The Spine Cytoskeleton and Memory Disorders

这个项目的长期目标是：(I)确定突触下细胞骨架中与 在记忆/认知障碍的啮齿动物模型中LTP巩固失败，以及(Ii)使用该信息 开发新的、临床上看似合理的策略来抵消这些缺陷。PPG的工作导致了一个模型 涉及共同调节双重肌动蛋白信号的三类膜受体的整合 组装和稳定肌动蛋白细丝的途径。我们的研究随后表明，离散误差是 在这个复杂的系统中，存在着三种截然不同的啮齿动物模型，与人类状况有关 记忆力有问题。我们还发现其中一种可释放的修饰物(脑源性神经营养因子： LTP模型中的BDNF)在直接应用于脑片或上调时可抵消突触可塑性的缺陷 被毒品迷住。拟议中的实验将采用一种新开发的方法，这种方法可以敏锐地、方便地 突触上的BDNF信号，使信号失败的分析成为关键的转换步骤 和潜在的治疗方法，并分析信号缺陷如何影响区域分布 学习过程中与LTP相关的突触变化。

The long-term objectives of this project are to (i) identify defects in the subsynaptic cytoskeleton related to the failure of LTP consolidation in rodent models of memory/cognitive impairments and (ii) use this information to develop novel, clinically plausible strategies for counteracting the defects. Work in the PPG led to a model of consolidation involving three classes of membrane receptors that collectively regulate dual actin signaling pathways for assembling and stabilizing actin filaments. Our studies then showed that discrete errors are present in this complex system in three distinctly different rodent models of human conditions associated with memory problems. We also found that one of the releasable modifiers (Brain-Derived Neurotrophic Factor: BDNF) in the LTP model offsets defects in synaptic plasticity when applied directly to brain slices or when upregulated by drugs. The proposed experiments will employ a newly developed method that acutely, facilitates BDNF signaling at synapses, make the critical translational step of moving the analysis of signaling failures and potential therapies to behaving animals, and analyze how signaling defects affect the regional distribution ('maps') of LTP-related synaptic changes during learning.