Decision Making in Mice During an Optimized Touchscreen Spatial Working Memory Task Sensitive to Medial Prefrontal Cortex Inactivation and NMDA Receptor Hypofunction.

Working memory is a fundamental cognitive process for decision-making and is a hallmark impairment in a variety of neuropsychiatric and neurodegenerative diseases. Spatial working memory paradigms are a valuable tool to assess these processes in rodents and dissect the neurobiology underlying working memory. The trial unique non-match to location (TUNL) task is an automated touchscreen paradigm used to study spatial working memory and pattern separation processes in rodents. Here, animals must remember the spatial location of a stimulus presented on the screen over a delay period; and use this representation to respond to the novel location when the two are presented together. Because stimuli can be presented in a variety of spatial configurations, TUNL offers a trial-unique paradigm, which can aid in combating the development of unwanted mediating strategies. Here, we have optimized the TUNL protocol for mice to reduce training time and further reduce the potential development of mediating strategies. As a result, mice are able to accurately perform an enhanced trial-unique paradigm, where the locations of the sample and choice stimuli can be presented in any configuration on the screen during a single session. We also aimed to pharmacologically characterize this updated protocol, by assessing the roles of the medial prefrontal cortex (mPFC) and N-methyl-D-aspartate (NMDA) receptor (NMDAr) functioning during TUNL. Temporary inactivation of the medial prefrontal cortex (mPFC) was accomplished by directly infusing a mixture of GABA agonists muscimol and baclofen into the mPFC. We found that mPFC inactivation significantly impaired TUNL performance in a delay-dependent manner. In addition, mPFC inactivation significantly increased the susceptibility of mice to proactive interference. Mice were then challenged with acute systemic injections of the NMDAr antagonist ketamine, which resulted in a dose-dependent, delay-dependent working memory impairment. Together, we describe an optimized automated touchscreen task of working memory, which is dependent on the intact functioning of the mPFC and sensitive to acute NMDAr hypofunction. With the vast genetic toolbox available for modeling disease and probing neural circuit functioning in mice, the TUNL task offers a valuable paradigm to pair with these technologies to further investigate the processes underlying spatial working memory.

Touchscreen cognitive testing: Cross-species translation and co-clinical trials in neurodegenerative and neuropsychiatric disease.

Translating results from pre-clinical animal studies to successful human clinical trials in neurodegenerative and neuropsychiatric disease presents a significant challenge. While this issue is clearly multifaceted, the lack of reproducibility and poor translational validity of many paradigms used to assess cognition in animal models are central contributors to this challenge. Computer-automated cognitive test batteries have the potential to substantially improve translation between pre-clinical studies and clinical trials by increasing both reproducibility and translational validity. Given the structured nature of data output, computer-automated tests also lend themselves to increased data sharing and other open science good practices. Over the past two decades, computer automated, touchscreen-based cognitive testing methods have been developed for non-human primate and rodent models. These automated methods lend themselves to increased standardization, hence reproducibility, and have become increasingly important for the elucidation of the neurobiological basis of cognition in animal models. More recently, there have been increased efforts to use these methods to enhance translational validity by developing task batteries that are nearly identical across different species via forward (i.e., translating animal tasks to humans) and reverse (i.e., translating human tasks to animals) translation. An additional benefit of the touchscreen approach is that a cross-species cognitive test battery makes it possible to implement co-clinical trials-an approach developed initially in cancer research-for novel treatments for neurodegenerative disorders. Co-clinical trials bring together pre-clinical and early clinical studies, which facilitates testing of novel treatments in mouse models with underlying genetic or other changes, and can help to stratify patients on the basis of genetic, molecular, or cognitive criteria. This approach can help to determine which patients should be enrolled in specific clinical trials and can facilitate repositioning and/or repurposing of previously approved drugs. This has the potential to mitigate the resources required to study treatment responses in large numbers of human patients.