Research Article: BACHD rats expressing full-length mutant huntingtin exhibit differences in social behavior compared to wild-type littermates

Date Published: February 7, 2018

Publisher: Public Library of Science

Author(s): Giuseppe Manfré, Arianna Novati, Ilaria Faccini, Andrea C. Rossetti, Kari Bosch, Raffaella Molteni, Marco A. Riva, Johanneke E. Van der Harst, Huu Phuc Nguyen, Judith R. Homberg, Sheila M Fleming.

http://doi.org/10.1371/journal.pone.0192289

Abstract

Huntington disease (HD) is a devastating inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms without any cure to slow down or stop the progress of the disease. The BACHD rat model for HD carrying the human full-length mutant huntingtin protein (mHTT) with 97 polyQ repeats has been recently established as a promising model which reproduces several HD-like features. While motor and cognitive functions have been characterized in BACHD rats, little is known about their social phenotype.

This study focuses especially on social behavior since evidence for social disturbances exists in human patients. Our objective was to compare social behavior in BACHD and wild-type (WT) rats at different ages, using two different measures of sociability.

Animals were tested longitudinally at the age of 2, 4 and 8 months in the social interaction test to examine different parameters of sociability. A separate cohort of 7 month old rats was tested in the three chamber social test to measure both sociability and social novelty. Gene expression analyses in 8 months old animals were performed by real time qRT-PCR to evaluate a potential involvement of D1 and D2 dopaminergic receptors and the contribution of Brain-derived neurotrophic factor (BDNF) to the observed behavioral alterations.

In the social interaction test, BACHD rats showed age-dependent changes in behaviour when they were-re introduced to their cagemate after a 24 hours-period of individual housing. The time spent on nape attacks increased with aging. Furthermore, a significant higher level of pinning at 2 months of age was shown in the BACHD rats compared to wild-types, followed by a reduction at 4 and 8 months. On the other hand, BACHD rats exhibited a decreased active social behaviour compared to wild-types, reflected by genotype-effects on approaching, following and social nose contact. In the three chamber social test, BACHD rats seemed to show a mild deficit in preference for social novelty, but no changes in social interest. Molecular analyses revealed that BACHD animals exposed to the social interaction test displayed decreased mRNA levels of the total form of BDNF in ventral striatum and unaltered striatal expression of D1 and D2 dopamine receptors.

Taken together, these results indicate deficits in several parameters representative of sociability. Altered BDNF expression in the ventral striatum may contribute to the deficits in sociability in 8 months old BACHD rats. These data support the validity of the BACHD rat model in mimicking features of certain social deficits that could be relevant to symptoms in patients.

Partial Text

Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that is caused by an unstable expansion of a CAG repeat within the coding region of the huntingtin (HTT) gene [1]. It is characterized by motor impairment, abnormal choreic involuntary movements and by psychiatric, psychological and intellectual disorders [2]. Although more emphasis has been placed on detecting the early cognitive and motor impairments [3–6], emotional dysfunction might also precede the clinical HD diagnosis [7,8]. Thus, the identification of early psychiatric symptoms may be particularly important in HD because of their deleterious effects on everyday functioning and quality of life [8,9]. Characterizing early neuropsychiatric phenotypes in animal models of HD is therefore especially important.

The use of multiple social paradigms permitted us to detect potential HD-related deficits in different specific aspects of social behavior. The social interaction test revealed abnormal social play and aggressive behavior in BACHD animals as well as a trend towards a decreased interaction with conspecifics. It is worth mentioning the fact that we decided to use familiar pairs (cagemates) to have a better translational value of the results since HD causes major disruption in family life [29]. The three chamber social test showed mild deficits in social recognition in transgenic animals, providing an estimation of the social interest towards an unknown conspecific as well as of the recognition abilities between familiar and novel conspecifics, with limited physical interaction. Additionally, striatal expression of D1, D2 receptors and BDNF was assessed and related to social contact and social interest in 8 month old animals, reporting a decrease in the expression of BDNF in the ventral striatum and intact dopamine receptor expression.

 

Source:

http://doi.org/10.1371/journal.pone.0192289

 

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