Neurobiological Mechanisms of Systems Consolidation

 描述(由申请人提供)：众所周知，新的情节和背景记忆存储在海马体中。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。这一过程被认为发生在海马体重播新获得的信息的不活动和睡眠期间。重播被认为推动了皮质内连接的形成，最终允许记忆在没有来自海马体的输入的情况下被提取。尽管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，以及2)确定这些细胞的重新激活是否对于记忆恢复和大脑皮层的长期存储是必要和充分的。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质中编码记忆的网络，并跟踪它们在巩固期间的活动。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，并确定对大脑皮层长期记忆存储的影响。标准的巩固模型预测，刺激海马区将重新激活在学习过程中标记的皮质神经元，并诱导长期存储。相反，在学习后让海马区沉默，应该会防止巩固和导致健忘症。我们的实验将：a)证实这些长期持有的假设，并提供机械性的洞察力，或者b)驳斥这些假设，并为理解海马体对记忆巩固的贡献提供一个新的框架。

 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.