The role of cortico-hippocampal interactions in encoding auditory memories

描述(申请人提供)：最近的一种听觉记忆需要海马体进行回忆；然而，这种记忆最终变得不依赖于海马体，并巩固在听觉皮质中。在睡眠过程中，海马体和皮质之间的相互作用被认为是记忆巩固过程的关键。在海马区和大脑皮层之间传递信息的一个潜在机制是重播，这是一种在受试者睡觉时，编码一种经验的神经系综会在海马区和大脑皮层自发地重新激活的现象。皮层-海马区重播为研究记忆提供了一个强大的模型，提供了一种对重新激活和转移的记忆内容进行解码的方法。此前研究重播的研究只关注与导航相关的空间信息如何编码到记忆中。我计划将这种基于回放的记忆巩固模型应用于听觉系统，以研究听觉记忆是如何在听觉皮质中编码的。我的研究计划分为三个主要目的：1)研究海马体重放与空间背景下听觉线索记忆巩固之间的因果关系；2)了解睡眠期间听觉皮质活动如何影响海马体重放哪些记忆；3)研究海马体重放如何在听觉皮质中转移和编码新的听觉记忆。我将调整目前在海马体(多个四极微驱动器阵列)中使用的记录方法，用于自由移动的啮齿动物的听觉皮质。此外，我将采用一种最近开发的可逆神经失活方法，称为DREADDS(由设计师药物独占激活的设计师受体)，用于听觉皮质。这种方法的优点是能够从基因上靶向神经元，并且可以非侵入性地激活(配体可以口服或通过IP注射)。在该奖项的培训期间，在马修·威尔逊的密切指导下，我打算学习使用两种新的方法：构建多部位微驱动器阵列和使用DREADD使神经回路失活。我还计划开发两个新工具--交错的立体电极探头和特定层流的可逆失活。我计划实现这些目标，完成并发表这项研究计划的第一个目标，并在12-18个月内申请教职。在获得教员职位后，我将过渡到该奖项的独立部分，在那里我将建立自己的实验室，完成并发表本研究计划的剩余目标，并开始研究听觉皮质中听觉物体的编码(在感知和记忆巩固期间)。马修和我已经明确讨论了这些研究和职业目标，在我的研究计划的指导阶段，我得到了他的全力支持。马修·威尔逊的实验室资金充足，皮考尔研究所和脑与认知科学系有充足的资源和设施来帮助我追求我的研究和职业目标。 与公共健康相关：听觉皮质和海马体是大脑的两个区域，对于记忆以前听到的声音是重要的。研究这两个大脑区域是如何相互作用的，将有助于更好地理解大脑中负责记忆存储的神经机制。这项研究还将提高我们对大脑皮质-海马区功能障碍的理解，如阿尔茨海默病和精神分裂症。

DESCRIPTION (provided by applicant): A recent auditory memory requires the hippocampus for recall; however, this memory eventually becomes hippocampus-independent and consolidated in auditory cortex. Interactions between the hippocampus and cortex during sleep are thought to be critical for this process of memory consolidation. One potential mechanism by which information can be transferred between hippocampus and cortex is replay, a phenomenon where neural ensembles encoding an experience are spontaneously reactivated in hippocampus and cortex while the subject is sleeping. Cortico-hippocampal replay provides a powerful model to study memory, providing a means to decode the content of the memory being reactivated and transferred. Previous research studying replay has only focused on how spatial information related to navigation is encoded into memory. I plan to apply this replay-based model of memory consolidation to the auditory system to study how auditory memories are encoded in auditory cortex. My research plan is divided into three main aims: 1) examining the causal relationship between hippocampal replay and the memory consolidation of auditory cues in a spatial context, 2) understanding how auditory cortical activity during sleep influences what memories are replayed by the hippocampus, and 3) studying how hippocampal replay transfers and encodes new auditory memories in auditory cortex. I will adapt recording methodologies currently used in the hippocampus (multi-tetrode microdrive arrays) for the auditory cortex of freely moving rodents. In addition, I will adapt a recently developed method of reversible neural inactivation called DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) for auditory cortex. This method has the advantage of being able to target neurons genetically and can be activated non-invasively (ligand can be taken orally or through an IP injection). During the training period of this award, under the close mentorship of Matthew Wilson, I intend to learn to use two new methodologies: building a multi-site microdrive array and inactivation of neural circuits using DREADDs. I also plan to develop two new tools- a staggered stereotrode probe and laminar-specific reversible inactivation. I plan to accomplish these goals, complete and publish the first aim of this research proposal, and apply for faculty positions within 12-18 months. After obtaining a faculty position, I will transition to the independent components of the award, where I will setup my own laboratory, complete and publish the remaining aims of this research proposal, and begin to study the encoding of auditory objects in auditory cortex (during both perception and memory consolidation). Matthew and I have explicitly discussed these research and career goals, and I have his complete support during the mentored phase of my research plan. Matthew Wilson's laboratory is well-funded, and there are ample resources and facilities within the Picower Institute and Department of Brain and Cognitive Sciences to aid me in my pursuit of my research and career goals. PUBLIC HEALTH RELEVANCE: Auditory cortex and the hippocampus are two regions of the brain that are important for remembering a previously heard sound. Investigating how these two brain areas interact with each other will help provide a better understanding of the neural mechanisms responsible for memory storage in the brain. This research will also improve our understanding of brain disorders with cortico-hippocampal dysfunction, such as Alzheimer's disease and Schizophrenia.