Neuronal Intracellular Signaling Underlying Synaptic, Circuit and Behavioral Plasticity

摘要 树突棘是一种蘑菇状的突触后区室， 信号级联对突触可塑性以及学习和记忆很重要。信令 脊柱中的事件涉及由数百种蛋白质相互作用组成的网络 广泛地。突触可塑性通常由棘中的Ca2+升高诱导，其激活了突触的可塑性。 多种信号通路。这导致肌动蛋白细胞骨架和膜的变化 动力学，这反过来又导致脊柱的结构和功能变化。最近的研究 已经证明这些蛋白质的活动具有多种时空模式， 其在不同的时间尺度上协调不同亚细胞区室中的信号传导活性。 为了更好地了解这一网络的运作原理及其机制， 可塑性，我们将开发工具来光学测量和操纵神经元中的信号活动 在大脑切片和清醒的动物中，在可塑性过程中。特别是，我们的目标是 开发创新技术，通过结合 先进的成像技术，新的光遗传学工具和基因组编辑技术。使用 这些工具，我们将确定内源性介导的信号传导活性的时间窗， 蛋白质，并阐明细胞内信号如何介导突触，电路和行为 可塑性。因此，这将有助于更好地了解信息是如何在不同的环境中处理的。 时间尺度，并提供新的见解的分子机制，学习和 记忆

Abstract Dendritic spines are mushroom-shaped postsynaptic compartments that host intracellular signaling cascades important for synaptic plasticity and, thereby, learning and memory. Signaling events in spines involve a network composed of hundreds of proteins interacting with each other extensively. Synaptic plasticity is typically induced by Ca2+ elevation in spines, which activates a variety of signaling pathways. This leads to changes in the actin cytoskeleton and membrane dynamics, which in turn causes structural and functional changes of the spine. Recent studies have demonstrated that the activities of these proteins have a variety of spatiotemporal patterns, which orchestrate signaling activity in different subcellular compartments at different time scales. To better understand the operational principles of this network and the mechanisms underlying plasticity, we will develop tools to optically measure and manipulate signaling activity in neurons in both brain slices and in awake, behaving animals during plasticity. In particular, we aim to develop innovative technology to image and measure endogenous proteins by combining advanced imaging techniques, new optogenetic tools and genome-editing technology. Using these tools, we will determine time windows of signaling activity mediated by endogenous proteins, and elucidate how intracellular signaling mediates synaptic, circuit and behavioral plasticity. This will thus lead to a better understanding of how information is processed at different time scales and provide new insights into the molecular mechanisms underlying learning and memory.