Project 2: Role of synaptic Plasticity in Hippocampal Memory

该项目的中心假设是，多个海马体兴奋回路中每一个的突触可塑性通过提供不同和互补的功能来贡献海马体在学习和记忆中的整体作用。虽然这样的想法已经被广泛建模，但由于技术上的困难，实证研究一直很少。最近发明的细胞类型限制性基因敲除技术和对所产生的突变的多学科分析提供了一种有效的方法。继我们之前对CA1和CA3回路的研究之后，本课题将重点放在齿状回(DG)。我们建议建立一个NMDA受体(NR)基因敲除小鼠品系，在该品系中，基因去除在成年DG颗粒细胞中是选择性的。通过让突变小鼠接受专门设计的行为规程，我们将检验穿孔路径(PP)-DG突触的可塑性在 模式分离和其他特定方面的海马体依赖的学习和记忆。将多电极记录技术应用于接受特殊设计的空间记忆任务(马车轮子迷宫)的突变小鼠，我们将与马修·威尔逊合作，寻找海马神经元活动与可能的行为损害之间的关联。我们还建议产生GluR6(G6)基因敲除小鼠品系，其中 DG颗粒细胞或CA3锥体细胞的消融是选择性的。在与Steve Heinemann的合作中，我们将确定突触前或突触后G6是否在苔藓纤维(Mf)-CA3突触上实现可塑性。通过对这些突变体进行几项行为任务，我们将检验MF突触的可塑性是否在记忆、模式分离、模式完成和快速一次尝试学习的特定方面发挥关键作用。我们还将寻找海马体 神经元活动与推测的行为损害相关。我们将把这些研究扩展到细胞类型受限、可逆诱导的NR1和G6突变小鼠，当它们从中心的核心#1项目中获得时。这些多学科的合作研究将促进我们对海马体回路在学习和记忆中作用的基础知识，从而有助于心理健康和疾病，因为记忆力障碍是衰老和重大神经退行性疾病(如阿尔茨海默氏症和帕金森氏病)的标志。

The central hypothesis of this project is that synaptic plasticity in each of multiple hippocampal excitatory circuits contributes to the overall role of the hippocampus in learning and memory by providing distinct and complementary functions. While such ideas have been modeled extensively, empirical studies have been scant due to technical difficulties. The recently invented cell type-restricted gene knockout technique and multidisciplinary analyses of the resulting mutants provide an effective approach. Following our previous studies on CA1 and CA3 circuits, this project focuses on dentate gyrus (DG). We propose to generate an NMDA receptor (NR) knockout mouse strain in which the gene ablation is selective in adult DG granule cells. By subjecting the mutant mice to specifically designed behavioral protocols, we will test the hypothesis that the plasticity at the perforant path (PP)-DG synapses plays a crucial role in pattern separation and other specific aspects of hippocampus-dependent learning and memory. Applying the multielectrode recording technique to the mutant mice undergoing a specifically designed spatial memory task ( wagon wheel maze"), we will seek, in collaboration with Matthew Wilson, hippocampal neuronal activity correlates of the putative behavioral impairments. We also propose to generate GluR6 (G6) knockout mouse strains in which the gene ablation is selective either in DG granule cells or CA3 pyramidal cells. In collaboration with Steve Heinemann, we will determine whether pre- or post-synaptic G6 gates plasticity at the mossy fiber (MF)-CA3 synapses. By subjecting these mutants to several behavioral tasks, we will examine whether the MF synaptic plasticity plays a crucial role in specific aspects of memory, pattern separation, pattern completion and rapid one-trial learning. We will also seek hippocampal neuronal activity correlates of putative behavioral impairments. We will extend these studies to cell type-restricted, reversibly inducible NR1 and G6 mutant mice when they become available from the Center's Core #1 project. These multidisciplinary and collaborative studies will advance our fundamental knowledge about the roles of hippocampal circuits in learning and memory and, thereby, contribute to mental health and illness because mnemonic impairments are a hallmark of aging and major neurodegenerative diseases such as Alzheimer's and Parkinsons's disease.