The role of astrocytes in visual critical period plasticity

星形胶质细胞在视觉关键期可塑性中的作用

• 批准号: 10709873
• 负责人: Laura Sancho Fernandez
• 金额: $ 7.38万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709873
• 关键词: Address; Adolescence; Adult; Age; Astrocytes; Binding; Biological; Biological Assay; Brain; Calcium; Candidate Disease Gene; Cellular Membrane; Contralateral; Data; Dendrites; Development; Electrophysiology (science); Environment; Excision; Extracellular Matrix; Eye; Faculty; Feedback; Future; Genes; Genetic Recombination; Goals; Heparan Sulfate Proteoglycan; Homeostasis; Image; Immediate-Early Genes; Immunoprecipitation; Integrins; Investigation; Knock-out; Knockout Mice; LDL-Receptor Related Protein 1; Laboratories; Lead; Low Density Lipoprotein Receptor; LoxP-flanked allele; Maps; Mass Spectrum Analysis; Measures; Mus; Neuroglia; Neuronal Plasticity; Neurons; Ocular Dominance; Organ; Paper; Peer Review; Physiology; Play; Postdoctoral Fellow; Protein Secretion; Proteins; Publishing; Reporting; Research; Research Personnel; Research Proposals; Role; Sampling; Series; Stereotyping; Structure; Synapses; Tamoxifen; Training; Transgenic Mice; Vertebral column; Virus; Visual; Visual Cortex; Work; Writing; cell type; comparison control; critical developmental period; critical period; cyr61 protein; differential expression; experience; experimental group; experimental study; functional plasticity; gene induction; in vivo imaging; inducible Cre; liquid chromatography mass spectroscopy; mRNA Expression; magnetic beads; meetings; member; monocular; monocular deprivation; nervous system disorder; neural; neural circuit; neuron component; novel; overexpression; permissiveness; receptor; repaired; response; synaptogenesis; therapeutic target

Project Summary/ Abstract Astrocytes play a crucial role in regulating the structure, physiology, and plasticity of neural circuits. The visual critical period provides an experimentally tractable paradigm in which to better understand how astrocytic factors can precisely modulate plasticity in cortical circuits. The critical period is a stereotyped developmental period during which proper visual experience is essential for the normal establishment of cortical circuits. As manipulations of visual input during the critical period lead to well-described cortical remodeling and lasting changes, these paradigms can be used to study the role of astrocytic factors in this form of plasticity. Cyr61 is a potential key astrocytic plasticity-regulating factor, as its mRNA expression increases throughout development and decreases after plasticity manipulations, suggesting it may be an “anti-plasticity” factor acting to restrict plasticity in adulthood. In Aim 1, the role of Cyr61 during the critical period will be examined by overexpressing it selectively in astrocytes in the mouse visual cortex. Mice will undergo monocular deprivation which typically results in cortical remodeling. Electrophysiology and in vivo imaging will be performed to assess remodeling differences between Cyr61 overexpressing and control mice. If Cyr61 is inhibiting plasticity, then overexpressing Cyr61 during the critical period is expected to reduce plasticity in response to monocular deprivation. Aim 2 asks if reducing the expression of Cyr61 in adulthood is sufficient to re-open the critical period for plasticity. To address this adult transgenic mice with Cyr61 knockout selectively in astrocytes will undergo monocular deprivation, and plasticity assessed in the same way as Aim 1. If Cyr61 is inhibiting adult plasticity, then removing it from adult astrocytes is predicted to increase the remodeling response to monocular deprivation. To determine how CYR61 regulates plasticity, Aim 3 uses mass spectrometry to identify binding partners of CYR61 protein. This will contribute to understanding the mechanism of action and will provide future avenues of investigation. The goal of these experiments is to examine whether specific astrocytic factors are necessary and sufficient to modulate critical period plasticity. This research proposal has important implications for understanding how to promote synaptic repair and circuit rewiring after neurological disease, damage, or developmental disruptions. The research and training plan will take place at the Salk Institute for Biological Studies, where there are multiple opportunities for postdoctoral researchers to enhance their training experience. The Salk Institute hosts a series of research seminars in which postdoctoral scholars both have the opportunity to interact with outside faculty and to present their own research. Moreover, the proposed training plan will include weekly meetings with the Sponsor to maintain progress, writing review papers, participating in peer review, and weekly laboratory meetings in which a lab member presents data and obtains experimental and critical feedback from the entire lab.

项目总结/摘要 星形胶质细胞在调节神经回路的结构、生理和可塑性方面起着至关重要的作用。的 视觉关键期提供了一个实验上易于处理的范例，可以更好地理解星形胶质细胞 因子可以精确地调节皮层回路的可塑性。关键期是一个定型的发展期， 在此期间，适当的视觉体验对于皮层回路的正常建立是必不可少的。作为 在关键期对视觉输入的操纵导致了描述良好的皮质重塑和持久的 变化，这些范例可用于研究星形胶质细胞因子在这种形式的可塑性中的作用。Cyr 61是一个 潜在的关键星形胶质细胞可塑性调节因子，因为其mRNA表达在整个发育过程中增加 在可塑性处理后降低，这表明它可能是一种“反可塑性”因素， 成年后的可塑性在目的1中，Cyr 61在关键时期的作用将通过过表达Cyr 61来检验。 它选择性地作用于小鼠视觉皮层的星形胶质细胞。小鼠将经历单眼剥夺， 导致皮质重塑将进行电生理学和体内成像以评估重塑 Cyr 61过表达小鼠和对照小鼠之间的差异。如果Cyr 61抑制可塑性，那么过度表达Cyr 61， Cyr 61在关键时期，预计将减少可塑性的单眼剥夺。目标2问 如果减少成年期Cyr 61的表达足以重新开启可塑性的关键期。解决 这种在星形胶质细胞中选择性敲除Cyr 61的成年转基因小鼠将经历单眼剥夺， 以与目标1相同的方式评估可塑性。如果Cyr 61抑制了成年人的可塑性，那么将其从成年人中移除， 预测星形胶质细胞增加对单眼剥夺的重塑反应。为了确定CYR 61 调节可塑性，目的3使用质谱法来识别CYR 61蛋白的结合伴侣。这将 有助于了解作用机制，并将提供未来的调查途径。目标 这些实验的目的是检查特定的星形胶质细胞因子是否是调节 临界期塑性这一研究建议对理解如何促进 神经系统疾病、损伤或发育中断后的突触修复和电路重新布线。 研究和培训计划将在索尔克生物研究所进行，那里有 为博士后研究人员提供多种机会，以提高他们的培训经验。索尔克研究所主办 一系列的研究研讨会，其中博士后学者都有机会与外界互动 教师和介绍自己的研究。此外，拟议的培训计划将包括每周与 申办者保持进展，撰写综述论文，参与同行评审，每周实验室 实验室成员在会议上展示数据，并从整个实验室获得实验和关键反馈。 实验室