Research reportNovel ethological endophenotypes in a transgenic mouse model of Huntington's disease

- 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.

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.