Differential effects of early environmental enrichment on emotionality related behaviours in Huntington's disease transgenic mice
Authors: Renoir Thibault , Pang Terence Y.C. , Mo Christina , Chan Grace , Chevarin Caroline , Lanfumey Laurence , Hannan Anthony J. 
Published: October 2012

Key points
Clinical diagnosis of Huntington's disease (HD) is determined on the basis of motor symptoms; however, the pre‐motor stages of the disease are commonly associated with psychiatric alterations including depression and anxiety.
Using the R6/1 transgenic mouse model of HD, this study is the first report on the effects of environmental enrichment (EE) at a very early stage on a broad range of behavioural tests assessing stress‐related measures.
Environmental enrichment did not prevent despair‐ and anhedonia‐like behaviours displayed by HD mice. However, EE reduced anxiety levels and corrected altered stress responses observed in HD mice.
Despite the enhanced hypothermic response to the serotonin 5‐HT1A receptor agonist 8‐OH‐DPAT exhibited by HD mice, we found a reduction in 5‐HT1A receptor mediated stimulation of [35S]GTP‐γ‐S binding in the dorsal raphe nucleus and the hippocampus of HD animals.
Our data suggest that early EE has beneficial effects on the anxiety‐like, but not on the depression‐like, behaviours in HD mice. We also provide evidence that 8‐OH‐DPAT induced hypothermia could be mediated by other targets besides the serotonin 5‐HT1A receptors.
Abstract  Psychiatric disorders such as depression and anxiety are reported in patients with Huntington's disease (HD). Recent studies suggest beneficial effects of environmental enrichment (EE) on HD progression possibly through the serotonergic system. We investigated the potential effectiveness of EE in correcting the affective‐like phenotype of female R6/1 HD mice. In addition to a behavioural battery of tests assessing depression and anxiety‐related endophenotypes, we recorded physiological measures, including body temperature regulation and defecation rate as indices of stress reactivity. Finally, following identification of changes in serotonin (5‐HT) receptor gene expression we measured the function of 5‐HT1A auto‐ and hetero‐receptors. We found that 8‐week‐old female HD mice exhibited higher immobility time in the forced swimming test and a decreased preference for saccharin solution. EE did not correct those depressive‐like behaviours but reduced anxiety‐related measures in unconditioned approach/avoidance conflict situations. Defecation rate in a large open field and change in temperature during exposure to the tail suspension test were both enhanced in HD compared to wild‐type animals. Despite the enhanced hypothermic response to the 5‐HT1A receptor agonist 8‐OH‐DPAT exhibited by HD mice, we found a reduction in 5‐HT1A receptor‐mediated stimulation of [35S]GTP‐γ‐S binding in the dorsal raphe nucleus and the hippocampus of HD animals. EE did not change 5‐HT1A receptor function. Our data suggest that early EE has beneficial effects on the anxiety‐like, but not on depression‐like, behaviours in HD. This is the first evidence that these affective endophenotypes can be dissociated via this form of environmental stimulation. As 5‐HT1A receptor dysfunction was not affected by EE, this receptor is unlikely to underlie the anxiety‐related phenotype of HD. However, the specific regulatory role of the 5‐HT1A autoreceptor in mediating depressive‐like behaviour in HD remains to be elucidated. Interestingly, by comparing in vivo and in vitro results, our findings suggest that 8‐OH‐DPAT‐induced hypothermia could be mediated by other targets besides the 5‐HT1A autoreceptor, including hippocampal 5‐HT7 receptors.