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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：
10442650
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/10442650
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 (Brain)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 neurological recovery novel novel strategies preconditioning promoter relating to nervous system 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，比如体育锻炼和