Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Engram cells retain Memory under retrograde amnesia


Science 29 May 2015:  Vol. 348  no. 6238  pp. 1007-1013

Engram cells retain memory under retrograde amnesia

Tomás J. Ryan,

RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.


Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively through the stabilization of memory engrams. By using learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. Although these properties are lacking in engram cells under protein synthesis inhibitor–induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with retained engram cell–specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process.

Memory consolidation is the phenomenon by which a newly formed memory transitions from a fragile state to a stable, long-term state. The defining feature of consolidation is a finite time window that begins immediately after learning, during which a memory is susceptible to disruptions, such as protein synthesis inhibition, resulting in retrograde amnesia. The stabilization of synaptic potentiation is the dominant cellular model of memory consolidation because protein synthesis inhibitors disrupt late-phase long-term potentiation of in vitro slice preparations. Although much is known about the cellular mechanisms of memory consolidation, it remains unknown whether these processes occur in memory engram cells. It may be possible to characterize cellular consolidation and empirically separate mnemonic properties in retrograde amnesia by directly probing and manipulating memory engram cells in the brain. The term memory engram originally referred to the hypothetical learned information stored in the brain, which must be reactivated for recall. Recently, several groups demonstrated that specific hippocampal cells that are activated during memory encoding are both sufficient and necessary for driving future recall of a contextual fear memory and thus represent a component of a distributed memory engram. Here, we applied this engram technology to the issue of cellular consolidation and retrograde amnesia.

We used the previously established method for tagging the hippocampal dentate gyrus (DG) component of a contextual memory engram with mCherry. To disrupt consolidation, we systemically injected the protein synthesis inhibitor anisomycin (ANI) or saline (SAL) as a control immediately after contextual fear conditioning (CFC).

Together, these findings show that engram cells activated through CFC training are both sufficient and necessary to evoke memory recall, satisfying two crucial attributes in defining a component of a contextual fear memory engram. What has been left to be demonstrated, however, is that these DG cells undergo enduring physical changes as an experience is encoded and its memory is consolidated. Although synaptic potentiation has long been suspected as a fundamental mechanism for memory and as a crucial component of the enduring physical changes induced by experience, this has not been directly demonstrated, until the current study, as a property of the engram cells. Our data have directly linked the optogenetically and behaviorally defined memory engram cells to synaptic plasticity.

On the basis of a large volume of previous studies, a concept has emerged in which retrograde amnesia arises from consolidation failure as a result of disrupting the process that converts a fragile memory engram, formed during the encoding phase, into a stable engram with persistently augmented synaptic strength and spine density. Indeed, our current study has demonstrated that amnesic engram cells in the DG 1 day after CFC training display low levels of synaptic strength and spine density that are indistinguishable from nonengram cells of the same DG. This correlated with a lack of memory recall elicited by contextual cues. However, direct activation of DG engram cells of the ANI group elicited as much freezing behavior as did the activation of these cells of the SAL group. This unexpected finding is supported by a set of additional cellular and behavioral experiments. Whereas amygdala engram cell reactivation upon exposure to the conditioned context is significantly lower in the ANI group as compared with the SAL group, optogenetic activation of DG engram cells results in normal reactivation of downstream CA3 and BLA engram cells. At the behavioral level, the amnesia rescue was observed under a variety of different conditions in which one or more parameters were altered. Thus, our overall findings indicate that memory engrams survive a posttraining administration of protein synthesis inhibitors during the consolidation window and that the memory remains retrievable by means of ChR2-mediated direct engram activation even after retrograde amnesia is induced. The drive initiated with light-activation of one component of a distributed memory engram (such as that in the DG) is sufficient to reactivate engrams in downstream regions (such as that in CA3 and BLA) that would also be affected by the systemic injection of a protein synthesis inhibitor (ANI).

These findings suggest that although a rapid increase of synaptic strength is likely to be crucial during the encoding phase, the augmented synaptic strength is not a crucial component of the stored memory. This perspective is consistent with a recent study showing that an artificial memory could be reversibly disrupted by depression of synaptic strength. On the other hand, persistent and specific connectivity of engram cells that we find between DG engram cells and downstream CA3 or BLA engram cells in both SAL and ANI groups may represent a fundamental mechanism of memory information storage. Our findings also suggest that the primary role of augmented synaptic strength during and after the consolidation phase may be to provide natural recall cues with efficient access to the soma of engram cells for their reactivation and, hence, recall.

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