Consolidation mechanisms in the developing visual cortex

描述（由申请人提供）：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的皮质可塑性（眼优势可塑性（ODP））的经典模型巩固的细胞机制。为了实现这一目标，我们将使用我们已经建立的触发视觉皮层ODP的方法，结合行为状态监测、皮层内输注、皮层固有信号的光学成像、免疫组织化学和体内单神经元电生理。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，翻译和转录后途径的作用，这些途径可能是长期修改皮质回路所必需的。我们提出以下具体目标：确定蛋白激酶A （PKA）在ODP巩固中的作用。在这个特定的目的中，我们将检验PKA信号是皮质可塑性巩固所必需的假设。这将通过a)抑制PKA活性b)激活PKA活性和c)在ODP巩固阶段抑制PKA- akap在视觉皮层的结合来实现。2. 确定蛋白质合成在ODP巩固中的作用。在这个特定的目标中，我们将测试蛋白质合成是皮层可塑性巩固所必需的假设。这将通过在ODP的巩固阶段可逆地抑制视觉皮层中的树突和全局蛋白合成来实现。3. 确定转录调控在ODP巩固中的作用。在这个特定的目标中，我们将测试染色质修饰是ODP巩固所必需的假设。这将通过测量组蛋白乙酰化的变化以及在ODP巩固期视觉皮层组蛋白乙酰化的增加或减少来完成。本提案中的研究将为内源性脑激活如何导致皮层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.