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。在睡眠和行为暂停期间， 海马体可以“重放”先前的经验--重新激活与海马体相对应的神经系统。 以时间压缩的方式进行原始体验。在睡眠中，这种重放被认为是 记忆巩固，而在行为过程中，重放被认为是另外一个更前瞻性的服务。 角色：通过检索存储的记忆来帮助计划或审议，以告知即将到来的 决策然而，重播的内容既不能完全反映最近的经验，也不能可靠地预测 未来的行为，让我们不清楚如何确切地再现的经验表示， 即将到来的选择。理解重放和行为之间的关系尤为关键 因为重放和尖波波纹（SWR;重放的网络活动签名）中的异常 与衰老和疾病中受损的记忆依赖行为同时观察到， 衰老确定重放内容如何随着年龄的增长而变化，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，以防止或逆转 记忆受损为了定义重放如何有助于记忆引导的决策， 正常的认知和与年龄相关的记忆障碍的背景下，我们已经制定了一个 基于神经反馈的操作性条件反射范式，目标是SWR。这种模式提供了快速 反馈取决于在空间环境的每次试验期间在特定点处的SWR的实时检测 记忆任务，并导致以试验阶段特异性方式发生的SWR显著增加。 因此，受试者在所需的试验阶段经历更多的重放，这立即发生 在记忆依赖任务的选择点之前。除了证明重播可以 在神经反馈的强化下，这种行为范式提供了更多的机会， 重放的内容与随后的行为。这一范式为本研究的三个目标奠定了基础。 建议：定义重放和记忆引导行为之间的关系，评估这是如何实现的。 关系随年龄变化，并适应操作性条件反射策略，以直接对抗年龄- 相关的重放功能障碍。我将在一个出色的指导团队的指导下完成这些目标 由洛伦·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。在指导期间， 在UCSF的奖励阶段，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，缩放实验以有效地检查 更多的年轻和年老的动物，并专注于专业发展，以促进 成功过渡到学术机构的独立教师职位。

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.