The role of astrocytes in visual critical period plasticity

项目摘要/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。这个 视觉关键期提供了一个实验上易于处理的范例，在其中可以更好地理解星形胶质细胞如何 因子可以精确地调节大脑皮层回路的可塑性。关键时期是千篇一律的发展 适当的视觉体验对正常建立大脑皮层环路至关重要的时期。AS 关键时期的视觉输入操作导致了描述良好的皮质重塑和持续 这些范式可以用来研究星形细胞因素在这种形式的可塑性中的作用。Cyr61是一种 潜在的关键星形细胞可塑性调节因子，因为其mRNA表达在发育过程中不断增加 并在塑性处理后有所下降，表明它可能是一种“反塑性”因素，对 成年期的可塑性。在目标1中，将通过过度表达来研究Cyr61在关键时期的作用 它选择性地存在于小鼠视皮层的星形胶质细胞中。小鼠将遭受单眼剥夺，这通常是 导致皮质重塑。将进行电生理学和活体成像以评估重构 Cyr61过表达小鼠与对照小鼠的差异。如果Cyr61抑制可塑性，那么过度表达 在关键期，Cyr61有望降低对单眼剥夺的可塑性。Aim 2问 如果在成年期减少Cyr61的表达就足以重新打开可塑性的关键期。致信地址 这只在星形胶质细胞中选择性敲除Cyr61基因的成年转基因小鼠将接受单眼剥夺，并 评估可塑性的方法与目标1相同。如果Cyr61抑制成人的可塑性，则将其从成人中移除 星形胶质细胞被预测会增加对单眼剥夺的重塑反应。要确定CyR61如何 调节可塑性，Aim 3使用质谱学来鉴定CYR61蛋白的结合伙伴。这将是 有助于理解行动机制，并将为今后的调查提供途径。目标是 这些实验中的一项是检查特定的星形细胞因子是否必要且足以调节 临界时期塑性。这项研究建议对于理解如何促进 神经疾病、损伤或发育中断后的突触修复和电路重新连接。 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来提升他们的培训经验。索尔克研究所主办 博士后学者都有机会与外界互动的一系列研究研讨会 并展示他们自己的研究成果。此外，拟议的培训计划将包括与 赞助商保持进度，撰写评审论文，参加同行评审，每周一次实验室 实验室成员提交数据并从整个实验室获得试验性和关键性反馈的会议 实验室。

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.