Abstract
Many neurological and psychiatric disorders are characterized by deficits in cognitive flexibility. Modeling cognitive flexibility in mice enables the investigation of mechanisms underlying these deficits. The majority of currently available behavioral tests targeting this cognitive domain are reversal learning tasks that require scheduled food restriction, extended training periods and labor-intensive, and stress-inducing animal handling. Here, we describe a novel 4-day (4-d) continuously running task measuring discrimination- and reversal learning in an automated home cage (CognitionWall DL/RL task) that largely eliminates these limitations. In this task, mice can earn unlimited number of food rewards by passing through the correct hole of the three-holed CognitionWall. To assess the validity and sensitivity of this novel task, the performance of C57BL/6J mice, amyloid precursor protein/presenilin1 transgenic (APP/PS1) mice, α-calmodulin kinase-II (αCaMKII) T305D knock-in mice, and mice with an orbitofrontal cortex lesion were examined. We found that C57BL/6J mice reach stable performance levels within the 4 d of the task, while experiencing only slight reductions in weight and no major effects on circadian rhythm. The task detected learning deficits in APP/PS1 transgenic and αCaMKII T305D mutant mice. Additionally, we established that the orbitofrontal cortex underlies reversal learning performance in our task. Because of its short duration and the absence of food deprivation and concurrent weight loss, this novel automated home-cage task substantially improves comprehensive preclinical assessment of cognitive functions in mouse models of psychiatric and neurological disorders and also enables analysis during specific developmental stages.
Highlights
In many brain disorders, including schizophrenia (Murray et al 2008; Leeson et al 2009) and autism (D’Cruz et al 2013), the balance between automatic and goal-directed responding is shifted toward less flexible behavioral patterns
Once mice have reached stable performance levels during discrimination learning (DL), the reward associations are reversed during a reversal learning (RL) phase, or changed toward a different stimulus dimension during a shift phase, to measure the ability of mice to flexibly adjust responses
In the 4-d continuously running automated home-cage CognitionWall discrimination learning and reversal learning (DL/RL) task, mice first had to learn to earn food by going through the left hole in the CognitionWall that was placed in front of a pellet reward dispenser, i.e., the discrimination learning (DL) stage
Summary
In many brain disorders, including schizophrenia (Murray et al 2008; Leeson et al 2009) and autism (D’Cruz et al 2013), the balance between automatic and goal-directed responding is shifted toward less flexible behavioral patterns. Once mice have reached stable performance levels during DL, the reward associations are reversed during a reversal learning (RL) phase, or changed toward a different stimulus dimension during a shift phase, to measure the ability of mice to flexibly adjust responses . These operant procedures require daily periods of total food deprivation until the feeding moment to maintain body weight at 90%–80% of original, prior to and during the entire training period of the task, in order to keep mice motivated to work for rewards. Mice had to participate in the continuously running task to obtain food rewards in the absence of any other food which restricted the availability of food to periods of active task participation
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