Differential effects of early environmental enrichment on emotionality related behaviours in Huntington's disease transgenic mice

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-HT_1A 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-HT_1A receptor agonist 8-OH-DPAT exhibited by HD mice, we found a reduction in 5-HT_1A 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-HT_1A 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-HT_1A 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-HT_1A 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-HT_1A autoreceptor, including hippocampal 5-HT₇ receptors.