Molecular Biology Program, Department of Natural Sciences, and.
School of Medicine, Lebanese American University, Byblos, Lebanon.
J Neurosci. 2019 Mar 27;39(13):2369-2382. doi: 10.1523/JNEUROSCI.1661-18.2019. Epub 2019 Jan 28.
Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted. It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing expression and signaling in the hippocampus. Understanding how exercise induces and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."
运动促进学习和记忆形成。这些效果取决于海马体 BDNF 的增加，BDNF 是一种与认知改善和抑郁症状缓解相关的生长因子。确定运动过程中产生的介导海马体表达的分子，将使我们能够利用运动的治疗潜力。在这里，我们报告在雄性小鼠中运动过程中产生的内源性分子诱导基因表达，并促进学习和记忆形成。运动过程中肌肉释放的代谢产物乳酸穿过血脑屏障，诱导海马体中基因表达和 TRKB 信号转导。事实上，我们发现乳酸依赖性 BDNF 的增加与空间学习和记忆保留的改善有关。乳酸的作用依赖于 Sirtuin1 去乙酰化酶的激活。SIRT1 增加转录共激活因子 PGC1a 和已知介导基因表达的分泌分子 FNDC5 的水平。这些结果揭示了一种内源性机制，可以解释身体运动如何导致 BDNF 的诱导，并确定乳酸作为一种潜在的内源性分子，可能对 BDNF 信号中断的中枢神经系统疾病具有治疗价值。已经确定运动促进学习和记忆形成，并缓解抑郁症状。这些作用是通过诱导海马体中的基因表达和信号转导来介导的。了解运动如何诱导基因表达，并确定介导这种诱导的分子，将使我们能够设计出模仿运动对大脑影响的治疗策略，特别是对于那些由于病情不能运动、且 BDNF 表达下降的中枢神经系统疾病患者。我们确定乳酸是运动过程中产生的内源性代谢产物，它穿过血脑屏障，以 BDNF 依赖的方式促进海马体依赖性学习和记忆。我们的工作确定了乳酸是“运动药丸”的组成部分。
