Memory strength gates the involvement of a CREB-dependent cortical fear engram in remote memory

Mariana R Matos,Priyanka Rao-Ruiz,Michel C Van Den Oever,Rolinka J Van Der Loo,Esther Visser,Titia Gebuis,Huibert D Mansvelder,August B Smit,Ioannis Kramvis,Robbert Zalm

doi:10.1038/s41467-019-10266-1

Mariana R Matos, Priyanka Rao-Ruiz + Show 8 more

Open Access

https://doi.org/10.1038/s41467-019-10266-1

Copy DOI

Abstract

Encoding and retrieval of contextual memories is initially mediated by sparsely activated neurons, so-called engram cells, in the hippocampus. Subsequent memory persistence is thought to depend on network-wide changes involving progressive contribution of cortical regions, a process referred to as systems consolidation. Using a viral-based TRAP (targeted recombination in activated populations) approach, we studied whether consolidation of contextual fear memory by neurons in the medial prefrontal cortex (mPFC) is modulated by memory strength and CREB function. We demonstrate that activity of a small subset of mPFC neurons is sufficient and necessary for remote memory expression, but their involvement depends on the strength of conditioning. Furthermore, selective disruption of CREB function in mPFC engram cells after mild conditioning impairs remote memory expression. Together, our data demonstrate that memory consolidation by mPFC engram cells requires CREB-mediated transcription, with the functionality of this network hub being gated by memory strength.

Highlights

Encoding and retrieval of contextual memories is initially mediated by sparsely activated neurons, so-called engram cells, in the hippocampus
We investigated (1) whether the medial prefrontal cortex (mPFC) harbors engram cells supporting remote contextual fear memory; (2) whether involvement of mPFC neurons is modulated by the strength of conditioning; and (3) whether CREB function in these neurons is required for memory persistence
Using a viral-TRAP based approach, we demonstrate that contextual fear memory induced by a single US exposure is allocated to neuronal ensembles in the mPFC during memory encoding and that the activity of these specific neurons is subsequently necessary and sufficient for memory expression one month later

Summary

Introduction

Encoding and retrieval of contextual memories is initially mediated by sparsely activated neurons, so-called engram cells, in the hippocampus. Persistence of memory is thought to depend on systems consolidation, a time-dependent process through which a given memory is gradually consolidated in cortical networks[7,8] This concept is supported by the observation that retrieval of contextual fear memory initially does not depend on activity in cortical areas, including the mPFC, cortical activity is required for memory retrieval at remote timepoints[9,10,11]. This allowed us to express a lasting molecular tag (e.g. Designer Receptor Exclusively Activated by Designer Drugs (DREADD)[22] or mCREB (a repressor of CREB function)) in activated neurons of wild-type mice Using this system, we found that engram cells in the mPFC are already defined during learning, but their functional contribution to memory expression requires CREB-mediated transcription and depends on memory strength

Methods

Results

Conclusion