The role of cortico-hippocampal interactions in encoding auditory memories

描述（由申请人提供）：最近的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，并在听觉皮层中巩固。睡眠期间海马体和皮层之间的相互作用被认为是记忆巩固过程的关键。信息可以在海马体和皮层之间传递的一种潜在机制是重放，这是一种当受试者睡眠时，编码体验的神经集合在海马体和皮层中自发地重新激活的现象。 皮质-海马重放为研究记忆提供了一个强大的模型，提供了一种解码被重新激活和转移的记忆内容的方法。以前研究重放的研究只集中在与导航相关的空间信息如何编码到记忆中。我计划将这个基于回放的记忆巩固模型应用于听觉系统，研究听觉记忆是如何在听觉皮层中编码的。我的研究计划分为三个主要目标：1）检查海马重放和空间背景下听觉线索的记忆巩固之间的因果关系，2）了解睡眠期间听觉皮层活动如何影响海马重放的记忆，3）研究海马重放如何在听觉皮层中传输和编码新的听觉记忆。我将调整目前用于海马体（多四极微驱动器阵列）的记录方法，用于自由移动的啮齿动物的听觉皮层。此外，我将采用最近开发的一种可逆神经失活方法，称为DREADD（仅由设计药物激活的设计受体）用于听觉皮质。这种方法的优点是能够遗传靶向神经元，并且可以非侵入性地激活（配体可以口服或通过IP注射）。 在这个奖项的培训期间，在Matthew Wilson的密切指导下，我打算学习使用两种新的方法：构建多站点微驱动器阵列和使用DREADDs灭活神经回路。我还计划开发两种新的工具-交错立体电极探针和椎板特异性可逆失活。我计划在12-18个月内完成这些目标，完成并发表本研究计划的第一个目标，并申请教职。获得教职后，我将过渡到该奖项的独立组成部分，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，并开始研究听觉皮层中听觉对象的编码（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，我在我的研究计划的指导阶段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内有充足的资源和设施，以帮助我追求我的研究和职业目标。 公共卫生相关性：听觉皮层和海马体是大脑的两个区域，对记住以前听到的声音很重要。研究这两个大脑区域如何相互作用，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.