Neuro-behavioural determinants of development and aging in genetically modified mice

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Many genetically modified mouse models have been developed to study the neurobiology of behaviour and brain function, but there have been difficulties in understanding the relationships between the genetic modification, age-related behavioural changes and measures of neural development and/or degeneration. We have identified four common errors in the study of mouse models: (1) the genotype of the mouse; (2) the neuro-behavioural testing methods; (3) failure to control for confounding variables; and (4) failure to understand the epigenetic influence of environmental variables. Our objectives are to conduct comparative studies of age-related changes in the cognitive, sensory, and motor functions of transgenic mice using our test batteries for the analysis of genotype, sex and age effects, while controlling for the confounds listed above. We maintain breeding colonies of 3xTg-AD and 5xFAD and MDGA2+/- mouse models and propose to study the lifespan development of these mice to determine the influence of the transgenes and post-natal environment on sex- and age-related changes in their behaviour, brain and physiology. There have been no comparative studies of mouse models of age-related cognitive changes. We propose eight sets of experiments to examine: (1) cognitive changes in these mice and their wildtype controls from 2-18 months of age in a battery of learning and memory, decision making and interval timing tasks; (2) the influence of sex- and age-related changes in sensory functions (vision, hearing, whiskering, olfaction) as confounds in the study of cognitive changes; (3) how age-related changes in motor function (locomotion, balance, co-ordination) affect measures of sensory and cognitive processes; (4) the social and environmental influences on age-related neuro-behavioural changes; (5) neurodevelopmental patterns of behaviour in the MDGA2+/- mice and age-related changes in neurobehavioural measures, such as frailty, which may predict age-related dysfunction and longevity; (6) the correlation of neuropathological and physiological changes with age-related behavioural deficits; (7) the effects of novel drugs to ameliorate neurobehavioural deficits in these mice; (8) sex differences and individual differences in each of the above neurobehavioural studies. Our research will benefit all researchers using transgenic mice by improving our understanding of mouse models for nervous system disorders and the unintended consequences of genetic manipulation and this will lead to improved translation of animal studies.