ataxic symptoms in HD and in other polyglutamine disorders and that the pharmacological activation of SK channels may serve as a potential way to improve the activity of cerebellar PCs and relieve the ataxic phenotype in HD patients.

Dataset Information

Responses to environmental enrichment differ with sex and genotype in a transgenic mouse model of Huntington's disease.

Publications

Responses to environmental enrichment differ with sex and genotype in a transgenic mouse model of Huntington's disease.

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