Zebrafish model of ageing-related cognitive decline and visual impairment

Primary Supervisor: Dr Matt Parker, School of Pharmacy and Biomedical Science, University of Portsmouth

Co-Supervisor: Dr J. Arjuna Ratnayaka, School of Medicine, University of Southampton

Project Summary

Rationale
Twelve-million people in the UK are aged 65 or over. Life expectancy is ~82 years; however, healthy life expectancy (“healthspan”: the amount of life lived in good health) is approximately 63 years1. With the gap between lifespan and healthspan a major societal challenge, it is critical that we understand the biological processes underlying the healthy ageing process. Two issues associated with ageing are: (1) decline in working memory; and (2) decline in visual ability. We propose these ageing-related issues are interrelated owing to several shared features, including accumulation of amyloid beta (Aβ) in the central nervous system2. Working memory deficits in older adults is related to degradation in attentional processes, resulting from reduced ability to suppress task-irrelevant information3. Visual field deficits result from relatively well-characterised structural and physiological changes in the ageing eye 4. Critically, what is not presently known is what, if any, are the shared effects of ageing on cognitive and visual field function at the behavioural, neural and molecular level.

Approaches to be used
This interdisciplinary programme of work will comprise cross-sectional behavioural testing across the lifespan of wild-type and specific genetically altered zebrafish lines5 (that show accelerated ageing and cognitive decline, provided by collaborators in Australia) in the Parker Laboratory, coupled with molecular characterisation of the visual/nervous system in the Ratnayaka laboratory. Cognitive tasks will include well established assays of working memory 6. With our industry collaborator, we will also develop novel assays to characterise the ontogeny of visual field processing in the ageing zebrafish. We will then characterise patterns of age-associated synaptic loss in the eye and brain to correlate with behavioural function using pre- (synaptophysin), and post- (PSD-95) synaptic markers.

Impact
Identify timelines of cognitive and visual defects in the life-course of the brain and eye, which will provide insights into healthy aging.

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Refs:
1. Age UK, Later Life in the UK, 2019, 2019.
2. Kam et al., PLoS ONE, 5.10, 2010, e13127.
3. Gazzaley et al., Nat Neuro, 8, 2005, 1298-1300.
4. Owsley, Ann Rev Vis Sci, 2, 2016, 111815-114550.
5. Newman, et al., Molecular Brain, 12, 2019, 1-5.
6. Fontana et al., Anim Cog, 2019, In Press