Neurobiological Mechanisms of Systems Consolidation

系统整合的神经生物学机制

• 批准号: 9070016
• 负责人: Brian J Wiltgen
• 金额: $ 33.35万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070016
• 关键词: Address; Affect; Amnesia; Anxiety; Biological; Brain; Cells; Data; Dementia; Diagnosis; Disease; Fright; Genetic; Goals; Health; Hippocampus (Brain); Human; Impairment; Knowledge; Label; Lead; Learning; Memory; Mental Depression; Mental disorders; Modeling; Molecular; Neurons; Neurosciences; Pharmacogenetics; Post-Traumatic Stress Disorders; Process; Proteins; Publishing; Schizophrenia; Sleep; Stroke; Structure; System; Systems Theory; Techniques; Testing; Time; Training; Transgenic Mice; conditioned fear; innovation; insight; long term memory; memory consolidation; memory encoding; memory retrieval; mouse model; nervous system disorder; neurobiological mechanism; novel strategies; optogenetics; prevent; receptor; research study; tool

 DESCRIPTION (provided by applicant): It is well established that new episodic and contextual memories are stored in the hippocampus. Over time, these memories are transferred to the cortex through a process called systems consolidation. This process is assumed to occur during periods of inactivity and sleep when the hippocampus replays newly acquired information. Replay is thought to drive the formation of intra-cortical connections that eventually allow memory to be retrieved without input from the hippocampus. Although these assumptions are widely accepted in the field, there is little direct evidence to support them. To address this significant gap in our knowledge, we will use recently developed genetic tools to: 1) identify and control hippocampal neurons that are active during learning and 2) determine if reactivation of these cells is necessary and sufficient for memory retrieval and long-term storage in the cortex. We will accomplish these goals by using newly generated transgenic mice to permanently label neurons that are active during learning. Tagging these cells will allow us to identify networks in the hippocampus and cortex that encode memory and follow their activity during the consolidation period. Next, we will use optogenetic and pharmacogenetic tools to control the activity of labeled hippocampal neurons and determine the effects on long-term memory storage in the cortex. Standard models of consolidation predict that hippocampal stimulation will reactivate cortical neurons that were tagged during learning and induce long-term storage. In contrast, silencing hippocampal ensembles after learning should prevent consolidation and induce amnesia. Our experiments will either: a) substantiate these long-held assumptions and provide mechanistic insight or b) refute these assumptions and provide a new framework for understanding the contributions of the hippocampus to memory consolidation.

 描述（由应用程序提供）：已经很好地确定，新的情节和上下文记忆存储在海马中。随着时间的流逝，这些记忆通过称为系统合并的过程将这些记忆转移到皮层中。假定在海马重播新获得的信息时，假定此过程发生在不活动和睡眠期间。人们认为重播可以驱动皮层内连接的形成，这些连接有时可以在没有海马的输入的情况下检索内存。尽管这些假设在该领域被广泛接受，但几乎没有直接的证据来支持它们。为了解决我们知识的这一重大差距，我们将使用最近开发的遗传工具来：1）识别和控制学习过程中活性的海马神经元，以及2）确定这些细胞的重新激活是否需要且足以在皮质中的记忆检索和长期存储。我们将通过使用新生成的转基因小鼠来永久标记在学习过程中活跃的神经元来实现这些目标。对这些单元格进行标记将使我们能够识别海马和皮层中编码内存并在整合期间关注其活动的网络。接下来，我们将使用光遗传学和药物遗传学工具来控制标记的海马神经元的活性，并确定对皮质中长期记忆存储的影响。巩固的标准模型预测，海马刺激将重新激活在学习和影响长期存储过程中标记的皮质神经元。相比之下，学习后的海马共同体沉默应防止巩固并影响失忆症。我们的实验要么将要么：a）证实这些长期以来的假设并提供机械洞察力或b）驳斥这些假设，并为了解海马对记忆巩固的贡献提供了新的框架。