Real-time manipulations to understand and improve memory processes

项目总结/摘要 海马体对于捕捉丰富的、多模式的经验表征和促进 这些经历的长期存储和后来的回忆。在睡眠和暂停期间， 行为，海马体可以“重放”先前的经验-重新激活神经系统 以时间压缩的方式对应于原始体验。在睡眠期间，这种重放是 被认为是记忆巩固的基础，而在行为过程中，重放被认为是额外的 服务于一个更前瞻性的角色：通过检索存储的记忆来帮助计划或审议， 为即将做出的决定提供信息。然而，重播的内容不仅反映了最近 经验也不能可靠地预测未来的行为，这使得人们不清楚未来的行为是如何表现出来的。 被重放的经历与即将到来的选择有关。了解重播与 和行为是特别关键的，因为在重放和尖波波纹（SWR; 重放的网络活动签名）与受损的记忆依赖性 行为和衰老疾病。确定重放内容如何随老化而变化，以及 这些变化是否会导致记忆引导行为的缺陷，有可能产生新的 预防或逆转记忆障碍的治疗策略。为了定义重播如何有助于 在正常认知和与年龄相关的记忆障碍的背景下， 我们已经开发了一种以SWR为目标的基于神经反馈的操作性条件反射范例。这 范例提供了快速反馈，取决于在特定时间点上的SWR的实时检测， 每次试验的空间记忆任务，并导致大大增加发生的SWR在一个试验 具体阶段。因此，受试者在所需的试验阶段经历更多的重放， 其发生在依赖于存储器的任务的选择点之前。除了展示 神经反馈可以增强重放，这种行为模式提供了更多的机会， 将重放的内容与后续行为联系起来。这一范式为这三个方面奠定了基础 该提案的目的：定义重放和记忆引导行为之间的关系，评估 这种关系如何随着年龄的变化，并适应操作性条件反射策略，以直接对抗 与年龄相关的重放功能障碍我将在一位杰出的导师的指导下完成这些目标。 由洛伦·弗兰克领导的团队，包括卡罗尔·巴恩斯、乌里·伊登和卡鲁内什·甘古利。期间 指导阶段的奖励在加州大学旧金山分校，我将进行建议的实时反馈研究，获得 在使用状态空间模型捕捉和量化重放内容方面的专业知识， 有效地检查更大群的年轻和老年动物，并专注于专业发展， 为了促进成功过渡到一个独立的教师职位在学术机构。

PROJECT SUMMARY/ABSTRACT The hippocampus is critical for capturing rich, multimodal representations of experience and facilitating the long-term storage and later recall of these experiences. During sleep and pauses in behavior, the hippocampus can “replay” prior experience – reactivating the neural ensemble corresponding to the original experience in a time-compressed manner. During sleep, such replay is thought to underlie memory consolidation, while during behavior, replay is thought to additionally serve a more prospective role: contributing to planning or deliberation by retrieving stored memories in order to inform upcoming decisions. However, the content of replay neither solely reflects recent experience nor reliably predicts future behavior, leaving it unclear how exactly the representations of experience that are replayed relate to upcoming choices. Understanding the relationship between replay and behavior is particularly critical because abnormalities in replay and sharp wave ripples (SWRs; the network activity signature of replay) have been observed concurrent with impaired memory-dependent behavior in aging and diseases of aging. Establishing how replay content changes with aging, and whether these changes cause deficits in memory-guided behavior, has the potential to generate new therapeutic strategies to prevent or reverse memory impairment. In order to define how replay contributes to memory-guided decision-making in normal cognition and in the context of age-related memory impairment, we have developed a neurofeedback-based operant conditioning paradigm that targets SWRs. This paradigm provides rapid feedback contingent upon real-time detection of SWRs at a specific point during each trial of a spatial memory task, and results in substantially increased occurrence of SWRs in a trial phase-specific manner. Consequently, subjects experience more replay at the required trial phase, which occurs immediately prior to the choice point of a memory-dependent task. In addition to demonstrating that replay can be enhanced by neurofeedback, this behavioral paradigm provides an increased opportunity to link the content of replay with subsequent behavior. This paradigm lays the foundation for the three aims of this proposal: to define the relationship between replay and memory-guided behavior, to assess how this relationship changes with age, and to adapt the operant conditioning strategy to directly counter age-related replay dysfunction. I will complete these aims with the guidance of an exceptional mentoring team led by Loren Frank and including Carol Barnes, Uri Eden, and Karunesh Ganguly. During the mentored phase of the award at UCSF, I will conduct the proposed real-time feedback studies, gain expertise in using state-space models to capture and quantify replay content, scale experiments to efficiently examine larger cohorts of young and aged animals, and focus on professional development in order to facilitate a successful transition into an independent faculty position at an academic institution.