Transcriptomic profile of mild exercise-enhanced adult hippocampal neurogenesis: Comparison with the effects of intense exercise

Mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance hippocampal function, while intense exercise (IE) above the LT negates such benefits. However, the question as to why ME more effectively enhances hippocampal function than does IE remains to be clarified. Here, we investigated adult hippocampal neurogenesis (AHN) as a mechanism of ME-induced cognitive improvement, and comprehensively delineated the transcriptomic profile of the hippocampus, using a rat whole-genome microarray approach through comparison with IE. Immunohistochemical results showed that less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 44 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF1), probably due to the timing of hippocampal tissue collection after the last training session and the technical feature of microarray. Rather, network analysis of the microarray data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with hippocampal neuroadaptations including AHN. In contrast, IE-influenced genes linked to immune response, a negative regulatory system of AHN and hippocampal function, were identified. Collectively, these results support our hypothesis that AHN could explain why ME enhances hippocampal function, and provide the ME-specific gene list that contain some potential regulators of this positive regulation. The list will become a foundation to elucidate the molecular pathway involving the ME-induced cognitive gain.强度低于乳酸阈（lactate threshold, LT）的温和运动（Mild exercise, ME）足以改善海马体功能，而高于该阈值的剧烈运动（Intense exercise, IE）则会抵消这类益处。然而，为何温和运动比剧烈运动更能有效改善海马体功能，这一问题仍有待阐明。本研究以成年海马神经发生（adult hippocampal neurogenesis, AHN）作为温和运动诱导认知改善的潜在机制，通过与剧烈运动组对比，采用大鼠全基因组微阵列技术全面解析了海马体的转录组特征。免疫组化结果显示，温和运动（ME）更有助于改善成年海马神经发生（AHN），尤其体现在新生神经元的存活与成熟方面。DNA微阵列分析结果显示，温和运动（ME）调控的基因数量多于剧烈运动（IE）（ME组：604个基因，IE组：415个基因），且仅有44个基因在两种运动强度下均发生表达改变。本次鉴定出的分子组分并未包含已知的运动诱导成年海马神经发生相关因子，如脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）与胰岛素样生长因子1（insulin-like growth factor 1, IGF1），这可能与末次训练后海马组织的采集时间以及微阵列技术的特性有关。与之相对，采用Ingenuity Pathway Analysis算法对微阵列数据进行网络分析后发现，温和运动（ME）调控的基因主要与脂质代谢、蛋白质合成及炎症反应相关，上述过程均被证实与包括成年海马神经发生（AHN）在内的海马神经重塑密切关联。而剧烈运动（IE）调控的基因则与免疫反应相关，免疫反应恰恰是成年海马神经发生（AHN）及海马体功能的负调控系统。综上，上述结果支持我们的假说：成年海马神经发生（AHN）可解释为何温和运动（ME）能够改善海马体功能，同时本研究还提供了温和运动特异性的基因列表，其中包含若干该正向调控过程的潜在调控因子。该基因列表将为阐明温和运动诱导认知获益的分子通路提供研究基础。