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Molecular mechanisms of exercise-induced synaptic plasticity in the hippocampus

运动诱发海马突触可塑性的分子机制

基本信息

批准号：
10657454
负责人：
GARY L WESTBROOK
金额：
$ 36.19万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657454
关键词：
Acute Address Advocate Affect Attention Behavioral Brain Brain region Cell membrane Cells Cerebellum Code Complex Confocal Microscopy Data Dendrites Dendritic Spines Distal Electrophysiology (science)Engineering Environment Exercise Experimental Designs Family Family member Foundations Gene Expression Genes Hippocampus Hour Human Immediate-Early Genes Immunohistochemistry Individual Knockout Mice Label Lateral Lead Learning Link Location Medial Mediating Medical Membrane Memory Messenger RNA Methods Molecular Monitor Moods Mus Neoplasm Metastasis Neurons Newborn Infant Organism Pattern Physical Exercise Physiological Positioning Attribute Prevention Process Property Proteins RNA Rehabilitation therapy Reporter Reporting Role Scientist Signal Transduction Specificity Stimulus Synapses Synaptic plasticity Tertiary Protein Structure Testing Time Transcript Vertebral column body system brain health cell type clinically relevant density dentate gyrus entorhinal cortex experimental study granule cell improved in vivo laser capture microdissection member neural neurological recovery novel novel strategies preconditioning promoter segregation synaptic function synaptogenesis transcriptome sequencing

项目摘要

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.

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。运动对大脑健康的价值不能被由于其影响情绪、学习和记忆以及预防和康复，神经系统疾病的康复然而，实验工作主要集中在以下方面的影响：持续运动数周或数月（1-3），这也可能对中枢神经系统产生直接影响通过改变多个器官系统产生间接影响。同样，大多数注意力在运动引起的海马可塑性是针对新生颗粒细胞的（1，3-7），但可塑性发生在更广泛的细胞中。许多成熟的颗粒细胞（8）。除了持续的好处，剧烈运动也被与学习和记忆的短期增加有关（9，10），可能由海马体介导（11-13）。这在分子水平上是如何发生的尚不清楚。因此，我们决定研究如何一个单一的插曲，运动会影响神经活动和大脑功能。我们开发了一种用于体内分析的新方法齿状颗粒细胞被一次随意运动激活。我们的方法，类似于“冲动” 功能，使我们能够检查运动引起的突触和分子变化，运动后的一段时间。成熟的齿状颗粒细胞，通过两小时的自主运动激活窗口，使用Fos-TRAP小鼠永久标记（14，15），其中立即早期基因启动子连接到荧光报告基因，永久标记活化的颗粒细胞。单集运动导致突触功能和树突棘密度的选择性增加，齿状回的一层，该层接收来自内嗅皮层的上下文信息。顶部在运动激活细胞的RNAseq中上调的基因是Mtss 1 L，这是一种先前未充分研究的基因编码， I-BAR结构域蛋白由于BAR结构域感知并诱导膜弯曲，我们假设 Mtss 1 L是树突棘和突触形成的早期效应物，锻炼的我们的初步数据引出了一些有趣的问题，这些问题将在本报告中得到解决。提议即：1. Mts 1 L定位在哪里，为什么对突触的影响仅限于特定的齿状回的板层？其他I-BAR家族成员的作用是什么？突触，但只有Mts 1 L是活性依赖性的？和3.运动诱发的突触变化是否是突触的学习和记忆的显着刺激？我们的方法提供了细胞特异性和时间特异性，将体内生理和临床相关刺激（运动）与单个突触联系起来，海马结构可塑性的特定基因的表达。