Mechanisms of Sympathetic Axon Pruning

描述(申请人提供)：成熟神经通路的重塑包括轴突生长以建立新的连接和轴突退化，从而消除终末。在没有细胞死亡的情况下，轴突终止被消除或修剪的机制还知之甚少。周围交感神经支配为研究正常生理和病理生理条件下的轴突修剪提供了一种特别容易处理的模型。处女啮齿动物子宫中的交感轴突密度在发情周期中波动很快，末梢轴突在雌激素水平上升时退化，当雌激素水平下降时再生。我们已经证明雌激素升高子宫脑源性神经营养因子，并假设这有助于交感神经轴突变性。我们假设脑源性神经营养因子激活p75神经营养素受体，从而刺激轴突内神经酰胺的形成。这通过膜通透性异常增加和肌动蛋白解聚来促进终末轴突变性。本研究探讨靶标诱导选择性终末轴突修剪的机制。第一个目的是评估p75NTR激活在生理条件下导致交感神经轴突变性的假说。在目标2中，我们探讨了p75NTR激活通过增加轴突膜的通透性和促进肌动蛋白细胞骨架的失稳而导致轴突变性的假说。在目标3中，我们调查了导致轴突变性的靶产生的配体的性质。具体地说，将评估脑源性神经营养因子、神经生长因子原和神经降压素的作用。这些研究使用易于处理的体内和体外方法来探索靶标配体、神经受体和信号转导通路之间的关系，并将为在生理和病理生理条件下如何完成选择性终末轴突变性提供新的信息。这些发现将有助于理解与正常神经系统可塑性相关的组织原理，以及某些疾病状态下的神经功能障碍。

DESCRIPTION (provided by applicant): Remodeling of mature neural pathways involves both axonal outgrowth to establish new connections and axonal degeneration whereby terminations are eliminated. Mechanisms by which axon terminations are eliminated, or pruned, in the absence of cell death are poorly understood. Peripheral sympathetic innervation presents an especially tractable model for studying axon pruning under normal physiological and pathophysiological conditions. Sympathetic axon density in the virgin rodent uterus fluctuates rapidly during the estrous cycle, with terminal axons degenerating when estrogen levels rise and regenerating when they decline. We have shown that estrogen elevates uterine brain derived neurotrophic factor, and hypothesize that this contributes to sympathetic axon degeneration. We hypothesize that brain derived neurotrophic factor activates the p75 neurotrophin receptor, which stimulates intra-axonal ceramide formation. This promotes terminal axon degeneration through abnormal increases in membrane permeability and actin depolymerization. The present study investigates mechanisms whereby targets elicit selective terminal axon pruning. The first aim evaluates the hypothesis that p75NTR activation is responsible for inducing sympathetic axon degeneration under physiological conditions. In aim 2, we explore the hypothesis that p75NTR activation produces axon degeneration by increasing permeability of axonal membranes, and by promoting destabilization of the actin cytoskeleton. In aim 3, we investigate the nature of ligands produced by the target that incur axon degeneration. Specifically, the roles of BDNF, pro-NGF and neurotrimin will be assessed. These studies use tractable in vivo and in vitro approaches to explore relationships among target- derived ligands, neural receptors, and signal transduction pathways, and will provide novel information on how selective terminal axon degeneration is accomplished under physiological and pathophysiological conditions. Findings will be pertinent to understanding both organizing principles related to normal nervous system plasticity, and to disturbances in innervation in certain disease states.