Protocol for three alternative paradigms to test spatial learning and memory in mice

Here, we describe three alternative paradigms to overcome the limitations of the most widely used spatial learning paradigm for rodents: the Morris water maze. We outline the preparation of behavioral testing rooms and mouse handling/habituation prior to testing. We then detail three spatial learning and memory tasks: the Barnes maze, active place avoidance, and novel object location tasks. These tests have been successfully used across multiple ages (from 2 to 24 months) in both wild-type and transgenic animals. For complete details on the use and execution of this protocol, please refer to Leiter et al. (2022). [Display omitted] •Preparation of rooms for behavioral testing of mice•Handling and habituation of mice prior to behavioral testing•Experimental design for three spatial learning and memory tasks Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics. Here, we describe three alternative paradigms to overcome the limitations of the most widely used spatial learning paradigm for rodents: the Morris water maze. We outline the preparation of behavioral testing rooms and mouse handling/habituation prior to testing. We then detail three spatial learning and memory tasks: the Barnes maze, active place avoidance, and novel object location tasks. These tests have been successfully used across multiple ages (from 2 to 24 months) in both wild-type and transgenic animals.