Project 2: Role of synaptic Plasticity in Hippocampal Memory

该项目的中心假设是，多个海马兴奋回路中的每一个中的突触可塑性通过提供独特和互补的功能而有助于海马在学习和记忆中的整体作用。虽然这些想法已经被广泛建模，但由于技术困难，实证研究很少。最近发明的细胞类型限制性基因敲除技术和由此产生的突变体的多学科分析提供了一种有效的方法。本研究在前人对海马CA 1和CA 3区回路研究的基础上，重点研究齿状回（DG）。我们建议产生一个NMDA受体（NR）基因敲除小鼠品系，其中成年DG颗粒细胞中的基因消融是选择性的。通过使突变小鼠接受专门设计的行为方案，我们将检验以下假设：穿通通路（PP）-DG突触的可塑性在以下方面起着至关重要的作用： 模式分离和其他特定方面的依赖于校园的学习和记忆。将多电极记录技术应用于经历专门设计的空间记忆任务（“马车轮迷宫”）的突变小鼠，我们将与Matthew Wilson合作，寻找海马神经元活动与假定的行为障碍的相关性。我们还提出产生GluR 6（G6）敲除小鼠品系，其中该基因 在DG颗粒细胞或CA 3锥体细胞中选择性消融。与Steve Heinemann合作，我们将确定突触前或突触后G6门在苔藓纤维（MF）-CA 3突触的可塑性。通过对这些突变体进行几项行为任务，我们将研究MF突触可塑性是否在记忆，模式分离，模式完成和快速一次性学习的特定方面起着至关重要的作用。我们还将寻找海马 神经元活动与假定的行为障碍相关。我们将这些研究扩展到细胞类型限制，可逆诱导的NR 1和G6突变小鼠，当它们从中心的核心#1项目。这些多学科和协作研究将推进我们对海马电路在学习和记忆中的作用的基本知识，从而有助于心理健康和疾病，因为记忆障碍是衰老和主要神经退行性疾病（如阿尔茨海默氏症和帕金森氏症）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.