Real-time manipulations to understand and improve memory processes

项目摘要/摘要 海马体对于捕捉丰富的、多模式的经验表征和促进 这些经历的长期储存和后来的回忆。在睡眠和暂停期间 行为，海马体可以“重放”先前的经验--重新激活神经细胞。 以时间压缩的方式与原始体验相对应。在睡眠期间，这样的重播是 被认为是巩固记忆的基础，而在行为过程中，重放被认为是额外的 扮演更具前瞻性的角色：通过检索存储的记忆来帮助计划或深思熟虑 以便通知即将做出的决定。然而，回放的内容都不只反映了最近 经验也不能可靠地预测未来的行为，这使得我们不清楚 重播的体验与即将到来的选择相关。理解重播与重播之间的关系 而行为尤其关键，因为重放中的异常和尖锐的波纹(SWR； 重放的网络活动特征)与受损的记忆依赖性同时观察到 老年行为与老年病。确定重播内容如何随年龄增长而变化，以及 无论这些变化是否导致记忆引导行为的缺陷，都有可能产生新的 预防或逆转记忆损伤的治疗策略。为了定义重播如何有助于 在正常认知和年龄相关记忆损害的背景下，记忆引导的决策， 我们已经开发了一种以神经反馈为基础的针对SWR的操作条件反射范式。这 范式根据在特定时间点的SWR实时检测来提供快速反馈 空间记忆任务的每一次试验，并导致试验中SWR的出现显著增加 阶段特定的方式。因此，受试者在所需的试验阶段经历了更多的回放， 这恰好发生在依赖于内存的任务的选择点之前。除了演示之外 这种回放可以通过神经反馈来增强，这种行为范式提供了更多的机会 将重放的内容与后续行为相关联。这一范式为以下三个方面奠定了基础 这项建议的目的：定义重演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而变化，并调整操作条件反射策略以直接对抗 与年龄相关的重播功能障碍。我将在一位杰出的导师的指导下完成这些目标 由罗兰·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。在.期间 在加州大学旧金山分校的指导阶段，我将进行建议的实时反馈研究，Gain 在使用状态空间模型捕获和量化重放内容、扩展实验以 有效地检查更多的年轻和老年动物队列，并专注于专业发展 以便顺利过渡到学术机构的独立教员职位。

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.