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。联想记忆将先前不相关的事物联系起来，人类的日常生活关键取决于形成和检索这种联想记忆的能力。例如，当探索一个新的城市时，我们能够快速编码重要景点的位置。人类是如何拥有在物体或事件与其相应的空间环境之间建立联想记忆的能力的呢？目前的项目旨在利用难得的人脑电生理记录的机会来回答这个问题，它提供了一个时间和空间分辨率，弥合了啮齿动物电生理研究和人类无创神经成像研究之间的差距。这些记录可能在神经外科癫痫患者植入颅内电极用于诊断目的。在这个项目中，患者被要求参与物体定位记忆任务，该任务要求患者在虚拟环境中学习不同物体的位置，同时从海马体和邻近的大脑区域记录单个神经元的活动和局部场电位。在之前的多项研究中，海马体已被确定为记忆和导航的关键区域，但联想记忆形成的确切神经元机制仍然难以捉摸。通过将目标定位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。更详细地说，我将首先确定海马体和邻近大脑区域中的单个神经元，这些神经元编码虚拟环境中物体或空间位置的信息。接下来，我将在整个任务过程中跟踪这些单元格类型的重新激活。我假设客体反应细胞和空间调节细胞在一种被称为“尖锐波纹”的特定电生理网络现象中同步重新激活。尖锐的波纹与海马体的兴奋性增加有关，与海马体和连接的大脑区域之间的同步增加有关，并且已被确定为记忆过程的生物标志物。在剧烈的波波纹中，物体响应和空间调节细胞的再激活可能导致编码整个物体定位关联的共同神经回路，并可能将这些回路从海马体转移到新皮层。总之，拟议的研究项目将使人们对联想记忆形成背后的人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来看都是相关的，因为可以推导出各种神经和精神疾病（如阿尔茨海默病）中联想记忆表现受损的机制解释。

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.