Learning Set Formation and Reversal Learning in Mice During High-Throughput Home-Cage-Based Olfactory Discrimination.

Rodent behavioral tasks are crucial to understanding the nature and underlying biology of cognition and cognitive deficits observed in psychiatric and neurological pathologies. Olfaction, as the primary sensory modality in rodents, is widely used to investigate cognition in rodents. In recent years, automation of olfactory tasks has made it possible to conduct olfactory experiments in a time- and labor-efficient manner while also minimizing experimenter-induced variability. In this study, we bring automation to the next level in two ways: First, by incorporating a radio frequency identification-based sorter that automatically isolates individuals for the experimental session. Thus, we can not only test animals during defined experimental sessions throughout the day but also prevent cagemate interference during task performance. Second, by implementing software that advances individuals to the next test stage as soon as performance criteria are reached. Thus, we can prevent overtraining, a known confounder especially in cognitive flexibility tasks. With this system in hand, we trained mice on a series of four odor pair discrimination tasks as well as their respective reversals. Due to performance-based advancement, mice normally advanced to the next stage in less than a day. Over the series of subsequent odor pair discriminations, the number of errors to criterion decreased significantly, thus indicating the formation of a learning set. As expected, errors to criterion were higher during reversals. Our results confirm that the system allows investigating higher-order cognitive functions such as learning set formation (which is understudied in mice) and reversal learning (which is a measure of cognitive flexibility and impaired in many clinical populations). Therefore, our system will facilitate investigations into the nature of cognition and cognitive deficits in pathological conditions by providing a high-throughput and labor-efficient experimental approach without the risks of overtraining or cagemate interference.