NMDA RECEPTOR-MEDIATED FEEDFORWARD MEMORY

NMDA 受体介导的前馈记忆

• 批准号: 8635548
• 负责人: Cha-Min Tang
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635548
• 关键词: Address; Affinity; Alzheimer' s Disease; Behavior; Binding; Binding Sites; Brain; Buffers; Data; Dendrites; Disease; Distal; Electrophysiology (science); Epilepsy; Equilibrium; Functional disorder; General Population; Glutamates; Glycine; Health; Hippocampus (Brain); Information Storage; Ingestion; Kinetics; Lead; Link; Mediating; Memory; Mental disorders; Molecular; Movement; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Nature; Neuronal Plasticity; Neurons; Optics; Pathogenesis; Pharmaceutical Preparations; Population; Preparation; Prevalence; Process; Reading; Recording of previous events; Rewards; Risk; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Simulate; Site; Slice; Stroke; Synapses; Technology; Testing; Theta Rhythm; Time; base; density; high reward; high risk; hippocampal pyramidal neuron; insight; millisecond; nervous system disorder; novel; operation; optogenetics; regenerative; response; theories; treatment strategy

Abstract: The brain receives time encoded signals whose information content is meaningful only if temporal sequences can be processed as a whole. This temporal binding process requires memory buffers, the nature and identity of which remain a mystery. Unraveling this mystery may provide insights for the pathogenesis and management of epilepsy, schizophrenia, and other neuro-psychiatric disorders. We postulate that the cellular substrates for these memory buffers are feedforward networks and that the molecular substrate for information storage is the bound- but-blocked state of the NMDA receptors. In preliminary studies we have demonstrated a phenomenon we called "Dendritic Hold and Read" (DHR). It is based on the idea that the glutamate-bound but Mg2+-blocked state of the NMDA receptor is a quasi-stable state that holds information on the history of synaptic excitation. This information can be held for hundreds of milliseconds and then be conditionally retrieved with a second independent 'gating' depolarization to produce a local regenerative dendritic spike. In this proposal we will combine electrophysiology, optogenetics, and state-of- the-art optical technologies to show that DHR enables the operation of feedforward memory in the hippocampus. More specifically, we will test pharmacologic means to manipulate the duration of the elementary unit of short term memory (Specific Aim 1). We will show that theta rhythm serves as the endogenous clock that drives feedforward memory (Specific Aim 2). And we will attempt to demonstrate the "time-to-space" transform that is the fundamental principle of feedforward memory (Specific Aim 3). This is a "high risk, high reward" proposal. The "risk" comes from proposing a totally novel theory of short term memory. This risk is counter balanced by compelling biophysical reasoning and abundance of preliminary data. The "reward" is in providing novel insights and treatment strategies for schizophrenia and Alzheimer's disease. It also provides insights into why distal dendrites are so excitable and epileptogenic .

摘要： 大脑接收时间编码信号，其信息内容只有在以下情况下才有意义： 时间序列可以作为一个整体来处理。这个临时绑定过程需要 内存缓冲区，其性质和身份仍然是一个谜。解开这个谜团可能 为癫痫、精神分裂症和其他疾病的发病机制和管理提供见解。 神经精神疾病。我们假设这些记忆缓冲区的细胞基质 是前馈网络，信息存储的分子基质是边界， 但是NMDA受体的阻断状态。 在初步的研究中，我们已经证明了一种现象，我们称之为“树枝状的持有 ”（《明史》）。这是基于这样的想法，即谷氨酸结合但Mg 2+阻断的状态， NMDA受体是一种准稳定状态，它保存着突触历史的信息， 激发这些信息可以保存数百毫秒，然后有条件地 用第二个独立的“门控”去极化恢复，以产生局部再生 树枝状尖峰在这项提案中，我们将结合联合收割机电生理学，光遗传学，和国家的- 最先进的光学技术表明，DHR使前馈存储器的操作， 海马体更具体地说，我们将测试药理学手段来操纵 短期记忆基本单位的持续时间（具体目标1）。我们将证明θ 节律作为驱动前馈记忆的内源性时钟（具体目标2）。和 我们将试图证明“时间到空间”的转换，这是基本原则， 前馈记忆（具体目标3）。 这是一个“高风险，高回报”的建议。“风险”来自于提出一个完全 短期记忆的新理论这种风险通过强制性的生物物理 推理和丰富的初步数据。“奖励”是提供新颖的见解， 精神分裂症和阿尔茨海默病的治疗策略。它还提供了深入了解 为什么远端树突如此容易兴奋和致癫痫 .