ASSESSMENT OF LEARNING AND MEMORY IN THE CVN MOUSE MODEL OF ALZHEIMER’S DISEASE IN AUTOMATED TOUCH SCREEN CHAMBERS

Abstract

According to previously published data and internal model validation, the CVN mouse model of AD exhibits cognitive impairments in contextual fear conditioning, Barnes maze and radial arm water maze most prominently at 9–12 months of age. To determine if impaired learning can be detected at an earlier age, we evaluated their cognitive performance by using a touch screen operant platform (Horner et al., 2013), which is similar to computerized CANTAB testing widely used in clinical setting. Cohorts of 4–5-month old male CVN (APPSDI/NOS2 knockout) and associated wild type (WT) mice were obtained from Charles River (Sulzfeld, Germany). Following acclimatization, animals were introduced to a restricted diet throughout the study period. Testing was conducted in Bussey-Saksida mouse touch screen chambers (Campden Instruments, Loughborough, UK). Mice were trained to develop screen-touching behavior using a 5-stage pretraining algorithm. Thereafter, they were tested in their ability to visually discriminate alternative black and white “lines-grid” stimuli on the touch screen. In order to test cognitive flexibility, the task of reversal of the acquired visual discrimination was implemented by switching the contingencies used in the visual discrimination test. During pretraining, CVN mice and WT mice required similar number of sessions to achieve the pretraining criterion. Furthermore, the majority of mice successfully acquired visual discrimination within 20 days, again without significant differences in the number of sessions required to reach the discrimination criterion between CVN and WT mice. We found that CVN mice did not exhibit gross cognitive impairment at 5–6 months of age and could learn a simple visual discrimination task at a rate comparable to that of WT mice. This is in line with the lack of deficits previously reported in other cognitive assays at comparable ages. However, CVN mice did demonstrate a slower rate of reversal learning at these ages. Further exploration of this slowed reversal learning phenotype is planned using this highly translatable touch screen approach in order to identify deficits in other touch screen tasks at an early age, but also at later ages, when the AD-related phenotypes are more prominent in terms of brain pathology and behavioral readouts.