Human brain mechanisms of associative memory formation during spatial navigation

记忆和导航是人类和动物的基本认知功能。联想记忆将原本不相关的事物相互联系起来，而人类的日常生活在很大程度上取决于这种联想记忆的形成和提取能力。例如，当探索一个新城市时，我们能够快速编码重要景点的位置。人类如何拥有在物体或事件及其对应的空间背景之间建立联想记忆的能力？目前的项目旨在利用来自人脑的电生理记录这一难得的机会来回答这个问题，这种记录提供了一种时间和空间分辨率，可以弥合啮齿类动物的电生理研究和人类的非侵入性神经成像研究之间的差距。这些记录在神经外科癫痫患者中是可能的，他们植入了用于诊断目的的颅内电极。在这个项目中，患者被要求参与物体位置记忆任务，这要求患者学习不同物体在虚拟环境中的位置，同时记录海马体和邻近大脑区域的单个神经元活动和局部场电位。在先前的多项研究中，海马体被认为是记忆和导航的关键区域，但联想记忆形成的确切神经机制仍不清楚。通过将物体位置记忆任务的行为数据与获得的神经元数据联系起来，将提供对人类大脑潜在工作原理的独特见解。更详细的是，我将首先识别海马体和邻近大脑区域中编码关于物体或虚拟环境中空间位置信息的单个神经元。接下来，我将在整个任务中跟踪这些细胞类型的重新激活情况。我假设物体反应细胞和空间调制细胞在一种特殊的电生理网络现象中同步重新激活，这种现象被称为“尖锐的波纹”。尖锐的波纹与海马区兴奋性的增强有关，与海马区和连接的大脑区域之间的同步性增加有关，并已被确定为记忆过程的生物标记物。因此，在剧烈的波纹中重新激活对物体反应和空间调制的细胞可能会导致编码整个物体位置关联的共同神经回路，并可能将这些回路从海马区转移到新皮质。总之，拟议的研究项目将使人们能够对联想记忆形成的大脑机制有独特的见解。由此产生的知识无论从基础科学的角度还是从临床的角度都是相关的，因为可以从机制上解释各种神经和精神疾病(如阿尔茨海默病)的联想记忆能力受损。

Memory and navigation are essential cognitive functions of humans and animals. Associative memories interconnect previously unrelated items and human everyday life critically depends on the ability of forming and retrieving such associative memories. For example, when exploring a new city, we are able to rapidly encode the locations of important sights. How does it come that humans possess this ability of building associative memories between objects or events and their corresponding spatial contexts?The current project has been designed to answer this question using the rare opportunity of electrophysiological recordings from the human brain, which provide a temporal and spatial resolution that bridges the gap between electrophysiological studies in rodents and noninvasive neuroimaging studies in humans. These recordings are possible in neurosurgical epilepsy patients implanted with intracranial electrodes for diagnostic purposes. For this project, patients are asked to participate in object-location memory tasks that require patients to learn the locations of different objects within a virtual environment, while single-neuron activity and local field potentials are recorded from the hippocampus and adjacent brain areas. The hippocampus has been identified as a key region for memory and navigation in multiple previous studies, but the exact neuronal mechanisms of associative memory formation remain elusive. By connecting the behavioral data from the object-location memory tasks with the acquired neuronal data, unique insights into the underlying working principles of the human brain will be provided.More detailed, I will first identify single neurons in the hippocampus and adjacent brain regions that encode information about either objects or spatial locations within the virtual environment. Next, I will track the reactivation of these cell types throughout the task. I hypothesize that object-responsive cells and spatially-modulated cells reactivate synchronously during a specific electrophysiological network phenomenon termed ‘sharp wave-ripple’. Sharp wave-ripples are associated with increased excitability in the hippocampus, with increased synchronization between the hippocampus and connected brain regions, and have been established as a biomarker for memory processes. Reactivation of object-responsive and spatially-modulated cells during sharp wave-ripples may thus lead to common neural circuits encoding the entire object-location associations and may transfer these circuits from the hippocampus to the neocortex.In sum, the proposed research project will enable unique insights into the human brain mechanisms underlying associative memory formation. The resulting knowledge will be relevant both from a basic science perspective and from a clinical perspective, because mechanistic explanations for impaired associative memory performance in various neurological and psychiatric diseases (such as Alzheimer’s disease) may be derived.