Medial temporal lobe contributions to flexible use of memory

描述（由申请人提供）：情景记忆——对单个事件的记忆——的一个强大方面是灵活地应用和结合过去经验的信息来指导新行为的能力。这种以新颖的方式结合经验来推断新关系的灵活性对于在不断变化的环境中的行为是必不可少的。内侧颞叶（MTL）的结构对于新情景记忆的形成至关重要，这些情景记忆将单个事件中的信息绑定在一起。然而，MTL如何支持跨不同事件获得的信息的灵活组合尚不清楚。本提案中提出的研究将使用功能性磁共振成像（fMRI）来研究跨不同发作或跨发作结合信息的机制。我们将进一步研究MTL的各个区域如何支持这些机制。实验1将验证跨情节绑定依赖于与当前经历共享元素的先前记忆的重新激活的假设。将使用一种新的方法来推断大脑状态，例如在没有外部行为反应的情况下推断被回忆的记忆的一般内容。我们将研究与先前经验重叠的新事件的编码是否会触发先前经验的重新激活，从而导致记忆的灵活使用。实验2和3将使用高分辨率功能磁共振成像来研究单个MTL子区域如何支持跨情景结合的关键过程。实验2将测试海马的CA3区是否支持MTL皮层内的再激活，正如CA3在模式完成-从部分线索回忆存储的记忆中的作用所预测的那样。当前和先前经验之间的重叠可以作为这样的部分线索。该研究将提供第一个直接证据，证明MTL介导重叠经历中过去事件的再激活，这种再激活支持跨事件绑定，以促进记忆的灵活使用。实验3将测试在两个经历中相同或不同的空间背景如何影响在两个情节中组合信息的可能性，并研究当前经验和先前经验的比较如何促进跨情节结合。将回忆起的记忆与当前事件进行比较，可能有助于检测存储记忆的变化，并触发新的编码，从而将新信息整合到现有记忆中。这种比较函数被认为依赖于海马体的CA1区。本研究将阐明MTL子区域如何支持从不同情节之间的关系中提取新知识，并为情境在引发跨情节结合中的作用提供新的证据。了解MTL分区域如何整合跨事件的信息，将提供一种手段来预测和促进灵活学习的发生，并有可能开发工具来加强以灵活性缺陷为特征的特定人群（如精神分裂症、轻度认知障碍、阿尔茨海默病和抑郁症患者）的这些过程。

DESCRIPTION (provided by applicant): A powerful aspect of episodic memory-memory for individual events-is the ability to flexibly apply and combine information from past experiences to guide new behavior. Such flexibility to combine experiences in novel ways to infer new relationships is essential to behavior in ever-changing environment. The structures of the medial temporal lobe (MTL) are critical for the formation of new episodic memories that bind information within single episodes. However, how MTL supports the flexible combination of information gained across distinct episodes is not well understood. The research presented in this proposal will use functional magnetic resonance imaging (fMRI) to investigate the mechanisms that enable binding of information across distinct episodes, or cross-episode binding. We will further investigate how individual regions of the MTL support these mechanisms. Experiment 1 will test the hypothesis that cross-episode binding relies on reactivation of prior memories that share elements with the current experiences. A novel method will be used that allows inference about brain states, such as inferring a general content of a recalled memory, without an external behavioral response. We will examine whether encoding of new events that overlap with prior experience triggers reactivation of the prior experience, leading to a flexible use of memory. Experiments 2 and 3 will use high- resolution fMRI to investigate how individual MTL subregions support the processes critical for cross-episodic binding. Experiment 2 will test whether the CA3 field of the hippocampus supports reactivation within MTL cortex, as predicted by the role of CA3 in pattern completion-recollection of stored memories from a partial cue. The overlap between current and prior experience may serve as such a partial cue. The proposed research will provide the first direct evidence that MTL mediates reactivation of past events during overlapping experiences and that such reactivation supports cross-episode binding to promote the flexible use of memory. Experiment 3 will test how spatial contexts that are either the same or different across two experiences affect the likelihood of combining information across the two episodes and investigate how comparison between current and prior experience promotes cross-episode binding. A comparison between recalled memories and current events may serve to detect a change from a stored memory and trigger new encoding, leading to an integration of the new information into existing memories. This comparator function is thought to rely on the CA1 field of the hippocampus. This research will elucidate how MTL subregions support the abstraction of new knowledge from the relationship between distinct episodes and provide new evidence for the role of context in eliciting cross-episode binding. Knowing how MTL subregions combine information across events will provide a means to both predict and promote the occurrence of flexible learning and potentially enable the development of tools to enhance these processes in specific populations characterized by deficits in flexibility, such as individuals with schizophrenia, mild cognitive impairment, Alzheimer's disease and depression. PUBLIC HEALTH RELEVANCE: The proposed research investigates how the structures of the medial temporal lobe support memory formation and flexible use of memory. Understanding the mechanisms that allow the flexible use of experience will provide a means to both predict and promote the occurrence of flexible learning and potentially enable the development of tools to enhance these processes in specific populations characterized by deficits in flexibility, such as individuals with schizophrenia, mild cognitive impairment, Alzheimer's disease and depression. !