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

已经开发了许多转基因小鼠模型来研究行为和脑功能的神经生物学，但是在理解转基因、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）未能控制混杂变量;（4）未能理解环境变量的表观遗传影响。我们的目标是进行比较研究的年龄相关的变化，在认知，感觉和运动功能的转基因小鼠使用我们的测试电池的基因型，性别和年龄的影响，同时控制上述混淆的分析。我们保持3xTg-AD和5xFAD和MDGA 2 +/-小鼠模型的繁殖群体，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它们的行为、大脑和生理学中与性别和年龄相关的变化的影响。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月龄的一系列学习和记忆、决策和间隔计时任务中的认知变化;（2）与性别和年龄相关的感觉功能变化的影响（视觉、听觉、嗅觉）作为认知变化研究中的混淆;（3）运动功能如何随年龄变化（运动、平衡、协调）影响感觉和认知过程的测量;（4）社会和环境对与年龄相关的神经行为变化的影响;（5）MDGA 2 +/-小鼠的神经发育行为模式和神经行为测量的年龄相关变化，例如虚弱，其可预测年龄相关的功能障碍和寿命;（6）神经病理学和生理学变化与年龄相关的行为缺陷的相关性;（7）改善这些小鼠的神经行为缺陷的新药的作用;（8）上述各项神经行为研究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，提高我们对神经系统疾病小鼠模型的理解，以及遗传操作的意外后果，这将导致动物研究的改进。

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.