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，这一观点已被广泛接受。众所周知，锻炼是一种强有力的环境因素，对身体健康有好处，比如增强力量和耐力。最近的一项研究发现，锻炼也可以提高认知能力，这一发现引起了人们极大的热情和兴趣，但人们对其中的机制却知之甚少。在啮齿类动物模型中，越来越多的证据表明，运动是神经可塑性的自然产生器。一个例子是海马体中新神经元的生长，这是由运动以及许多其他变化（例如，营养因子、生长因子、毛细血管）强烈调节的。利用自然发生器的机制可以用于治疗广泛的神经系统问题，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止每个假设基质（例如，新神经元）的变化。另一个是不偏不倚地探索遗传机制。我们两者都建议。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。目标1和目标2是确定显示出较大或较小益处的基因型组。这一重要信息将被贡献到这些菌株的表型和遗传信息数据库中，并在未来用于从基因到生理到行为的多个生物组织层面确定运动的认知益处机制。除了为遗传分析奠定基础之外，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，即局灶伽马辐射，以直接验证易感基因型中需要新的神经元来增强运动学习的假设。为此，我们建议使用基因型C57BL/6J作为主要证据，因为在该菌株中，运动、神经发生和学习之间存在很强的相关性。

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.