Translating Cognitive Decline in Mice
How touchscreen-based assays can change the way cognitive impairment is tested in Alzheimer’s disease mouse models. A Q&A with Dr. Maksym Kopanitsa
Cognitive decline is one of the most distinctive hallmarks of Alzheimer’s disease that represents a heavy burden for patients and caregivers. The quest to identify the next AD blockbuster drug typically includes cognitive testing in mouse models using techniques like learning in water maze.
This test involves placing an animal in a pool of water and measuring the time taken for the animal to reach a submerged platform, so that they can stop swimming. Virtually every reputable mouse model of Alzheimer’s disease has been tested using this method. However, it makes one stop and wonder – would you do that with a human patient? Certainly, no one makes individuals with mild cognitive disability swim repetitively in a pool of water until they find a platform to rest on.
To ensure better translation of cognitive assessment from rodents to humans, one can use alternatives such as touchscreen-based operant testing where mice are trained to use their nose to touch a screen. Mice performing touchscreen tasks are not much different from humans who are assessed in various cognitive test batteries such as CANTAB.
To hear more about touchscreen technology, Dr. Anjli Venkateswaran, a Senior Product Manager with Charles River Discovery Services, at Charles River connected recently with Dr. Maksym Kopanitsa, head of translational biology at Charles River Finland, which specializes in diseases of the central nervous system to discuss the intricacies of this strategy.
AV: Can you share a little history on how touchscreen testing in mice evolved?
MK: The first attempts to to use standardized, touchscreen based assessments of cognitive abilities were done in humans by Trevor Robbins and Barbara Sahakian in Cambridge (UK). About 30 years ago, these scientists developed CANTAB, or the Cambridge Neuropsychological Test Automated Battery, in order to detect cognitive impairments in individuals with Alzheimer’s disease and Parkinson’s disease. The idea to use automated touchscreen approach for tests in animals came a little later and was attempted by several research groups However, the most lasting practical implementation of touchscreen test in rodents was done in the lab of Prof. Robbins by Tim Bussey and other colleagues in mid-90s. Their first experiments were done in rats, and touchscreen tasks have been adapted for mice about 15 years ago. Although we can see that development of this technique was “human-to-mouse”, recently there was a study, where an object-location associative task, worked-out initially for mice and rats, was used in humans. So, perhaps we may see more examples of reverse translation in the near future.
AV: What are the major benefits of touchscreen testing compared to traditional methods like water maze?
MK: As you already mentioned, one of the principal benefits of touchscreen-based tasks in mice is their greater similarity to the setting in which human subjects are tested. Although in both techniques animals rely on vision, arguably nose poke reactions to images on the screen are more translational than the time it takes a rat to swim to the platform area. For some mouse models of neurodegenerative diseases, swimming may be too strenuous an exercise because of their impaired locomotor abilities. It is likely that learning for nutritional reward, which is given for correctly performed touchscreen task, has different molecular and anatomical substrates than learning acquired from the desire to escape an unpleasant experience in the water maze. Finally, touchscreen tasks are automated and more amenable for fine tuning than water maze testing. At the same time, some complex touchscreen tasks require long training periods, so sophistication comes at the expense of time. This is why it will be always a “horses for courses” situation and researchers will want to use water maze testing, touchscreen tasks and other methods of cognitive assessment, depending on their scientific priorities.
AV: How would one go about designing a touchscreen study to test a new drug candidate for AD?
MK: First, we would need to select an appropriate mouse model with relevant construct validity. For example, if the compound targets beta amyloid accumulation, we would choose mice that have higher concentration of beta amyloid oligomers or exhibit beta amyloid plaques. For substances aimed at tau protein, we would select mice that demonstrate tau hyperphosphorylation and aggregation. There are also transgenic mice that combine both amyloid and tau pathological features, for example CVN mice, available from Charles River.
Next, I would ask the question: which neuropsychological domain are we going to target with this drug? Is this learning and memory, attention or, perhaps, motivation? Although every touchscreen task requires a combination of various cognitive skills, we can look more specifically, for example into discriminatory learning, sustained attention or tenacity to produce repetitive touch responses in different tests. Good news is that some of these tests can be combined in a battery, so the same set of mice can be tested sequentially in different tasks. Finally, I would look into what CANTAB tasks have reported a deficit in Alzheimer’s disease patients and whether those CANTAB tasks have analogous mouse versions.