Please cite this article in press as: Mo C, et al. Novel ethological endophenotypes in a transgenic mouse model of Huntington’s disease. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.04.003 ARTICLE IN PRESS G Model BBR-8838; No. of Pages 11 Behavioural Brain Research xxx (2014) xxx–xxx Contents lists available at ScienceDirect Behavioural Brain Research jou rn al hom epage: www.elsevier.com/locate/bbr Research report Novel ethological endophenotypes in a transgenic mouse model of Huntington’s disease Christina Mo a,b,∗ , Thibault Renoir a,∗,1 , Anthony J. Hannan a,b,1 a Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, University of Melbourne, Parkville, Melbourne, Australia b Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Melbourne, Australia h i g h l i g h t s • We describe protocols to assess ethologically-relevant behaviors in R6/1 HD mice. • Olfactory and nest-building tests were sensitive to early decline in HD mice. • Male vocalization testing revealed a late-stage sexual deficit in HD mice. • Species-specific assays may improve modeling of the functional impact of disease. a r t i c l e i n f o Article history: Received 11 February 2014 Received in revised form 27 March 2014 Accepted 1 April 2014 Available online xxx Keywords: Huntington’s disease Olfactory Nest-building Sexual Vocalization Ethological a b s t r a c t Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder with a characteristic triad of cognitive, affective and motor symptoms. Transgenic HD mice show excellent construct and face validity for many of these symptoms, however the decline in some facets of every day activity in humans is difficult to model. One approach is the assessment of species-relevant behaviors. Here we described three ethologically appropriate tests in the mouse—olfactory sensitivity, nest-building and sexually-motivated vocalizations. In R6/1 HD mice, olfactory and nest-building tests were sensitive to early dysfunctions induced by the HD mutation. Male vocalization testing revealed a late-stage sexual disinterest in R6/1 HD mice compared to WT littermates. We show that essential, species-relevant functions are disrupted by the HD mutation. The development of integrative behavioral assays which more closely model ‘activities of daily living’ (ADL) will facilitate the testing of novel therapeutic interventions in animal models as well as their clinical translation. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a trinucleotide repeat in the HD gene [39]. HD patients show decline in a characteristic triad of cognitive, affective and motor symptoms as well as circadian, metabolic and peripheral dysfunctions [1,73]. This culminates in the impairment of activities of daily living (ADL) [33], basic activi- ties necessary for self-care such as dressing, personal hygiene and mobility [43]. Assessments which incorporate ADL measures such ∗ Corresponding authors at: Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, 30 Royal Parade, University of Melbourne, Melbourne 3010, VIC, Australia. Tel.: +61 0431961855; fax: +61 0390353107. E-mail addresses: christina.mo@unimelb.edu.au, omosqrt@gmail.com (C. Mo), tibo.renoir@gmail.com (T. Renoir). 1 The authors contributed equally as joint last authors. as the Unified Huntington’s Disease Rating Scale (UHDRS) are sen- sitive to impairments in gene carriers prior to disease diagnosis [6]. Animal models have been essential in the advancement of ther- apies and understanding etiology in HD [23]. Transgenic mouse models of HD show excellent face and construct validity and can recapitulate well the symptoms of HD using the standard test bat- tery for behaviors [13,67]. However, impaired ADL such as the early decline in occupational performance and safe driving [6] cannot be directly modeled in animals. Patient-based outcomes such as ADL assessments are instrumental in the evaluation of pharmaco- logical agents in disease [85]. Assessment of behaviors relevant to the model species (ethological behaviors) may reveal how essen- tial functions are impacted by the HD mutation. This ethological approach may offer an improved approach to pre-clinical testing of therapeutics. Three behaviors relevant to daily function in a mouse are olfac- tory detection, building a nest and sexual communication. Olfaction http://dx.doi.org/10.1016/j.bbr.2014.04.003 0166-4328/© 2014 Elsevier B.V. All rights reserved.