Mouse genetic differences in exercise-induced hippocampal neurogenesis & learning

描述（申请人提供）：基因与环境相互作用影响大脑功能和行为已被广泛接受。运动是一个强有力的环境因素，对身体健康有已知的好处，如力量和耐力。最近发现，锻炼也可以提高认知能力，这引起了人们的极大热情和兴趣，但机制还远未被理解。越来越多的啮齿动物模型证据表明，运动是神经可塑性的天然生成器。一个例子是海马体中新神经元的生长，这是由运动沿着许多其他变化（例如，营养因子、生长因子、毛细血管）。利用天然发电机的机制可以用于治疗各种神经问题，如认知老化，神经退行性疾病，中风或头部创伤。找到机制的一种方法是系统地阻断每个假设底物的变化（例如，新神经元）。另一个是对遗传机制的公正探索。我们建议两者都要。初步数据表明，运动诱导的海马神经发生和学习的变化取决于小鼠的基因型。目的1和2是确定显示较大与较小益处的基因型集合。这些关键信息将有助于建立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学到行为的多个生物组织水平上运动的认知益处机制。除了为遗传分析奠定基础外，我们还在目标3中提出了一种创新方法，以减少运动小鼠的神经发生，局灶性伽马辐射，以直接测试新神经元是增强易感基因型运动学习所必需的假设。为此，我们建议使用基因型C57 BL/6 J作为主要证据，因为这种菌株在运动，神经发生和学习之间存在很强的相关性。公共卫生相关性：该项目的目标是发现运动在从基因到生理学到行为的多个生物组织水平上的促认知效应的机制。

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.