NMDA RECEPTOR-MEDIATED FEEDFORWARD MEMORY

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进行处理。此临时绑定过程需要 记忆缓冲器，其性质和身份仍然是一个谜。解开这个谜团可能会 为癫痫、精神分裂症和其他疾病的发病机制和治疗提供见解 神经精神障碍。我们假设这些记忆缓冲器的细胞衬底 是前馈网络，用于信息存储的分子衬底是边界- BUT-阻断状态的NMDA受体。 在初步研究中，我们展示了一种现象，我们称之为“树突夹持” 这是基于这样的想法，即谷氨酸结合但被镁离子阻断的状态 NMDA受体是一种准稳定状态，它保存着有关突触历史的信息 激动人心。此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来检索以产生局部再生 树枝状的尖刺。在这项建议中，我们将结合电生理学、光遗传学和 最先进的光学技术表明，DHR使前馈存储器在 海马体。更具体地说，我们将测试药物手段来操纵 短期记忆基本单位的持续时间(具体目标1)。我们将展示theta 节奏是驱动前馈记忆的内源性时钟(具体目标2)。和 我们将尝试演示“时间到空间”的转换，这是 前馈记忆(具体目标3)。 这是一个“高风险、高回报”的提议。“风险”来自于提出一个完全 新奇的短时记忆理论。这一风险被令人信服的生物物理抵消了 推理和丰富的初步数据。“回报”在于提供新奇的见解和 精神分裂症和阿尔茨海默病的治疗策略。它还提供了对 为什么远端树突会如此兴奋和致痫 。

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 .