NMDA RECEPTOR-MEDIATED FEEDFORWARD MEMORY

描述（由申请人提供）： 大脑接收的时间编码信号的信息内容是有意义的，只有当时间序列可以作为一个整体处理。这个时间绑定过程需要内存缓冲区，其性质和身份仍然是一个谜。解开这个谜团可能会为癫痫，精神分裂症和其他神经精神疾病的发病机制和管理提供见解。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NMDA受体的结合但阻断状态。 在初步研究中，我们已经证明了一种我们称之为“树突状保持和读取”（DHR）的现象。它是基于这样的想法，谷氨酸结合，但Mg2+阻断状态的NMDA受体是一个准稳定的状态，持有信息的历史突触兴奋。这个信息可以保持数百毫秒，然后有条件地检索与第二个独立的“门控”去极化，以产生局部再生树突棘。在这个提议中，我们将结合联合收割机电生理学、光遗传学和最先进的光学技术来证明DHR能够在海马体中实现前馈记忆的操作。更具体地说，我们将测试药理学手段来操纵短期记忆的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）。我们将试图证明“时间到空间”的转换，这是前馈记忆的基本原理（具体目标3）。 这是一个“高风险，高回报”的建议。“风险”来自于提出一个全新的短期记忆理论。这种风险被令人信服的生物物理推理和丰富的初步数据抵消。“奖励”是为精神分裂症和阿尔茨海默病提供新的见解和治疗策略。它也提供了为什么远端树突是如此兴奋和致癫痫的见解。

DESCRIPTION (provided by applicant): 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.