Jung, O.; Hoffmeister-Ullerich, S.; Omriouate, A.; Plumhoff, J.; Kreutz, M. R.; Grochowska, K. M.; Morellini, F.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The disease is characterized by movement disorders, and it also presents with personality changes, including apathy and aggression, along with cognitive decline. While most animal models for HD have been validated for motor deficits, less is known about alterations in other behavioral functions. Here, we performed a longitudinal study to analyze the behavior of a knock-in mouse model of HD with a chimeric mouse/human exon 1 containing 140 CAG repeats inserted in the murine huntingtin gene. We specifically inquired about the onset of cognitive impairments in knock-in mice and whether changes in various behavioral functions such as locomotion, anxiety, and cognition correlate at the individual level. Our data indicate that female and male knock-in mice exhibit reductions in body weight, novelty-induced locomotion, and remote spatial memory retrieval. However, social behavior, working, and short-term memory remain unaffected. Within knock-in mice, lower open-field activity correlated with poorer remote memory performance. Moreover, CAG repeat length negatively correlated with locomotor activity and spatial memory, indicating that greater repeat expansion predicts more severe behavioral impairment. These findings identify early affective changes, followed by selective long-term memory and locomotor deficits, in knock-in mice, supporting this model as a useful platform for studying prodromal HD and repeat-length-dependent disease variability.