A Touchscreen Motivation Assessment Evaluated in Huntington's Disease Patients and R6/1 Model Mice

Abstract

Apathy is pervasive across many neuropsychiatric disorders but is poorly characterized mechanistically, so targeted therapeutic interventions remain elusive. A key impediment has been the lack of validated assessment tools to facilitate translation of promising findings between preclinical disease models and patients. Apathy is a common symptom in Huntington's disease. Due to its established genetic basis and the availability of defined animal models, this disease offers a robust translational framework for linking motivated behavior with underlying neurobiology and an ideal context in which to evaluate a quantitative, translational apathy assessment method. In this study we therefore aimed to demonstrate the validity of using touchscreen-delivered progressive ratio tasks to mirror apathy assessment in Huntington's disease patients and a representative mouse model. To do this we evaluated Huntington's disease patients ( n = 23) and age-matched healthy controls ( n = 20), and male R6/1 mice ( n = 23) and wildtype controls ( n = 29) for apathy-like behavior using touchscreen-delivered progressive ratio tasks. The primary outcome measure of the assessment was breakpoint, defined as the highest number of touchscreen responses emitted before task engagement ceased. Patients and R6/1 mice were both found to exhibit significantly reduced breakpoints relative to their respective control groups, consistent with apathy-like behavior. This performance was also not associated with motoric differences in either species. These data demonstrate the utility of touchscreen-delivered progressive ratio tasks in detecting clinically relevant motivational deficits in Huntington's disease. This approach may offer a platform from which clinically relevant mechanistic insights concerning motivation symptoms can be derived and provide an effective route for translation of promising preclinical findings into viable therapeutic interventions.

Evidence for an apathy phenotype in aged mice

“…It is common practise to use food restriction to motivate animals to learn operant tasks however this may create an artificial state which is more obvious in control animals thus biasing results for these types of task. These findings are in line with studies using a mouse model of Huntington's disease, in which apathy is a core symptom, where they found a reduction in rate of response in a PR schedule of reinforcement, relative to controls (Heath et al, 2019;Oakeshott et al, 2012). This was also found in a study using Huntington's disease patients with apathy, and apathy questionnaire scores negatively correlated with breakpoint scores (Heath et al, 2019).…”

Similar cognitive deficits in mice and humans in the chronic phase post-stroke identified using the touchscreen-based paired-associate learning task

“…In two studies, the authors aimed to understand cognitive decline linked to mutations in the Dlg gene family in humans and mice, demonstrating successful parallel assessment of PAL using the touchscreen platforms 16,17 . Furthermore, parallel touchscreen-based assessments have recently been applied to characterise clinically relevant motivational deficits in Huntington's disease patients and mice 31 . In the present study, we assessed the visuospatial PAL in both chronic stroke survivors and mice in chronic phase post-stroke using CANTAB and rodent touchscreen platforms, respectively.…”

“…Characterising a comparable cognitive assessment method in humans and mice constitutes a preliminary step towards narrowing the translational gap to improve our understanding of cognitive impairment post-stroke. To date, three studies had targeted cognitive dysfunction in other pathological conditions, using parallel touchscreen-based approach 16 , 17 , 31 . In two studies, the authors aimed to understand cognitive decline linked to mutations in the Dlg gene family in humans and mice, demonstrating successful parallel assessment of PAL using the touchscreen platforms 16 , 17 .…”

MouseBytes, an open-access high-throughput pipeline and database for rodent touchscreen-based cognitive assessment

“…Efforts to address these important gaps in data collection, automation, and translational research led to the development of the rodent touchscreen testing method (Horner et al, 2013; Mar et al, 2013; Oomen et al, 2013). This technology allows the use of tests in rodents that are highly similar, and in some cases identical, to human cognitive tests (Heath et al, 2019; Nilsson et al, 2016; Nithianantharajah et al, 2015; Romberg et al, 2013a). Touchscreen testing systems have standardised behavioural protocols that are under the control of a computer system, allowing for increased standardisation of outcomes.…”