Department of Neurosurgery, Henan Provincial People´s Hospital, Henan University People's Hospital, Henan University School of Medicine, People's Hospital of Zhengzhou University, Zhengzhou, China.
Dr. Senckenbergische Anatomie, Goethe-University Frankfurt, Frankfurt am Main, Germany.
PLoS One. 2021 May 5;16(5):e0250743. doi: 10.1371/journal.pone.0250743. eCollection 2021.
The adult, mature central nervous system (CNS) has limited plasticity. Physical exercising can counteract this limitation by inducing plasticity and fostering processes such as learning, memory consolidation and formation. Little is known about the molecular factors that govern these mechanisms, and how they are connected with exercise. In this study, we used immunohistochemical and behavioral analyses to investigate how running wheel exercise affects expression of the neuronal plasticity-inhibiting protein Nogo-A in the rat cortex, and how it influences motor learning in vivo. Following one week of exercise, rats exhibited a decrease in Nogo-A levels, selectively in motor cortex layer 2/3, but not in layer 5. Nogo-A protein levels returned to baseline after two weeks of running wheel exercise. In a skilled motor task (forelimb-reaching), administration of Nogo-A function-blocking antibodies over the course of the first training week led to improved motor learning. By contrast, Nogo-A antibody application over two weeks of training resulted in impaired learning. Our findings imply a bimodal, time-dependent function of Nogo-A in exercise-induced neuronal plasticity: While an activity-induced suppression of the plasticity-inhibiting protein Nogo-A appears initially beneficial for enhanced motor learning, presumably by allowing greater plasticity in establishing novel synaptic connections, this process is not sustained throughout continued exercise. Instead, upregulation of Nogo-A over the course of the second week of running wheel exercise in rats implies that Nogo-A is required for consolidation of acquired motor skills during the delayed memory consolidation process, possibly by inhibiting ongoing neuronal morphological reorganization to stabilize established synaptic pathways. Our findings suggest that Nogo-A downregulation allows leaning to occur, i.e. opens a 'learning window', while its later upregulation stabilizes the learnt engrams. These findings underline the importance of appropriately timing of application of Nogo-A antibodies in future clinical trials that aim to foster memory performance while avoiding adverse effects.
成年成熟的中枢神经系统（CNS）的可塑性有限。身体锻炼可以通过诱导可塑性和促进学习、记忆巩固和形成等过程来克服这种局限性。目前人们对控制这些机制的分子因素知之甚少，也不知道它们与运动之间是如何联系的。在这项研究中，我们使用免疫组织化学和行为分析来研究跑步轮运动如何影响大鼠皮质中神经元可塑性抑制蛋白 Nogo-A 的表达，以及它如何影响体内运动学习。经过一周的运动，大鼠的 Nogo-A 水平下降，选择性地出现在运动皮层的第 2/3 层，而不是第 5 层。经过两周的跑步轮运动，Nogo-A 蛋白水平恢复到基线。在一项熟练的运动任务（前肢伸展）中，在第一周的训练过程中给予 Nogo-A 功能阻断抗体的治疗导致运动学习的改善。相比之下，在两周的训练过程中给予 Nogo-A 抗体的治疗导致学习受损。我们的研究结果表明，Nogo-A 在运动诱导的神经元可塑性中具有双模态、时间依赖性的作用：尽管活动诱导的抑制可塑性抑制蛋白 Nogo-A 最初似乎有利于增强运动学习，可能是通过允许在建立新的突触连接方面有更大的可塑性，但这个过程不会在持续的运动中持续下去。相反，在大鼠跑步轮运动的第二周过程中，Nogo-A 的上调表明，在延迟记忆巩固过程中，Nogo-A 对于获得的运动技能的巩固是必需的，可能是通过抑制正在进行的神经元形态重建来稳定已建立的突触通路。我们的研究结果表明，Nogo-A 的下调允许学习发生，即打开“学习窗口”，而其随后的上调稳定了已学习的记忆痕迹。这些发现强调了在未来旨在促进记忆表现而避免不良反应的临床试验中，正确应用 Nogo-A 抗体的重要性。
