Halliday Matthew R, Abeydeera Dishan, Lundquist Adam J, Petzinger Giselle M, Jakowec Michael W
Department of Neurology.
Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, California, USA.
Neuroreport. 2019 Jun 12;30(9):619-627. doi: 10.1097/WNR.0000000000001239.
Exercise and other forms of physical activity lead to the activation of specific motor and cognitive circuits within the mammalian brain. These activated neuronal circuits are subjected to increased metabolic demand and must respond to transient but significant reduction in available oxygen. The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a regulatory mediator of a wide spectrum of genes involved in metabolism, synaptogenesis, and blood flow. The purpose of this study was to begin to explore the potential relationship between exercise in the form of running on a motorized treadmill and the activation of genes involved in exercise-dependent neuroplasticity to begin to elucidate the underlying molecular mechanisms involved. Mice were subjected to treadmill exercise and striatal tissues analyzed with a commercial microarray designed to identify transcripts whose expression is altered by exposure to hypoxia, a condition occurring in cells under a high metabolic demand. Several candidate genes were identified, and a subset involved in metabolism and angiogenesis were selected to elucidate their temporal and regional patterns of expression with exercise. Transcript analysis included Hif1a (hypoxia-inducible factor 1α), Ldha (lactate dehydrogenase A), Slc2a1 (glucose transporter 1), Slc16a1 (monocarboxylate transporter 1), Slc16a7 (monocarboxylate transporter 2), and Vegf (vascular endothelial growth factor). Overall these results indicate that several genes involved in the elevated metabolic response with exercise are consistent with increased expression of HIF-1α suggesting a regulatory role for HIF-1α in exercise-enhanced neuroplasticity. Furthermore, these increases in gene expression appear regionally specific; occurring with brain regions we have previously shown to be sites for increased cerebral blood flow with activity. Such findings are beginning to lay down a working hypothesis that specific forms of exercise lead to circuit specific neuronal activation and can identify a potentially novel therapeutic approach to target dysfunctional behaviors subserved by such circuitry.
运动及其他形式的身体活动会导致哺乳动物大脑内特定运动和认知回路的激活。这些被激活的神经元回路会面临代谢需求的增加，并且必须应对可用氧气的短暂但显著的减少。转录因子缺氧诱导因子1α（HIF-1α）是参与代谢、突触形成和血流的众多基因的调节介质。本研究的目的是开始探索以电动跑步机跑步形式的运动与参与运动依赖性神经可塑性的基因激活之间的潜在关系，以开始阐明其中潜在的分子机制。对小鼠进行跑步机运动，并使用一种商业微阵列分析纹状体组织，该微阵列旨在识别其表达因暴露于缺氧（一种在高代谢需求细胞中出现的情况）而改变的转录本。鉴定出了几个候选基因，并选择了一组参与代谢和血管生成的基因来阐明它们在运动时的时间和区域表达模式。转录本分析包括Hif1a（缺氧诱导因子1α）、Ldha（乳酸脱氢酶A）、Slc2a1（葡萄糖转运蛋白1）、Slc16a1（单羧酸转运蛋白1）、Slc16a7（单羧酸转运蛋白2）和Vegf（血管内皮生长因子）。总体而言，这些结果表明，几个参与运动时代谢反应增强的基因与HIF-1α表达增加一致，提示HIF-1α在运动增强的神经可塑性中起调节作用。此外，这些基因表达的增加似乎具有区域特异性；发生在我们之前已证明是活动时脑血流量增加部位的脑区。这些发现开始提出一个工作假设，即特定形式的运动导致特定回路的神经元激活，并可确定一种潜在的新治疗方法来针对由此类回路支持的功能失调行为。
