Impaired burrowing is the most prominent behavioral deficit of aging htau mice.

htau mice are deficient of murine tau but express all six human tau isoforms, leading to gradual tau misprocessing and aggregation in brain areas relevant to Alzheimer’s disease. While histopathological changes in htau mice have been researched in the past, we focused here on functional consequences of human tau accumulation. htau mice and their background controls – murine tau knock-out (mtau−/−) and C57Bl/6J mice – underwent a comprehensive trial battery to investigate species-specific behavior, locomotor activity, emotional responses, exploratory traits, spatial and recognition memory as well as acquisition, retention and extinction of contextual fear at two, four, six, nine and twelve months of age. In htau mice, tau pathology was already present at two months of age, whereas deficits in food burrowing and spatial working memory were first noted at four months of age. At later stages the presence of human tau on a mtau−/− background appeared to guard cognitive performance; as mtau−/− but not htau mice differed from C57Bl/6J mice in the food burrowing, spontaneous alternation and object discrimination tasks. Aging mtau−/− mice also exhibited increased body mass and locomotor activity. These data highlight that reduced food-burrowing performance was the most robust aspect of the htau phenotype with aging. htau and mtau−/− deficits in food burrowing pointed at the necessity of intact tau systems for daily life activities. While some htau and mtau−/− deficits overlap, age differences between the two genotypes may reflect distinct functional effects and compared to C57Bl/6J mice, the htau phenotype appeared stronger than the mtau−/− phenotype at young ages but milder with aging.