Ko, S. Y., Rong, Y., Ramsaran, A. I., Chen, X., Rashid, A. J., Mocle, A. J., … & Frankland, P. W. (2025). Systems consolidation reorganizes hippocampal engram circuitry. Nature, 643, 735–743. https://doi.org/10.1038/s41586-025-08993-1
Engram labeling (FOS-CreERT2), eGRASP synaptic mapping, fiber photometry, optogenetics
Mouse hippocampus
This paper reveals how episodic memories transform from precise to generalized “gist” memories through time-dependent reorganization of hippocampal synaptic architecture. Using eGRASP to visualize engram-to-engram synapses, the authors discovered striking structural changes over 4 weeks of consolidation. CA3-to-CA1 engram synapses not only increased in density but also became significantly more clustered on CA1 dendrites – with inter-synapse distances decreasing as memories aged. This synaptic clustering, known to enhance neuronal activation probability, coincided with “promiscuous” activation of CA1 neurons in novel contexts. Simultaneously, DG engram filopodial contacts onto parvalbumin interneurons decreased, reducing feed-forward inhibition onto CA3 neurons. Adult-born neurons were critical orchestrators – directly contacting CA3 engram thorny excrescences and forming new interconnections between adjacent engram neurons. Eliminating neurogenesis prevented all these structural changes, freezing engram connectivity in a “recent memory state” that maintained precision. Conversely, exercise-induced neurogenesis accelerated synaptic reorganization and gist memory emergence to just 14 days post-training.
Here we report that time-dependent reorganization of hippocampal engram circuitry is sufficient to explain shifts in memory precision associated with systems consolidation. Using engram labelling tools in mice, we demonstrate that the passage of time rewires hippocampal engram circuits, enabling hippocampal engram neurons to be promiscuously active and guide behaviour in related situations that do not match the original training conditions.