Neocortical-Hippocampal Circuits Underlying Pattern Separation in Humans

项目摘要 记忆对我们的生活至关重要。有了他们，我们创造了独特的历史，与我们周围的世界联系在一起， 并做出明智的决定。随着我们年龄的增长，记忆力的丧失会发生，而且记忆力的变化也会更加普遍 功能可能是阿尔茨海默病的最早迹象之一，这是一项重大的公共卫生挑战，影响更多的人 超过560万美国人。过去的研究表明，区分相似助记符的能力 经历(即模式分离)是阿尔茨海默氏症高危老年人记忆损害的早期迹象 疾病。这种记忆障碍被认为是随后认知能力下降的早期先兆，并可能 在疾病的早期阶段成为合适的治疗靶点。然而，这样的目标是不可能的。 对支持人类模式分离的电路级动力学没有完全的了解。而当 长期以来，计算理论一直表明，海马体和大脑中的 新大脑皮层，该领域在识别人类这种网络水平的动态方面一直面临挑战，原因是 使用功能磁共振成像的时间分辨率有限，使用脑电的空间分辨率有限。我建议在以下方面填补这个空白 利用难得而独特的机会从大脑皮层和海马体记录知识 用于临床监测的植入颅内电极的人体具有卓越的空间和时间分辨率 而他们正在进行模式分离记忆任务。我将从最低限度收集神经记录数据 15例经手术在海马区植入深度电极的临床监测 加州大学洛杉矶分校癫痫综合病房的大脑皮层。我提出了三个具体目标：(1)检验假设 海马体和大脑皮层中的theta能力的增加将预测成功的辨别能力 在模式分离任务上；(2)检验在编码过程中，海马-新皮质相互作用的假设 会有方向性的偏差，使海马体领导皮质，反映新学到的整合 信息进入新皮质部位；以及(3)检验假设，在提取过程中，海马-新皮质 相互作用将是有方向性的，因此皮质引领海马体，反映出 记忆来自新皮质部位的内容。建议的研究是可行的，具有出色的研究和 加州大学欧文分校的培训环境以及临床基础设施和癫痫监测股的可用性 研究专用记录设备。利用这些资源，我已经收集了 支持所有三个假设。在Michael Yassa博士和Jack Lin博士的共同指导下，我将获得 临床和认知神经科学方面的高级培训。李·斯文德赫斯特博士的额外指导 电子工程，我正在使用技术来分析高维数据和方向性测量 用于网络分析。在这群导师的帮助下，我的目标是填补关于以下方面的关键知识空白 人脑中的记忆机制，首要目标是将这一知识应用于逆转 衰老和阿尔茨海默病中的记忆力丧失。

Project Summary Memories are crucial to our lives. With them, we generate a unique history, connect with the world around us, and make informed decisions. Memory loss occurs as we get older, and more pervasive changes in memory function can be among the earliest signs of Alzheimer’s disease, a major public health challenge affecting more than 5.6 million Americans. Past studies have shown that the ability to discriminate among similar mnemonic experiences (i.e. pattern separation) is an early sign of memory impairment in older adults at risk for Alzheimer’s disease. This disruption in memory is thought to be an early harbinger of subsequent cognitive decline and may be a suitable therapeutic target in the earliest stages of the disease. However, such targeting is impossible without a complete understanding of the circuit-level dynamics that support pattern separation in humans. While computational theories have long suggested a necessary role for interactions between the hippocampus and the neocortex, the field has struggled with challenges in identifying such network level dynamics in humans due to limited temporal resolution using fMRI and limited spatial resolution using EEG. I propose to fill this gap in knowledge using a rare and unique opportunity to record from both the neocortex and the hippocampus with superior spatial and temporal resolution in humans implanted with intracranial electrodes for clinical monitoring while they engage in a pattern separation memory task. I will collect neural recording data from a minimum of 15 patients undergoing clinical monitoring with surgically implanted depth electrodes in the hippocampus and the neocortex at the UCI Comprehensive Epilepsy Unit. I propose three specific aims: (1) Test the hypothesis that increased theta power in the hippocampus and neocortex will predict successful discrimination performance on pattern separation task; (2) Test the hypothesis that during encoding, hippocampal-neocortical interactions will be directionally biased such that the hippocampus leads the cortex, reflecting the integration of newly learned information into neocortical sites; and (3) Test the hypothesis that during retrieval, hippocampal-neocortical interactions will be directionally biased such that the cortex leads the hippocampus, reflecting the access of memory content from neocortical sites. The proposed studies are feasible with the excellent research and training environment at UC Irvine and the availability of clinical infrastructure and an epilepsy monitoring unit with research-dedicated recording equipment. Using these resources, I have already collected preliminary data in support of all three hypotheses. With the joint mentorship of Dr. Michael Yassa and Dr. Jack Lin, I will receive advanced training in clinical and cognitive neuroscience. With additional mentorship of Dr. Lee Swindlehurst in electrical engineering, I am employing techniques to analyze high dimensional data and directionality measures for network analysis. With the help of this constellation of mentors, I aim to fill a critical gap in knowledge about memory mechanisms in the human brain, with the overarching goal of applying this knowledge to reversing memory loss in aging and Alzheimer’s disease.