BDNF and Spine-Related Disorders of Memory and Cognition

描述（由申请人提供）：记忆和认知障碍与异常树突棘和/或调节脊柱肌动蛋白细胞骨架的信号干扰有关。补充结果表明，长期增强（LTP），一种被认为是记忆编码基础的突触可塑性形式，需要脊柱肌动蛋白重塑。这些观察结果表明，LTP巩固的细胞骨架机制中的缺陷代表了记忆障碍的共同神经生物学基础，以及在各种情况下改善认知表现的治疗靶点。目前关于#P01NS045260资金更新的提案解决了这一假设。项目研究表明，在六种不同类型记忆障碍的啮齿动物模型中，LTP稳定性受损：中年、早期亨廷顿病（HD）、脆性x综合征（FXS）、天使综合征、短期压力和低雌激素水平。在迄今为止测试的每个实例中，LTP相关的脊柱细胞骨架重组是有缺陷的，输注和/或上调脑源性神经营养因子（BDNF）可以挽救LTP和细胞骨架的变化。此外，活动驱动的肌动蛋白重塑被证明涉及介导脊柱f -肌动蛋白组装和稳定的不同级联反应，这在动物模型中受到不同程度的损害，但都受到BDNF的促进。在这些发现的基础上提出的研究：i)在七种截然不同的啮齿动物记忆障碍模型中，识别与LTP相关的活动驱动的肌动蛋白信号缺陷；Ii)确定啮齿动物模型中行为诱导的肌动蛋白信号传导和学习是否受损；iii)测试BDNF蛋白含量的慢性上调是否通过BDNF的TrkB受体和肌动蛋白调节级联增加信号传导，如体外和体内评估；iv)在每个啮齿类动物模型中，测试后一种效应伴随着行为异常减少的预测。将有四个项目，由不同的pi指导：每个项目都有自己的啮齿动物模型，并以细胞骨架信号传导的不同方面为重点。核心A将为所有项目提供显微镜、电生理学、行为研究和选择神经化学分析设备，并将支持管理和动物/试剂功能。总之，拟议的研究有望测试记忆障碍中最终常见缺陷的存在，并彻底评估使突触可塑性和行为正常化的临床相关策略。

DESCRIPTION (provided by applicant): Memory and cognitive disorders are associated with abnormal dendritic spines and/or disturbances to signaling regulating the spine actin cytoskeleton. Complementary results show that long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory encoding, requires spine actin remodeling. These observations suggest the hypothesis that defects in the cytoskeletal mechanisms of LTP consolidation represent a shared neurobiological basis for memory disturbances, and a therapeutic target for improving cognitive performance, in a variety of conditions. The present proposal for renewal of #P01NS045260 funding, addresses this hypothesis. Program studies have shown that LTP stabilization is impaired in rodent models of six different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), Angelman Syndrome, short-term stress, and low estrogen levels. In each instance thus far tested, LTP-related reorganization of the spine cytoskeleton was defective and infusions and/or upregulating Brain-Derived Neurotrophic Factor (BDNF) rescued LTP and cytoskeletal changes. Moreover, activity-driven actin remodeling was shown to involve distinct cascades mediating spine F-actin assembly and stabilization, that are differentially impaired across the animal models, but both facilitated by BDNF. The proposed studies build on these findings to: i) identify defects in activity-driven signaling to actin, associated with LTP, in seven distinctly different rodent models of memory impairment; ii) determine if behaviorally induced actin signaling and learning is impaired in the rodent models; iii) test if chronic up-regulation of BDNF protein content increases signaling through BDNF's TrkB receptor and actin regulatory cascades as assessed in vitro and in vivo; and iv) test the prediction that the latter effects are accompanied by a reduction in behavioral abnormalities in each of the rodent models. There will be four Projects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. Core A will provide analytical facilities for microscopy, electrophysiology, behavioral studies, and select neurochemical assays employed by all projects, and will support Administrative and Animal/Reagent functions. In all, the proposed studies are expected to test for the presence of a final, common defect in memory disorders and to thoroughly evaluate a clinically relevant strategy for normalizing synaptic plasticity and behavior.