Decoding the memory engram: bridging neural dynamic and gene expression markers of episodic learning

Objetivo

How does a memory trace form in the brain? Episodic memories, our autobiographical recollection of past events, are known to depend on the hippocampal circuit. A rich field of research has developed to study the emergence and properties of memory engrams in the hippocampus. Engrams are operationally defined as groups of neurons that are activated during a salient episode, and whose subsequent reactivation can trigger memory recall. But these neural populations are often identified through indirect measures of neural dynamics, using expression of immediate early genes such as Fos to tag and manipulate recently active neurons. By contrast, direct neural recordings in the hippocampus have revealed a repertoire of spatial and navigation-related signals during repetitive exploration and movement. This is typified by place cells, neurons that activate only when an animal occupies specific areas of physical space. Research on place cells and engrams has progressed largely in parallel, and their connections remains highly contested. How do place cells and engram cells build a memory trace? We will address this outstanding question through experiments that combine in vivo identification of engram populations with large scale neural recordings, optogenetic and chemogenetic circuit manipulations, and mouse virtual reality (VR) paradigms. We will first study a novel VR paradigm where mice exhibit fast, episodic learning, and characterize how hippocampal place codes are reshaped by plasticity during few-shot behavioral learning. We will then investigate the links between Fos expression dynamics, place coding, and neural plasticity during episodic learning and recall. Finally, we will test the causal influence of Fos engrams on local hippocampal network dynamics and memory-guided behavior. Our aim is to understand the role of engram populations in neural circuit dynamics, which will provide fundamental insights into the cellular and dynamical substrates of memory.