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

许多转基因小鼠模型已被开发用于研究行为和脑功能的神经生物学，但在理解基因修饰、与年龄相关的行为变化和神经发育和/或退化的测量之间的关系方面存在困难。我们已经确定了小鼠模型研究中的四个常见错误：(1)小鼠的基因型；(2)神经行为测试方法；(3)对混杂变量控制不到位；(4)不了解环境变量对表观遗传的影响。我们的目标是在控制上述混杂因素的同时，使用我们的测试电池对转基因小鼠的认知、感觉和运动功能的年龄相关变化进行比较研究，以分析基因型、性别和年龄的影响。我们维持3xTg-AD、5xFAD和MDGA2+/-小鼠模型的繁殖菌群，并建议研究这些小鼠的寿命发育，以确定转基因和出生后环境对其行为、大脑和生理的性别和年龄相关变化的影响。目前还没有对与年龄相关的认知变化的小鼠模型进行比较研究。我们提出了八组实验来检验：(1)这些小鼠及其野生型对照在2-18个月大的一系列学习和记忆、决策和间隔时间任务中的认知变化；(2)性别和年龄相关的感觉功能（视觉、听觉、胡须、嗅觉）变化在认知变化研究中的影响；(3)运动功能（运动、平衡、协调）的年龄相关变化如何影响感觉和认知过程的测量；(4)社会环境对年龄相关神经行为变化的影响；(5) MDGA2+/-小鼠的神经发育行为模式和神经行为指标的年龄相关变化，如虚弱，这可能预测与年龄相关的功能障碍和寿命；(6)神经病理和生理变化与年龄相关性行为缺陷的相关性；(7)新型药物对改善这些小鼠神经行为缺陷的作用；(8)上述神经行为研究中的性别差异和个体差异。我们的研究将使所有使用转基因小鼠的研究人员受益，通过提高我们对神经系统疾病小鼠模型的理解和基因操作的意外后果，这将导致改进动物研究的翻译。

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.