Responses to Environmental Enrichment Differ with Sex and Genotype in a Transgenic Mouse Model of Huntington's Disease

Abstract

BackgroundEnvironmental 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 FindingsWe 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/SignificanceWe 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.

A ketogenic diet delays weight loss and does not impair working memory or motor function in the R6/2 1J mouse model of Huntington's disease

“…3). There were trends for earlier male mortality (as found in some prior reports: [41, 43]), regardless of diet treatment. There was a trend for the KD to reduce lifespan in females, but not males (Fig.…”

Genetic Deletion of Transglutaminase 2 Does Not Rescue the Phenotypic Deficits Observed in R6/2 and zQ175 Mouse Models of Huntington's Disease

“…It is possible that the previous report of increased survival in R6/2 mice after TG2 ablation could be modulated by the CAG repeat of the model studied. Another possible explanation as to why we did not see difference in R6/2 survival after TG2 ablation may be because of the housing conditions utilized in our study, which have been shown previously to improve survival [34], [35]. Since our goal is to uncover robust targets for HD, we provided the animals with a moderate enriched environment (namely: group housing, a range of bedding, plastic bones and tunnels) as well as easy access to food and water.…”

Reduced expression of conditioned fear in the R6/2 mouse model of Huntington's disease is related to abnormal activity in prelimbic cortex

“…All mice were kept on a 12-hour light cycle (lights on at 0700) and individually housed with ad libitum access to food and water. Although group housing is known to provide environmental enrichment and social benefits to mice (Balcombe, 2006), we opted for individual housing to facilitate comparisons of our results with studies from our lab as environmental enrichment is known alter the phenoptype of R6/2 mice (Wood et al, 2010). In fact, individual housing is appropriate for mice with a surgically implanted headstage (see below).…”