The role of astrocytes in visual critical period plasticity

点击翻译按钮获取中文摘要

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.