Reactivation of Neural Ensembles during the Retrieval of Recent and Remote Memory

Background: Episodic memories are encoded within hippocampal and neocortical circuits. Retrieving these memories is assumed to involve reactivation of neural ensembles that were established during learning. Although it has been possible to follow the activity of individual neurons shortly after learning, it has not been possible to examine their activity weeks later during retrieval. We addressed this issue by using a stable form of GFP (H2B-GFP) to permanently tag neurons that are active during contextual fear conditioning. Results: H2B-GFP expression in transgenic mice was increased by learning and could be regulated by doxycycline (DOX). Using this system, we found a large network of neurons in the hippocampus, amygdala, and neocortex that were active during context fear conditioning and subsequent memory retrieval 2 days later. Reactivation was contingent on memory retrieval and was not observed when animals were trained and tested in different environments. When memory was retrieved several weeks after learning, reactivation was altered in the hippocampus and amygdala but remained unchanged in the cortex. Conclusions: Retrieving a recently formed context fear memory reactivates neurons in the hippocampus, amygdala, and cortex. Several weeks after learning, the degree of reactivation is altered in hippocampal and amygdala networks but remains stable in the cortex.