Consolidation mechanisms in the developing visual cortex

描述(申请人提供)：巩固是指依赖时间的过程，将不稳定的大脑可塑性或记忆转化为更持久的形式。这在海马体中得到了最好的描述，但类似的过程也发生在发育中的视觉皮质中，可能对视觉回路的成熟至关重要。我们的目标是确定控制经验依赖性皮质可塑性(眼优势可塑性)经典模型巩固的细胞机制。为了实现这一目标，我们将使用我们已建立的在视觉皮质中触发ODP值的方法，结合行为状态监测、皮质内输注、固有皮质信号的光学成像、免疫组织化学和体内单个神经元电生理学。这些技术结合在一个简单的实验设计中，使我们能够检查激酶、翻译和转录后通路的作用，这可能是皮质回路长期修改所必需的。我们提出了以下具体目标：1.确定蛋白激酶A(PKA)在ODP期巩固中的作用。在这个特定的目标中，我们将检验PKA信号是巩固皮质可塑性所必需的假设。这将通过a)抑制PKA活性，b)激活PKA活性，以及c)在视皮层中抑制在ODP巩固阶段的PKA-AKAP结合来实现。2.确定蛋白质合成在ODP值巩固中的作用。在这个特定的目标中，我们将检验蛋白质合成是巩固皮质可塑性所必需的假设。这将通过可逆地抑制视皮层中树突状和整体蛋白质的合成来实现。3.确定转录调控在ODP巩固中的作用。在这个特定的目标中，我们将测试这一假设，即染色质修饰是巩固ODP所必需的。这将通过测量组蛋白乙酰化的变化，并通过增加或减少组蛋白乙酰化在视皮层中的整合阶段来实现。公共卫生相关性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.