NMDA RECEPTOR-MEDIATED FEEDFORWARD MEMORY

描述(由申请人提供)： 只有当时间序列可以作为一个整体进行处理时，大脑才会接收时间编码的信号，其信息内容才有意义。这种时间绑定过程需要记忆缓冲，其性质和身份仍然是个谜。解开这个谜团可能会为癫痫、精神分裂症和其他神经精神障碍的发病机制和治疗提供洞察力。我们假设这些记忆缓冲器的细胞底物是前馈网络，用于信息存储的分子底物是NMDA受体的结合但被阻断的状态。在初步研究中，我们演示了一种我们称为“树突持有和阅读”(DHR)的现象。它的基础是NMDA受体的谷氨酸结合但镁离子阻断的状态是一种准稳定状态，包含了突触兴奋历史的信息。这一信息可以被保存数百毫秒，然后有条件地通过第二次独立的门控去极化来检索，以产生局部再生的树突尖峰。在这项提案中，我们将结合电生理学、光遗传学和最先进的光学技术来展示DHR能够在海马体中实现前馈记忆的操作。更具体地说，我们将测试操纵短期记忆基本单位持续时间的药理学方法(具体目标1)。我们将展示theta节奏作为驱动前馈记忆的内源性时钟(特定目标2)。我们将尝试演示“时间-空间”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”的提议。“风险”来自于提出一种全新的短期记忆理论。这一风险被令人信服的生物物理推理和丰富的初步数据所抵消。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。它还提供了对为什么远端树突如此容易兴奋和致痫的见解。

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.