Understanding the rules of life

Bioscience for an integrated understanding of health

Category: Standard Studentships

Zebrafish as a tool to understand retinal degeneration and cognitive decline across the lifecourse”

Project No.2244

Primary Supervisor

Dr Matthew Parker- University of Portsmouth

Co-Supervisor(s)

Dr Arjuna Ratnayak – University of Southampton

 

Summary

Rationale: There are 12 million people in the UK 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 years[1]. With the gap between lifespan and healthspan a major societal challenge, it is critical that we understand the biology underpinning the healthy ageing process. Major issues associated with ageing are: (1) decline in cognitive abilities (including memory); and (2) decline in visual ability (including macular degeneration). We know these are linked owing to several critical shared risk factors (lifestyle, such as smoking), histopathlogical features (such as

APoE and Aβ deposits), and epidemiological data (cognitive decline and retinopathy are closely correlated) [2,3]. Working memory deficits in older adults is related to degradation in the control of attentional processes, resulting from reduced ability to suppress task-irrelevant information[4]. Visual field deficits result from relatively well-characterised structural and physiological changes in the ageing eye [5]. 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 genetically altered zebrafish in the Parker Laboratory, coupled with molecular characterisation of the visual/nervous system in the Ratnayaka laboratory. Cognitive tasks will include several well-characterised tests of working memory and cognition in zebrafish, which show ageing-related differences in zebrafish [6,7]. With our industry collaborator (Zantiks ltd.), we will develop completely novel field tests to examine the ontogeny of visual field processing in ageing zebrafish. The recent discovery of a specialised zone in the zebrafish retina, equivalent to the human macula, offers great significance to potential findings. We will also characterise patterns of age-associated synaptic loss in the retina and brain to correlate with behavioural function using pre- (synaptophysin), and post- (PSD-95) synaptic markers. In-vivo imaging will map neural calcium dynamics in young vs. aged animals whilst lightsheet microscopy will capture retina-brain changes in transgenic zebrafish lines. Impact: Identify timelines of cognitive and visual defects in the life-course of the brain and eye, which will provide insights into healthy ageing. Refs: 1. Age UK, Later Life in the UK, 2019. 2. Kam et al., PLoS ONE, 5.10, 2010, e13127. 3. Rozzini et al., Am J Alz Dis Dem, 29, 2014, 256-262. 4. Gazzaley et al., Nat Neuro, 8, 2005, 1298-1300. 5. Owsley, Ann Rev Vis Sci, 2, 2016, 111815-114550. 6. Cleal et al., Neurobiol age, 102, 2021, 1-16. 7. Cleal et al., Beh Res Meth, 2021, 53, 536–557