Mouse tests of cognition
John Stephenson
Progressive loss of short-term memory is a defining feature of Alzheimer’s disease. Some of the genes and proteins that are involved in learning and memory and which, when altered, may be involved in the loss of memory seen in Alzheimer’s disease have been identified.
Potential treatments for Alzheimer’s disease are initially investigated in animal models of the disease.
Genetically altered mice, in which genes known to be involved in Alzheimer’s disease have been altered, deleted or increased, are being used to study their ability to learn and remember simple behavioural and cognitive tasks.
Morris water maze
One of the most commonly used tests is the Morris water maze. We are currently using this test to study how a mutation of the APP gene, APPswe, that was originally identified in a large Swedish family with early-onset Alzheimer’s disease, affects learning and memory in genetically-altered mice that carry the mutation (Tg2576 mice), and whether treatments that reduce the effects of the mutation, also improve cognitive performance.
In this test, the mouse is placed into a large tank of water and it has to learn to swim to a small platform hidden just below the surface of the water. The test is repeated over several days, and the ability of the mouse to remember the platform location is assessed by measuring the amount of time taken to find it. Around the walls of the room are large posters or objects to provide spatial cues for the mouse to assist the mouse in remembering the location of the platform relative to these cues. Therefore, this is a test of spatial memory.
Cue mouse
To ensure that the performance of the mouse is not impeded by visual or motor problems, on the first day of training, the platform is made visible by being placed just above the water surface and by a conspicuous marker placed on it. Any mice that cannot find the platform in this task are excluded from any further testing.
Test mice
The control (wild-type) mice have learnt the location of the platform and reach it quickly. Double transgenic APPswe/X11mice locate the platform more slowly but concentrate their search efforts in the vicinity of the platform whereas APPswe mice are unable to remember the approximate location of the platform and search the entire pool.
Figure showing swimming paths of mice on the last day (14th) of training 
Because they can remember and learn, normal mice find the platform more quickly in the last days of the test than they do in the first few days. In contrast, the Alzheimer’s mice do not learn and they take as long to find the platform on the last day as they did on the first day. Therefore, any new treatment should improve the performance of the Alzheimer’s mouse in the water maze.
Burrowing task. This task is carried out in a box which is divided by a wall into a smaller dark compartment and a larger brightly lit compartment that are linked by an underpass. The mice prefer to stay in the darker area and, when placed in the light compartment, will use the underpass to enter the dark co mpartment. The task is made progressively more difficult by :
(i) filling the underpass with sawdust, which the mice must remove,
(ii) by covering the whole floor with sawdust and the mice must remember where the underpass was located and,
(iii) by putting a piece of cardboard in the underpass which the mice must remove in order to gain access to the dark compartment.
Hebb-Williams maze. This is a square black plastic box (60cm x 60cm x 10cm high), with a start box and a finish box at opposite corners. It is filled with water to a depth of about 1cm and, in order to escape from the water the mouse has to paddle across to the dry finish box. Initially, the mouse is given some simple practive mazes in which the finish box can be seen from the start box. The task is then made progressively more difficult by introducing barriers to create a series of increasingly complex maze designs. The test is based on that described by
Rabinovitch and Rosvold in 1951. They placed food in the finish box as a reward rather than escape from water.
2 practice maze patterns
5 progressively more complex maze patterns
The above tasks are normally performed each day over several days. Learning and memory are measured from the gradual reductions in the time it takes the mice to complete the test by remembering the location of the hidden platform, underpass, or finish box, from one day to the next.