Cellular and Systems Mechanisms of L&M
Siena, Italy
May 31, 2017


Pasted Graphic
May 31, 2017
Susumu Tonegawa

Massachusetts Institute of Technology, Boston, USA & RIKEN Brain Science Institute, Japan

1- Engram Cell Circuits for Memory Retention
Our study (Ryan et al., Science 2015) suggested that while a rapid increase of synaptic strength is crucial for encoding of a memory, a newly formed pattern of connectivity between the upstream and downstream engram cell ensembles may serve as the primary means for long-term memory storage. Supporting this concept is the fact that a mouse suffering from retrograde amnesia can be induced to express the full level of memory by optogenetic stimulation one day after encoding, despite the fact that these engram cells are without enhanced synaptic strength, and that these amnesic engram cells (in hippocampal DG) retain preferential connectivity with downstream engram cells (in CA3 and BLA) (Ryan et al., Science 2015). We have further investigated this hypothesis from several different angles and have shown that the engram-to-engram connectivity is stable both in control and amnesic mice, lasting for at least 8 days after encoding, and that optogenetic activation of the engram in amnesic mice is stimulus strength-dependent.
These and other recent studies on memory engram cells are generating the concept of “silent engram cells” that hold memory information but are not susceptible to reactivation by natural cues for recall. These silent engram cells are found not only in retrograde amnesia but also in mouse models of early Alzheimer’s disease (Roy et al., Nature 2016). Furthermore, our recent study revealed that remote episodic memory is in a silent state during recent time points, and that hippocampal episodic memory engram cells that are active in recent time points are converted to the silent state over time. The common structural and physiological features of these silent engram cells, compared to active engram cells, are reduced spine density and reduced synaptic strength. We have also showed that a silent engram could be converted to an active engram by repeated optogenetic enhancement of synaptic strength (Roy et al., Nature 2016). Based on these observations, we propose that the primary purpose of molecular consolidation of memory is to make memory engram cells accessible to natural recall cues.

2: Maturation of Silent Engrams and Systems Consolidation of Memory
We have investigated the systems consolidation of episodic memory by applying engram and optogenetic technologies. The results indicate that the PFC engrams for remote memory are formed rapidly on day 1 of learning. However, these PFC engrams are inactive in the sense that they cannot be re-activated by natural cues for memory retrieval. The “silent” PFC engrams undergo slow maturations during the following few weeks with the aid of input from hippocampal engram cells via the deep layer of the medial entorhinal cortex. Conversely, the hippocampal engram cells formed rapidly on day 1 de-mature slowly and become silent. For contextual fear memory, an active engram is rapidly formed in BLA and remains active throughout the systems consolidation, but there is a switch in the route through which recall cues are delivered: through the hippocampal-entorhinal circuit at recent times and through PFC engram cells at remote times. This study identified the engrams and neural circuits crucial for systems consolidation of a memory.