Engram Cells and Amnesia: Reactivating Lost Memories with Light

Researchers at MIT have shown that memories seemingly lost to amnesia can be recovered by directly activating specific brain cells with light.

In a study published in Science, investigators led by Susumu Tonegawa at MIT used optogenetics to reactivate memories that ordinary recall methods could not retrieve. The work, led by Tomas Ryan, Dheeraj Roy, and Michelle Pignatelli, addresses a long-standing debate in neuroscience about whether retrograde amnesia results from destroyed memory traces or from an inability to access intact memories.

Amnesia: storage loss or retrieval failure?

Retrograde amnesia, which can follow trauma, stress, or diseases such as Alzheimer’s, has been interpreted in two ways. One view holds that neurons storing a memory are damaged or erased, preventing the memory from existing. The other view holds that the memory is stored but that the mechanisms to retrieve it are impaired. Tonegawa and his colleagues report evidence supporting the latter: amnesia can be a problem of retrieval rather than storage.

Memory engram cells and optogenetics

Memory researchers have long proposed that learning activates a specific set of neurons that undergo lasting physical or chemical changes. When those neurons are naturally reactivated—by a sight, a smell, or another cue—the full memory returns. These neurons are often called memory engram cells.

Optogenetics, a technique that makes neurons responsive to light by inserting light-sensitive proteins, allowed the team to pinpoint and control such engram cells in the hippocampus. In earlier work, the group had identified engram cell ensembles and shown they could evoke memories when stimulated with light. The current study goes further by examining whether those cells show the synaptic and structural changes typically associated with long-term memory consolidation.

Synaptic strengthening and memory consolidation

The researchers first labeled hippocampal engram cells tied to a newly formed memory and measured their properties. They observed increased synaptic strength and a higher density of dendritic spines specifically in those consolidated engram cells—changes consistent with long-term potentiation (LTP), a process believed to stabilize memories.

To test the role of protein synthesis in this consolidation, the team used anisomycin, a compound that blocks protein production in neurons. When administered immediately after learning, anisomycin prevented the expected strengthening of synapses in engram cells. One day later, mice treated in this way did not display behavioral signs of remembering when exposed to natural recall cues, consistent with retrograde amnesia.

Restoring memory by activating engram cells

Surprisingly, despite the lack of synaptic strengthening caused by anisomycin, direct optogenetic activation of the same engram cells restored full behavioral evidence of the memory. In other words, although natural cues failed to trigger recall after protein synthesis was blocked, artificially stimulating the engram-bearing cells with light recovered the memory.

These results indicate that the engram cells themselves can retain information even when synaptic consolidation is disrupted, and that strengthened synapses are more crucial for the brain’s ability to access or retrieve memories than for storing the memory content itself.

Engram ensembles and memory storage

Follow-up experiments suggested that memories are stored not solely in the strengthened synapses of individual engram cells but across a connected circuit—a pathway of engram cell ensembles spanning multiple brain regions. The pattern of connectivity among these ensembles appears to encode the memory information, while synaptic strengthening within those ensembles facilitates retrieval using natural cues.

As Tomas Ryan summarizes, engram synapse strengthening is key to retrieving a specific memory, while the connectivity pattern across engram ensembles underlies storage. This distinction helps explain how a memory can remain present in the brain even when it is inaccessible by ordinary means.

Implications

Experts note that the study challenges the conventional view that synaptic changes alone constitute memory storage. Instead, synaptic modifications may primarily enable retrieval. The findings point to new ways of thinking about memory disorders: if retrieval pathways can be targeted directly, it may become possible to restore seemingly lost memories without reconstructing synaptic changes.

Source: MIT news report on research published in Science, May 2015.

Research article: “Engram cells retain memory under retrograde amnesia” by Tomás J. Ryan, Dheeraj S. Roy, Michele Pignatelli, Autumn Arons, and Susumu Tonegawa. Published online May 29, 2015 in Science. doi:10.1126/science.aaa5542

Summary of the scientific abstract

Memory consolidation transforms an unstable new memory into a lasting one. Using cell-specific labeling, the authors identified increased synaptic strength and dendritic spine density in consolidated engram cells. When protein synthesis was blocked, these features were absent, and natural recall failed. However, direct optogenetic activation of those engram cells still produced memory retrieval, correlating with preserved engram-specific connectivity. The authors propose that engram cell connectivity stores memory information while synaptic strengthening supports the retrieval process.