Any scientist who intends to study mechanisms of action of novel therapeutics or effects of disease-relevant mutations on cognitive performance in rodents faces a question: Will the results have translational relevance? Although it is common to rely on well-validated, robust and expedient cognitive testing routines, many of them are somewhat simplistic (e.g., novel object exploration) or concomitant with unnaturally high stress levels (e.g., Morris water maze, forced swim test or fear conditioning). If the behavior readout is too basic, modulating it with drugs or mutations may not be able to tell much about subtle changes in brain function that often underlie cognitive disorders in humans. Using tasks that involve strong negative emotions due to anxiety or expected punishment can lead to results that would be hard to relate to human behavior during normal day-to-day activities or in a clinical setting. Therefore, techniques that allow for data-rich, low-stress and translational tests of cognitive behavior are urgently required by both academia and industry.
Recently, there have been important advances in the application of touch-sensitive screens for testing cognitive behavior in several animal species. Touchscreen tests utilize images on a touch-to a particular (“correct”) image stimulus or to different stimuli in correct screen locations, so their cognitive performance can be assessed in a highly quantitative, but also, automated and non-intrusive way. To stimulate responding, partial food restriction is often implemented. Animals receive a nutritional reward for correctly touching the right place on the screen. Currently available touchscreen tasks for rodents address simple forms of operant and Pavlovian conditioning as well as more complex cognitive paradigms, such as visual discrimination learning, object-location paired-associates learning and visuomotor conditional learning. Attention abilities of rodents can be examined in the 5-choice serial reaction time and continuous performance tasks, whereas cognitive flexibility, perseverance and motivation can be studied in the reversal of visual discrimination, extinction and fixed/progressive ratio tasks, respectively.
Many rodent touchscreen tasks closely parallel elements of computerized assessments of humans, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB). The face validity of the touchscreen approach in studies of mouse models of brain disorders has been recently demonstrated in experiments on mice with a deficiency of PSD-93, an important synaptic protein. These mutant mice exhibited deficits in reversal learning, paired-associates learning and showed impaired attention in the 5-choice serial reaction time task compared to the performance of their non-mutant, normal littermates. Humans with rare mutations in the DLG2 gene, which encodes PSD-93, may present with symptoms of schizophrenia, autism and intellectual disability. Notably, in CANTAB tests such as Intra-Extradimensional Set-shifting, Paired Associates Learning and Rapid Visual Information Processing, which resembled the output of mouse touchscreen testing routines, individuals with DLG2 mutations performed worse than control subjects. So striking was the similarity of the cognitive change patterns in mice and humans with PSD-93 deficiency that it prompted a “reverse translation” experiment, whereby individuals with DLG2 deletions and control participants were offered the mouse object-location paired-associates learning task adapted for a human touchscreen tablet. Remarkably, the specific cognitive deficit in human mutation carriers was confirmed using the “mouse” test.
The relative ease with which humans with various neurodegenerative and neurodevelopmental conditions can be assessed using CANTAB or similar approaches will undoubtedly stimulate further touchscreen-based experiments in animal models of corresponding diseases. To make touchscreen tests in animals less of a “black box” and to facilitate their use in establishing the construct, face and predictive validities of animal models of brain disorders, it will be necessary to combine them with state-of-the art electrophysiological and imaging approaches. The touchscreen tests may be relatively longer than other, simpler cognitive paradigms in animals. However, eventual elucidation of the neural circuitry that underlines cognitive performance during various touchscreen tasks in combined behavioral and electrophysiological/imaging experiments will certainly make the touchscreen-based approach an invaluable preclinical tool for evaluations of pharmacological substances and validations of animal disease models.
Maksym Kopanitsa, PhD is Head of Translational Biology at the Charles River’s Discovery Research Services site in Finland, which specializes in CNS diseases
Filed Under: Drug Discovery
