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。在睡眠和行为暂停期间， 海马体可以“重放”先前的经验--重新激活对应于 以时间压缩的方式进行原创体验。在睡眠中，这样的回放被认为是 记忆巩固，而在行为过程中，重放被认为另外服务于更具前瞻性的 角色：通过检索存储的记忆来帮助计划或深思熟虑，以便通知即将到来的 决定。然而，回放的内容不仅反映了最近的经验，也不能可靠地预测 未来的行为，让人不清楚重播的经验的具体表现是如何联系的 为即将到来的选择。理解重播和行为之间的关系尤为重要 因为重放异常和尖锐的波纹(SWR；重放的网络活动特征) 已经观察到在衰老和疾病中同时存在记忆依赖行为受损 衰老。确定重播内容如何随年龄增长而变化，以及这些变化是否会导致 记忆引导的行为，有可能产生新的治疗策略来预防或逆转 记忆力受损。为了定义回放对记忆引导决策的贡献， 在与年龄相关的记忆损伤的背景下，我们已经开发出一种 以SWR为目标的基于神经反馈的可操作性条件作用范式。这一范例提供了快速 反馈取决于在每次空间试验期间特定点处的SWR的实时检测 记忆任务，并导致以试验阶段特定方式大幅增加SWR的出现。 因此，受试者在所需的试验阶段会经历更多的重播，这会立即发生 在依赖于内存的任务的选择点之前。除了展示重播可以被 在神经反馈的增强下，这种行为范式提供了更多的机会将 具有后续行为的重播内容。这一范式为以下三个目标奠定了基础 建议：定义重播和记忆引导行为之间的关系，以评估这一点 关系随着年龄的变化而变化，并调整操作条件反射策略来直接对抗年龄- 相关的重播功能障碍。我将在一支出色的指导团队的指导下完成这些目标 由罗兰·弗兰克领导，包括卡罗尔·巴恩斯、乌里·伊登和卡鲁内什·甘古利。在接受指导的过程中 在加州大学旧金山分校的颁奖阶段，我将进行拟议的实时反馈研究，获得专业知识 使用状态空间模型来捕获和量化重放内容，扩展实验以有效地检查 增加幼年和老年动物的数量，并专注于专业发展，以促进 成功地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.