Mouse genetic differences in exercise-induced hippocampal neurogenesis & learning

描述(申请人提供)：人们普遍认为基因与环境相互作用会影响大脑功能和行为。锻炼是一个强有力的环境因素，众所周知对身体健康有好处，比如力量和耐力。最近发现锻炼还可以提高认知能力，这激起了人们的热情和兴趣，但人们对运动的机制还知之甚少。在啮齿动物模型中，越来越多的证据表明，锻炼是神经可塑性的自然生成器。一个例子是海马区新神经元的生长，它受到运动和许多其他变化(如营养因子、生长因子、毛细血管)的强烈调控。利用天然生成器的机制可能有助于治疗广泛的神经问题，如认知老化、神经退行性疾病、中风或头部创伤。寻找机制的一种方法是系统地阻止每个假设底物(例如，新神经元)的变化。另一个是对遗传机制的不偏不倚的探索。我们两个都提出了。初步数据表明，运动导致的海马神经发生和学习能力的变化取决于小鼠的基因。目标1和目标2是确定显示出较大益处与较小益处的几组基因类型。这些关键信息将被贡献给这些菌株的表型和遗传信息数据库，并在未来用于确定从基因到生理再到行为的多个生物组织水平上运动对认知有益的机制。除了为基因分析奠定基础外，我们还在目标3中提出了一种创新的方法来减少运动小鼠的神经发生，焦点伽马辐射，以直接测试这一假设，即在易感基因型别的运动中需要新的神经元来加强学习。为此，我们建议使用C57BL/6J基因型作为主要证据，因为这种菌株在运动、神经发生和学习之间有很好的相关性。公共卫生相关性：该项目的目标是在从基因到生理再到行为的生物组织的多个层面上发现运动的前认知效应的机制。

DESCRIPTION (provided by applicant): It is widely accepted that genes interact with environment to affect brain function and behavior. Exercise is a potent environmental factor with known benefits for physical health such as strength and stamina. The recent discovery that exercise can also enhance cognitive performance has generated much enthusiasm and interest, but mechanisms are far less understood. A growing body of evidence in rodent animal models suggests that exercise is a natural generator of neural plasticity. One example is growth of new neurons in the hippocampus, which is strongly regulated by exercise along with many other changes (e.g., trophic factors, growth factors, capillaries). Harnessing mechanisms of the natural generator could be useful for treating a wide range of neurological problems such as cognitive aging, neurodegenerative disease, stroke, or head trauma. One approach to find a mechanism is to systematically block changes in each hypothesized substrate (e.g., new neurons). Another is unbiased exploration of genetic mechanisms. We propose both. Preliminary data suggest that exercise induced changes in hippocampal neurogenesis and learning vary depending on genotype in mice. Aims 1 and 2 are to identify sets of genotypes that display larger versus smaller benefits. This crucial information will be contributed to a database of phenotypic and genetic information on these strains, and used in the future to identify mechanisms for cognitive benefits of exercise at multiple levels of biological organization from genes to physiology to behavior. In addition to laying the groundwork for the genetic analysis, we also propose an innovative method in aim 3 to reduce neurogenesis in exercising mice, focal gamma radiation, to directly test the hypothesis that new neurons are required for enhanced learning from exercise in predisposed genotypes. For this, we propose to use the genotype C57BL/6J, as proof of principal, because a strong correlation between exercise, neurogenesis, and learning is well established for this strain. PUBLIC HEALTH RELEVANCE: The goal of this project is to discover mechanisms for pro cognitive effects of exercise at multiple levels of biological organization from genes to physiology to behavior.