Sex-Dependent Changes in Social Behaviors in Motor Pre-Symptomatic R6/1 Mice

Abstract

BackgroundThe R6/1 mouse line is one of the most widely employed models of Huntington Disease (HD), a complex syndrome characterized by motor and non-motor deficits. Surprisingly, its behavioral phenotype during the early phases of the pathology when the motor impairments are not manifest yet has been poorly investigated. It is also not clear whether the expression of HD-like symptoms at the pre-motor stage in this mouse model differs between the two sexes.MethodsMale and female 12 weeks-old R6/1 mice and their wild-type littermates were tested on a battery of tests modeling some of the major neuropsychiatric non-motor symptoms of HD: alterations in social interest, social interaction and communication, as well as disturbances in prepulse inhibition of the acoustic startle response (PPI) and circadian patterns of activity. The lack of motor symptoms was confirmed during the entire experimental period by means of the tail test for clasping.ResultsR6/1 mice displayed marked alterations in all social behaviors which were mainly observed in males. Male R6/1 animals were also the only ones showing reduced body weight. Both male and female transgenic mice displayed mild alterations in the circadian activity patterns, but no deficits in PPI.ConclusionsThese results demonstrate the validity of the R6/1 mouse in mimicking selected neuropsychiatric symptoms of HD, the social deficits being the clearest markers of the pre-motor phase of the pathology. Furthermore, our data suggest that male R6/1 mice are more suitable for future studies on the early stages of HD.

Genetic deletion of the Histone Deacetylase 6 exacerbates selected behavioral deficits in the R6/1 mouse model for Huntington's disease

“…Vocalizations were then analyzed with Avisoft SASLab Pro (Version 5.013, Avisoft, Berlin, Germany) as previously described (Pietropaolo et al. 2011). …”

FoxP1 orchestration of ASD-relevant signaling pathways in the striatum

“…Huntington's and Parkinson's disease mouse models provide evidence for the involvement of MSNs in directing the production of USVs (Pietropaolo et al 2011;Grant et al 2014). Additionally, knockout of the Drd2 receptor reduces the number of USVs produced by mouse pups (Curry et al 2013).…”

Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington's disease

“…In Study 1, the effects of a single injection of WIN (0.4 mg/kg) were assessed on motor (open field test), social (interaction test with an adult female) and cognitive abilities (Y maze test for spatial recognition), in R6/1 mice and their wild-type littermates at 12 weeks of age. At this age behavioral abnormalities in these parameters are already observed in these transgenic animals (Pietropaolo et al, 2011b), while brain CB 1 receptors are still present and functional (Dowie et al, 2009). In Study 2, the impact of repeated daily injections of WIN (0.1 mg/kg), starting at 8 weeks of age, was assessed on the progressive appearance of HD phenotypes, testing R6/1 and wild-type littermates at 12, 14 and 16 weeks of age for body weight loss and behavioral deficits.…”

“…On the same day, tail samples were used for PCR genotyping (Mangiarini et al, 1996). Only male mice were used for experiments, since we have previously described a more marked behavioral phenotype in R6/1 male mice compared to females (Pietropaolo et al, 2011b). For study 1 a total of 38 mice were subjected to behavioral testing: 19 WT (9 VEH and 10 WIN) and 19 R6/1 (9 VEH and 10 WIN).…”