basis of those findings, the current study sought to assess the putative female-specific depression-like behaviors at 8 weeks of age (prior to any cognitive and motor deficits that are observed from 12 and 15 weeks of age respectively in this transgenic line [31,32]) and further investigate the possible dysregulation of 5-HT signaling in HD animals. Results Altered affective behaviors in female HD mice Measuring the time of immobility in the forced-swimming test (FST), we found overall effects of genotype (F(1,97) = 11.7, p,0.001) and treatment (F(1,97) = 10.3, p,0.01) as well as a significant interaction between sex and genotype (F(1,97) = 6.36, p,0.01). We also found a significant interaction between sex, genotype and treatment with sertraline (F(1,97) = 3.85, p,0.05). Indeed compared to WT animals, only female HD mice exhibited augmented immobility times (Fig. 1B). In addition, acute administration of sertraline decreased the mean immobility times of all groups (p,0.05) except for male HD mice (Fig. 1A). A second cohort of mice was then used to study the effects of acute sertraline on the tail-suspension test (TST) as a second measure of depression-related behavior. Looking at time of immobility, we found overall effects of sex (F(1,67) = 7.35, p,0.05) and treatment (F(1,67) = 33.5, p,0.001) but no effect of genotype (F(1,67) = 2.16, p = 0.15) nor any significant between factors interactions. Indeed regardless of genotype, acute sertraline decreased immobility times of both male (Fig. 1C) and female (Fig. 1D) animals on the TST. Anhedonia, defined as a decrease in the perceived pleasant or rewarding properties of events, is a core symptom in depression and can be assessed using the well-validated saccharin preference test [33]. We found a significant interaction between sex and genotype (F(1,44) = 5.84, p,0.05) on saccharin preference (Fig. 2A). Indeed compared to WT animals, only female HD mice exhibited reduced saccharin preference (p,0.05). Interestingly there was an overall effect of genotype (F(1,44) = 12.3, p,0.01) on total fluid intake (Fig. 2B), but no significant effect of sex or interactions. In order to extend the study of the emotionality-related behaviors, mice were exposed to the novelty-suppressed feeding test (NSFT) in which we measured the latency of the animal to eat in an aversive environment. This paradigm provides an anxiety- related measure and has been shown to be sensitive to both anxiolytics and chronic antidepressants [34]. Analyzing the latency to feed (Fig. 3A), we found a significant effect of both sex (F(1,55) = 9.6, p,0.01) and genotype (F(1,55) = 13.3, p,0.001) as well as a significant interaction (F(1,55) = 4.2, p,0.05). Since latency data failed to pass the normality test (p,0.05, Shapiro- Figure 1. Effect of sex, HD mutation and acute sertraline administration on immobility time in mice exposed to the forced- swimming test (FST) and the tail suspension test (TST). (A) Analyzing FST performances we found no differences in immobility time (in sec) between R6/1 (HD) and wild-type (WT) vehicle-injected male mice. Acute injection with sertraline (20 mg/kg, i.p.) decreased immobility time in male WT mice but not HD animals. (B) Control (vehicle-injected) female HD mice exhibited augmented immobility time when compared to WT animals. The behavioral deficit observed in HD mice was rescued by acute sertraline which also decreased immobility in WT female mice. Looking at immobility time in mice exposed to TST, we found a significant effect of sertraline in both (C) male and (D) female animals without any effect or interaction with the genotype. Values represent means (6 SEM) of n = 8–15 mice per group. WT vs. HD: (*) p,0.05; Vehicle vs. sertraline20: (+) p,0.05, (++) p,0.01. doi:10.1371/journal.pone.0022133.g001 PLoS ONE | www.plosone.org 2 July 2011 | Volume 6 | Issue 7 | e22133