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（由申请人提供）：众所周知，新的情景记忆和背景记忆储存在海马体中。随着时间的推移，这些记忆通过一个称为系统整合的过程转移到大脑皮层。这个过程被认为发生在不活动和睡眠期间，当海马体重放新获得的信息时。回放被认为是驱动皮层内连接的形成，最终允许记忆在没有海马体输入的情况下被检索。虽然这些假设在该领域被广泛接受，但几乎没有直接证据支持它们。为了解决我们知识中的这一重大差距，我们将使用最近开发的遗传工具来：1）识别和控制在学习过程中活跃的海马神经元，2）确定这些细胞的重新激活是否是必要的和足够的记忆检索和长期存储在皮层中。我们将通过使用新产生的转基因小鼠永久标记在学习过程中活跃的神经元来实现这些目标。标记这些细胞将使我们能够识别海马体和皮层中编码记忆的网络，并在巩固期间跟踪它们的活动。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动，并确定对皮层长期记忆储存的影响。巩固的标准模型预测，海马刺激将重新激活在学习过程中被标记的皮层神经元，并诱导长期存储。相反，在学习后沉默海马集合应该阻止巩固和诱导健忘症。我们的实验将：a）证实这些长期持有的假设，并提供机械的见解或B）反驳这些假设，并提供一个新的框架，了解海马体的贡献，记忆巩固。