Longitudinal Assessment of Working Memory Performance in the APPswe/PSEN1dE9 Mouse Model of Alzheimer’s Disease Using an Automated Figure-8-Maze

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with a long preclinical and prodromal phase. To enable the study of disease mechanisms, AD has been modeled in many transgenic animal lines and cognitive functioning has been tested using several widely used behavioral tasks. These tasks, however, are not always suited for repeated longitudinal testing and are often associated with acute stress such as animal transfer, handling, novelty, or stress related to the task itself. This makes it challenging to relate cognitive dysfunction in animal models to cognitive decline observed in AD patients. Here, we designed an automated figure-8-maze (F8M) to test mice in a delayed alternation task (DAT) in a longitudinal manner. Mice were rewarded when they entered alternate sides of the maze on subsequent trials. Automation as well as connection of the F8M set-up with a home cage reduces experimenter interference and minimizes acute stress, thus making it suitable for longitudinal testing and facilitating clinical translation. In the present study, we monitored cognitive functioning of 2-month-old APPswe/PSEN1dE9 (APP/PS1) mice over a period of 4 months. The percentage of correct responses in the DAT did not differ between wild-type and transgenic mice from 2 to 6 months of age. However, 6-month-old mice displayed an increase in the number of consecutive incorrect responses. These results demonstrate the feasibility of longitudinal testing using an automated F8M and suggest that APP/PS1 mice are not impaired at delayed spatial alternation until 6 months of age under the current experimental conditions.

Abnormal whisker movements in the 3xTg‐AD mouse model of Alzheimer's disease

“… 19 In addition, repeat testing of the same animal can impact behavioural tasks, as animals will habituate and learn tasks over time, which may affect their behaviour. 53 Indeed, we have previously shown that a mouse model of anxiety has different whisker movements to control mice 24 ; therefore, an altered sensitivity to stress is likely to affect our results. The lack of automation of our set‐up may also confound testing over different ages, while here we made sure that all data was collected over a period of just a few days, with all the equipment kept the same throughout.…”

“…Nevertheless, it is rather difficult to conduct such a study, especially to 17 months, due to the increased mortality rates in older 3xTg‐AD mice 19 . In addition, repeat testing of the same animal can impact behavioural tasks, as animals will habituate and learn tasks over time, which may affect their behaviour 53 . Indeed, we have previously shown that a mouse model of anxiety has different whisker movements to control mice 24 ; therefore, an altered sensitivity to stress is likely to affect our results.…”

“…Nevertheless, it is rather difficult to conduct such a study, especially to 17 months, due to the increased mortality rates in older 3xTg-AD mice 19. In addition, repeat testing of the same animal can impact behavioural tasks, as animals will habituate and learn tasks over time, which may affect their behaviour 53.…”

Two complementary circuits for spatial navigation in mouse: evidence from Fos mapping

“…In this work, we successfully implemented a novel behavioral task that tests the ability of mice to follow the correct path and to retrieve a reward, based solely on the spatial context presented. Although similar automated maze devices were constructed previously [11,12,[15][16][17][18], and the T-Maze protocol has been tested in a plethora of previous studies [10,[19][20][21][22][23], it was always used in the win-shift arrangement, where spatial information merely supported the rule learning. The animals had to remember the given spatial orientation and utilize it to choose the opposite arm during the choice phase.…”

“…We designed and implemented an automated, semi-autonomous system for spatial memory tests. It is based on the T-Maze paradigm [9][10][11][12], with modifications allowing for reliable dependence on visual cues. It allows for a relatively high throughput with minimum human intervention.…”