Regulated Genetic Studies of Memory Formation

描述(申请人提供)：记忆可能是我们认知生活中最重要的组成部分，在许多精神和神经退行性疾病中被破坏或改变。然而，令人惊讶的是，我们在细胞和分子水平上对哺乳动物大脑中的神经元是如何被改造以存储记忆的知之甚少。这种困难很大程度上源于修改大脑内离散神经元群体中的分子信号的技术困难。该项目使用了一系列转基因小鼠，使转基因的受调控表达可以针对边缘系统内离散和重叠的神经元亚群。我们将使用一种激活形式的CaMKII的表达，当其在纹状体神经元中特异表达时，能够扰乱先前建立的恐惧条件记忆。我们将测试这一假设，即CaMKII的激活通过不分青红皂白地激活通常用于编码信息的细胞机制来擦除记忆痕迹的组成部分。在包括海马体、内嗅觉皮质和杏仁核在内的边缘系统的不同部分中，CaMKII的激活对先前建立的记忆的影响将被检测。本课程将研究激活剂对神经元兴奋性、基线突触传递和突触可塑性的影响。最后，将通过检测谷氨酸受体转运的影响来探讨CaMKII功能的分子机制。综上所述，这些实验的结果将有助于理解CaMKII信号在几个大脑结构中的作用，以及这些结构在编码不同记忆成分方面的作用。

DESCRIPTION (provided by applicant):Memory is perhaps the most crucial component our cognitive life and is disrupted or altered in numerous psychiatric and neurodegenerative disorders. Yet we know surprisingly little at the cellular and molecular level about how neurons in the mammalian brain are modified to store memories. Much of this difficulty arises from the technical difficulty in modifying molecular signaling in discrete populations of neurons within the brain. This project uses a series of genetically modified mice that allow the regulated expression of transgenes to be targeted to discrete and overlapping subpopulations of neurons within the limbic system. We will use expression of an activated form of CaMKII that is able to disrupt previously established fear conditioned memories when expressed specifically in striatal neurons. We will test the hypothesis that CaMKII activation erases components of the memory trace by indiscriminate activation of cellular mechanisms that are normally used to encode information. The effect of CaMKII activation within various components of the limbic system including hippocampus and entorhinal cortex and amygdala on previously established memories will be examined. The effect of kinase activation on neuronal excitability, baseline synaptic transmission and synaptic plasticity will be examined. Finally, the molecular mechanisms of CaMKII function will be investigated by examining effects glutamate receptor trafficking. Taken together the results of these experiments will help provide an understanding of the role of CaMKII signaling in several brain structures and the role of these structures in encoding different components of memory.