Molecular mechanisms of exercise-induced synaptic plasticity in the hippocampus

神经元具有处理和响应复杂刺激的非凡能力，如体育锻炼和 生物体外部环境的变化。锻炼对大脑健康的价值不能 其影响被低估，因为它影响情绪、学习和记忆以及预防和康复 从神经系统疾病中恢复。然而，实验工作在很大程度上集中在 持续运动几周或几个月(1-3个月)，这也可能对中枢神经系统产生直接影响 通过多器官系统的改变而产生的间接影响。同样，运动引起的注意力最多 海马区的可塑性主要发生在新生颗粒细胞(1，3-7)，但可塑性发生在更多的颗粒细胞上。 也有大量成熟颗粒细胞(8)。除了持续的好处外，急性运动也是 与学习和记忆(9，10)的短期增加有关，这可能是由海马体(11-13)调节的。这在分子水平上是如何发生的还不清楚。因此，我们决定研究一集 锻炼会影响神经活动，影响大脑功能。我们开发了一种新的体内分析方法 由一次自愿运动激活的齿状颗粒细胞。我们的方法，类似于一种“冲动” 功能的工程学术语，使我们能够检查运动诱导的突触和分子变化 运动后的天数。成熟的齿状颗粒细胞，通过自愿运动在两小时内激活 窗口，用Fos-Trap小鼠(14，15)永久标记，其中立即早期基因 启动子连接到一个荧光报告程序，永久标记激活的颗粒细胞。的单集 运动导致外分子突触功能和树突棘密度的选择性增加 齿状回的一层，该层接受来自内嗅皮层的背景信息。顶层 在运动激活细胞的RNAseq中上调的基因是Mtss1L，这是一个先前未被研究的基因编码 对于I-bar结构域蛋白。当杆状结构域感应并诱导膜弯曲时，我们假设 Mtss1L是树突棘和突触形成的早期效应者 锻炼身体。我们的初步数据引出了一些有趣的问题，这些问题将在本文中讨论 求婚。即：1.Mtss1L在哪里定位？为什么对突触的影响仅限于特定的 齿状回中的板层？其他I-bar家族成员的影响是什么？几个表达在 突触，但只有Mtss1L是活动依赖的？；以及3.运动诱导的突触变化是主要的特异性吗？ 通过显著刺激学习和记忆的突触？我们的方法提供了细胞和时间的特异性，将生理和临床上相关的刺激(运动)与个体突触和 促进海马体结构可塑性的特定基因表达。

Neurons have the remarkable ability to process and respond to complex stimuli such as physical exercise and changes in an organism’s external environment. The value of exercise for brain health cannot be underestimated as its effects impact mood, learning and memory as well as prevention and rehabilitation and recovery from neurological illness. However, experimental effort largely has been focused on the effects of sustained exercise over periods of weeks or months (1-3), which can involve direct effects on the CNS as well as indirect effects through alterations in multiple organ systems. Likewise, most attention in exercise-induced hippocampal plasticity has been directed at newborn granule cells (1, 3-7), but plasticity occurs in the far more numerous mature granule cells as well (8). Aside from its sustained benefits, acute exercise has also been linked to short term increases in learning and memory (9, 10) that are likely mediated by the hippocampus (11-13). How this occurs at the molecular level is not clear. Thus we decided to examine how a single episode of exercise affects neural activity and impacts brain function. We developed a novel approach for in vivo analysis of dentate granule cells activated by a single episode of voluntary exercise. Our approach, akin to an "impulse" function in engineering terms, allowed us to examine exercise-induced synaptic and molecular changes over a period of days post-exercise. Mature dentate granule cells, activated by voluntary exercise during a two-hour window, were permanently marked using Fos-TRAP mice (14, 15), in which the immediate early gene promoter linked to a fluorescent reporter, permanently marks activated granule cells. The single episode of exercise resulted in selective increases in synaptic function and dendritic spine density in the outer molecular layer of the dentate gyrus, the lamina receiving contextual information from entorhinal cortex. The top upregulated gene in RNAseq of exercised-activated cells was Mtss1L, a previously understudied gene coding for an I-BAR-domain protein. As BAR domains sense and induce membrane curvature, we hypothesize that Mtss1L is an early effector of dendritic spine and synapse formation following stimuli such as exercise. Our preliminary data lead to a number of interesting questions that will be addressed in this proposal. Namely: 1. Where is Mtss1L localized and why are the effects on synapses limited to a specific lamina in the dentate gyrus?; What are the effects of other I-BAR family members as several are expressed at synapses but only Mtss1L is activity-dependent?; and 3. Do exercise-induced synaptic changes prime specific synapses for learning and memory by salient stimuli? Our approach provides the cellular- and temporal-specificity to link physiologically- and clinically-relevant stimuli in vivo (exercise) to individual synapses and expression of specific genes contributing to structural plasticity in the hippocampus.