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Characterising the translatability of mice models of human aging: a behavioural comparison of multiple memory functions in humans and mice

Primary Supervisor: Dr Carlo De Lillo, Department of Neuroscience, Psychology and Behaviour

Secondary supervisors: Dr Todor Gerdjikov; Prof Elizabeta Mukaetova-Ladinska

PhD project title: Characterising the translatability of mice models of human ageing: a behavioural comparison of multiple memory functions in humans and mice

University of Registration: University of Leicester

Project outline:

Mice are very promising models of human ageing as they are affected by similar decline associated to heathy ageing and diseases as observed in humans. Nonetheless, translating findings from mice models into successful interventions in people is still proving challenging (Gotz et al. 2018). Thus, it is important to characterise which functions decline in human in relation to heathy ageing and dementia and are appropriately modelled in mice. The assessment of memory functions in mice models is meaningful only when completed with tasks pertinent to the ethology of the species (Gerlai and Clayton, 1999). Equally critical is the ecological validity of memory tasks in studies of healthy aging and dementia in people (Bayley et al 2010; Burgess et al. 2006). This project entails testing mice with a naturalistic search/foraging task, recently developed by the supervisors. The task allows measuring several functions (Working-memory; Long-term-memory and monitoring patterns of reward availability, thus acting as a cognitive test-battery within a single task. An immersive Virtual Reality (VR) version of the task, also piloted by the supervisors, allows the comparison of people and mice. Search is a ubiquitous cognitive problem in humans (Hills et al., 2015), required by activities ranging from internal scanning of semantic memory to everyday real-world tasks (e.g. searching for missing keys). The project assays memory functions involved in search tasks in young/old participants and AD sufferers. It will reveal functions selectively affected by dementia in people, as well as whether or not they are adequately modelled by mice models. Pilot data show striking similarities between young adult humans and young mice in these functions. The present project features testing mice (young healthy, aged, AD models) and people (< 35 YOA; over 65 YOA, AD sufferers).

Objectives:

  • To determine which functions decline with age or AD and are appropriately modelled in mice.
  • To validate a new testing battery for mice and humans based on a single simple task.
  • To identify new indicators of early cognitive decline in dementia in people.

Methods:

The study is based on a newly developed task (see Fig1) where mice (tested in an arena) and people (tested with a VR version of it) search for rewards (sugar pellets or food images) among sets of containers. An olfactory version will be used with AD mice models (Tg2576) prone to develop retinal disease. The structure of the task will be identical except that the containers to search will be scented with essential oils, rather than being differentiated by colour patterns. Independent variables are: species (humans/mice); presence/absence of disease (people with AD/controls, Tg2576/control mice; age (young/old). The dependent variables are behavioural measures of different memory functions assessed by the task (Fig1D).

References:

  1. Bailey, P.E., Henry, J.D., Rendell, P.G., Phillips, L.H. & Kliegel, M. (2010) “Dismantling the “age–prospective memory paradox: The classic laboratory paradigm simulated in a naturalistic setting” Quarterly Journal of Experimental Psychology, 63, p.646-652
  2. Burgess, P. W., Alderman, N., Forbes, C., Costello, A., Laure, M. C., Dawson, D. R., … & Channon, S. (2006). The case for the development and use of “ecologically valid” measures of executive function in experimental and clinical neuropsychology. Journal of the International Neuropsychological Society, 12(02), 194–209.
  3. Götz, J., Bodea, L. & Goedert, M. (2018). Rodent models for Alzheimer disease. Nature Review Neuroscience 19, 583–598.
  4. Hills, T. Todd, P.M. Lazer, D. Redish, D. (2015) Exploration versus exploitation in space, mind, and society. Trends in Cognitive Sciences. 19 (1): 46-54.

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

Techniques that will be undertaken during the project:

  • Behavioural comparison of mice tested in foraging tasks and humans tested in Virtual Reality analogues of the task.
  • Assessment of memory function using foraging tasks as cognitive test batteries in patients diagnosed with Alzheimer’s disease (AD) and preclinical mouse models of AD.
  • Matched controls will be used for both humans and mice of similar age but not affected by AD. Different age groups of humans and mice will also be compared.

Contact: Dr Carlo De Lillo, University of Leicester