The CRE/CREB Pathway and Visual Cortical Plasticity

描述（由申请人提供）：发育过程中视觉体验的改变诱导初级视觉皮层中连接的显著重组。经验依赖性可塑性的能力随着年龄的增长而下降。视觉皮层可塑性需要激活cAMP反应元件（CRE）信号通路，这是一种导致基因表达的活性依赖性级联反应。这个建议的目的是更好地定义参与钙和cAMP依赖性信号成分在视觉皮层可塑性。我们使用的主要模型是单眼剥夺效应，它是指单眼剥夺引起的视觉皮层功能和形态的变化。我们的假设是，CRE/CREB信号调节的可塑性随着年龄的增长和ERK，p90 RSK，和CREB发挥不同的作用的可塑性机制的损失的基础。 具体而言，所提出的实验解决的主要问题是：（1）CREB活性是否调节眼优势可塑性的关键期？我们将使用转基因小鼠，这些小鼠在成年后具有可调节的CREB功能增强。(2)p90 RSK是视皮层活动依赖性基因表达的调节开关吗？我们将表达RSK 2的突变形式，以检查RSK活性是否控制CRE介导的基因表达和视觉皮层可塑性。(3)CRE/CREB通路的信号成分在视觉皮层中是如何调节的？我们将使用生物化学的方法来阐明视觉皮层中不同信号成分的相互作用。(4)CREB、ERK、p90 RSK和活性如何相互作用调节视皮层神经元树突形态？我们将使用表达突变形式的信号分子和GFP的病毒系统，以评估这些信号蛋白在树突状形态控制中的作用。 我们希望这项研究能够揭示发育可塑性的基本机制，以及为什么它会随着年龄的增长而下降。我们的研究结果可能有助于开发增强发育和成熟大脑可塑性的疗法，可能有助于治疗中枢视觉功能障碍和其他难治性大脑疾病。

DESCRIPTION (provided by applicant): Alterations of visual experience in development induce dramatic reorganization of connections in the primary visual cortex. The capacity for experience-dependent plasticity declines with age. Visual cortical plasticity requires the activation of the cAMP responsive element (CRE) signaling pathway, an activity-dependent cascade that leads to gene expression. The objective of this proposal is to better define the involvement of calcium and cAMP-dependent signaling components in visual cortical plasticity. The primary model that we use is the monocular deprivation effect, which refers to changes in visual cortical function and morphology induced by monocular deprivation. Our hypotheses are that regulation of CRE/CREB signaling underlies the loss of plasticity with age and that ERK, p90RSK, and CREB play distinct roles in the plasticity mechanism. Specifically, the major questions addressed by the proposed experiments are: (1) Does CREB activity regulate the critical period for ocular dominance plasticity? We will use transgenic mice engineered to have regulatable enhancement of CREB function in the adult. (2) Is p90RSK the regulatory switch for activity dependent gene expression in the visual cortex? We will express a mutant form of RSK2 to examine whether RSK activity controls CRE-mediated gene expression and visual cortical plasticity. (3) How are signaling components of the CRE/CREB pathway regulated in the visual cortex? We will use biochemical approaches to elucidate the interactions of different signaling components in the visual cortex. (4) How do CREB, ERK, p90RSK, and activity interact to regulate the dendritic morphology of visual cortical neurons? We will use viral system that expresses mutant forms of signaling molecules together with GFP in order to assess the role of these signaling proteins in the control of dendritic morphology. It is our hope that this research will shed light on basic mechanisms underlying developmental plasticity and why it declines with age. Our findings may help in the development of therapies to enhance plasticity in the developing and mature brain, potentially allowing treatments for central visual dysfunction and other intractable brain disorders.