Abstract
With the growing popularity of touchscreen cognitive testing in rodents, it is imperative to understand the fundamental effects exposure to this paradigm can have on the animals involved. In this study, we set out to assess hippocampal-dependant learning in the APP/PS1 mouse model of Alzheimer’s disease (AD) on two highly translatable touchscreen tasks – the Paired Associate Learning (PAL) task and the Trial Unique Non-Matching to Location (TUNL) task. Both of these tests are based on human tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and are sensitive to deficits in both mild cognitive impairment (MCI) and AD. Mice were assessed for deficits in PAL at 9–12 months of age, then on TUNL at 8–11 and 13–16 months. No cognitive deficits were evident in APP/PS1 mice at any age, contrary to previous reports using maze-based learning and memory tasks. We hypothesized that daily and long-term touchscreen training may have inadvertently acted as a cognitive enhancer. When touchscreen-tested mice were assessed on the Morris water maze, they showed improved task acquisition compared to naïve APP/PS1 mice and wild-type (WT) littermate controls. In addition, we show that touchscreen-trained WT and APP/PS1 mice show increased cell proliferation and immature neuron numbers in the dentate gyrus compared to behaviorally naïve WT and APP/PS1 mice. This result indicates that the touchscreen testing paradigm could improve cognitive performance, and/or mask an impairment, in experimental mouse models. This touchscreen-induced cognitive enhancement may involve increased neurogenesis, and possibly other forms of cellular plasticity. This is the first study to show increased numbers of proliferating cells and immature neurons in the hippocampus following touchscreen testing, and that touchscreen training can improve cognitive performance in maze-based spatial navigation tasks. This potential for touchscreen testing to induce cognitive enhancement, or other phenotypic shifts, in preclinical models should be considered in study design. Furthermore, touchscreen-mediated cognitive enhancement could have therapeutic implications for cognitive disorders.
Highlights
Touchscreen-based cognitive testing methods have been developed for rodents in an effort to substantially improve translation between preclinical studies and clinical trials (Palmer et al, 2021)
The decreased rate of correction trials in APPswe/PS1 E9 (APP/PS1) mice appeared to be driven by an increased number of unique trials performed in this group [Figure 2E, t(1) = 2.21, p = 0.042]
The increased number of unique trials performed could be related to the increased perseverative behavior we have previously shown in APP/PS1 mice during difficult touchscreen tasks (Shepherd et al, 2019)
Summary
Touchscreen-based cognitive testing methods have been developed for rodents in an effort to substantially improve translation between preclinical studies and clinical trials (Palmer et al, 2021). Touchscreen testing has been widely adopted as a method to assess cognitive decline in preclinical animal models of Alzheimer’s disease (Romberg et al, 2011, 2013; Piiponniemi et al, 2017; Shepherd et al, 2019, 2021; Van den Broeck et al, 2019; Saifullah et al, 2020). This paradigm has great utility for non-invasive early detection of impairments in these animal models, enabling elucidation of mechanism of disease progression and screening of novel therapeutics (reviewed in Shepherd et al, 2016; Palmer et al, 2021). A number of unique and essential methodological components of touchscreen testing have documented effects on aging, memory, mood and brain health and exposure to the paradigm itself could have the potential to alter or shift behavioral phenotypes and neurobiology of the animals undergoing training
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