Consolidation mechanisms in the developing visual cortex

描述（申请人提供）：巩固是指将大脑可塑性或记忆的不稳定形式转化为更持久形式的时间依赖性过程。这在海马体中得到了最好的描述，但类似的过程发生在发育中的视觉皮层中，并且可能是视觉回路成熟所必需的。我们的目标是确定巩固经验依赖性皮层可塑性（眼优势可塑性（ODP））的经典模型的细胞机制。为了实现这一目标，我们将使用我们建立的方法触发ODP在视觉皮层结合行为状态监测，皮质内输液，光学成像的内在皮质信号，免疫组织化学和单神经元电生理学在体内。这些技术结合在一个简单的实验设计，使我们能够检查激酶，翻译和转录后通路，可能是必要的长期持久的修改皮层电路的作用。我们提出以下具体目标：1。确定蛋白激酶A（PKA）在ODP巩固中的作用。在这个特定的目标，我们将测试的假设，PKA信号所需的皮层可塑性的巩固。这将通过a）抑制PKA活性B）激活PKA活性和c）在ODP的巩固期抑制PKA-AKAP在视皮层中的结合来实现。2.确定蛋白质合成在巩固ODP中的作用。在这个特定的目标，我们将测试的假设，蛋白质合成所需的皮层可塑性的巩固。这将通过在ODP的巩固阶段可逆地抑制视皮层中的树突和全局蛋白质合成来实现。3.确定转录调节在ODP巩固中的作用。在这个特定的目标，我们将测试的假设，染色质修饰所需的巩固ODP。这将通过测量组蛋白乙酰化的变化和通过在ODP的巩固期增加或减少视皮层中的组蛋白乙酰化来实现。这项提案中的研究将为内源性大脑激活如何导致皮质回路的长期变化提供重要的新见解。这将提高我们对正常和病理性大脑发育和记忆形成的理解。

Description (provided by applicant): Consolidation refers to time-dependent processes that convert labile forms of brain plasticity or memory into more permanent forms. This has been best described in the hippocampus, but similar processes occur in the developing visual cortex and may be essential for the maturation of visual circuits. Our goal is to identify the cellular mechanisms governing the consolidation of a classic model of experience-dependent cortical plasticity (ocular dominance plasticity (ODP). To achieve this goal we will use our established methods of triggering ODP in the visual cortex combined with behavioral state monitoring, intracortical infusion, optical imaging of intrinsic cortical signals, immunohistochemistry and single-neuron electrophysiology in vivo. These techniques are combined in a simple experimental design that allows us to examine the role of kinase, translational and post-transcriptional pathways that may be necessary for long-lasting modifications of cortical circuitry. We propose the following specific aims: 1. Determine the role of protein kinase A (PKA) in the consolidation of ODP. In this specific aim, we will test the hypothesis that PKA signaling is required for the consolidation of cortical plasticity. This will be accomplished by a) inhibiting PKA activity b) activating PKA activity and c) inhibiting PKA-AKAP binding in the visual cortex during the consolidation phase of ODP. 2. Determine the role of protein synthesis in the consolidation of ODP. In this specific aim, we will test the hypothesis that protein synthesis is required for the consolidation of cortical plasticity. This will be accomplished by reversibly inhibiting dendritic and global protein synthesis in the visual cortex during the consolidation phase of ODP. 3. Determine the role of transcriptional regulation in the consolidation of ODP. In this specific aim, we will test the hypothesis that chromatin modification is required for the consolidation of ODP. This will be accomplished by measuring changes in histone acetylation and by increasing or decreasing histone acetylation in the visual cortex during the consolidation phase of ODP. PUBLIC HEALTH RELEVANCE The research in this proposal will provide important new insights into how endogenous brain activation leads to long-lasting changes in cortical circuits. This will improve our understanding of normal and pathological brain development and memory formation.