A zebrafish screen to identify genes affecting working memory and age-related cognitive decline.

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With advances in diet and health care there has been an increase in the general age of the population. With increases in age comes an increase in age-related disease including a decline in mental ability; As animals age their memory and ability to learn new things as well as to adapt to changes in their surroundings declines. However, this physical and mental deterioration is not uniform; there are many who continue with good health well into their 80s and 90s whilst others suffer increasingly debilitating mental decline and disease. There are many factors that influence healthy ageing including diet and general life style but it is also influenced by ones initial mental ability and genetic makeup. Here we aim to identify genes that influence mental ability and age-related deterioration in memory and learning using zebrafish as the experimental system. Zebrafish have become an established system for the identification of genes affecting human development and disease as many genes and the cell biological processes the genes regulate are conserved between fish and humans. Zebrafish are an ideal system in which to search for genes affecting mental ageing as, in addition to conservation of genetic structure and neural processes, zebrafish show gradual ageing over a 2 year period and are capable of performing behavioural tasks similar to those used in mammals and humans to assess mental ability and mental decline. Above all, it is relatively easy to generate lines of fish carrying genetic mutations and many loss of function lines that can be used in our studies already exist.Here we take advantage of the availability of lines of zebrafish that carry mutations disrupting the function of individual genes to identify genes that affect memory and learning and age-related deterioration of these processes. We shall assess individuals from 50-75 different families of fish that carry mutations in specific genes for performance in behavioral tasks commonly used to assess working memory and response times (delayed matching to sample, 5 choice serial reaction time), at 2 different ages: young (6 months) and old (2 years). Fish that perform very well or very badly in these tasks when compared to a normal population are kept and an additional 20-40 siblings from the family assessed in the same tasks. When all mutant members within a family show the same behaviour, the mutation is taken as affecting a gene that controls an aspect of memory and learning. Analysis of performance at 6 months will identify genes affecting learning, memory and response times as measures of mental ability per se. By comparing responses at 2 years with those at 6 months we will be able to identify genes affecting the rate of change in memory and response times i.e the conservation of mental processes. The outcome of this study will be the elucidation of genes and molecular processes influencing mental ability and maintenance of mental ability in old age. It is important to gain insight into the genetics of age-related mental deterioration as it helps understanding of how environmental factors may interact with genetics to influence the rate of mental decline in old age. This knowledge helps us develop strategies to minimize the impact of ageing on society. Moreover, understanding age-related changes in mental ability sets a background against which it is possible to assess the effects of pathological disease states such as dementia.