Courtesy of RIKEN
Schematic model showing how memory is consolidated in the prefrontal cortex and how circuitry through the amygdala shifts as hippocampal engram cells become silent and cortical engrams become active.
Source: Courtesy of RIKEN

A new study on mice from the Massachusetts Institute of Technology (MIT) has identified a new schematic model and timeline illustrating how memories are consolidated in the prefrontal cortex (PFC) after being relayed from one part of the brain to another for long-term storage.

This report, "Engrams and Circuits Crucial for Systems Consolidation of a Memory," was published online ahead of print April 6 in the journal ScienceSusumu Tonegawa, director of the RIKEN-MIT Brain Science Institute and Center for Neural Circuit Genetics (CNCG) was senior author of this study. These findings challenge historical models of long-term memory formation and may lead to revisions of some dominant memory consolidation models, according to the MIT researchers.

Other contributors to this groundbreaking study include lead author Takashi Kitamura, postdocs Sachie Ogawa, Teruhiro Okuyama, and Mark Morrissey; along with graduate student Dheeraj Roy, technical associate Lillian Smith, and former postdoc Roger Redondo.

Life Sciences Database/Wikimedia Commons
Human prefrontal cortex (PFC) in red. 
Source: Life Sciences Database/Wikimedia Commons

The new MIT study by Kitamura et al. reveals, for the first time, that memories are initially formed simultaneously in the hippocampus and specialized neurons in the prefrontal cortex called “engram cells” that consolidate long-term memories over time. In a statement to MIT News, Tonegawa said, "This and other findings in this paper provide a comprehensive circuit mechanism for consolidation of memory."

To determine which specific areas of the cerebral cortex were important for forming a long-term memory, the researchers blocked inputs to different brain areas during conditioning and memory recall over a 3-week period. Surprisingly, the researchers found that long-term memories remain "silent" in the prefrontal cortex for about two weeks before maturing and becoming consolidated into permanent long-term memories.

Lead author Takashi Kitamura said in a statement, "We discovered the existence of cortical engram cells, but it turns out that they are not formed gradually over time. They actually form at the same time as the initial memory in the hippocampus." Morrissey added, "They're formed in parallel but then they go different ways from there. The prefrontal cortex becomes stronger and the hippocampus becomes weaker." 

The Prefrontal Cortex, Hippocampus, and Amygdala Work in Concert to Consolidate Long-Term Memories Over a 12-Day Timeframe

Courtesy of Takashi Kitamura, Tonegawa lab
An MIT study of the neural circuits that underlie memory process reveals, for the first time, that memories are formed simultaneously in the hippocampus and the long-term storage location in the brain’s cortex. This image shows memory engram cells (green and red) which are crucial for permanent memory storage in the prefrontal cortex.
Source: Courtesy of Takashi Kitamura, Tonegawa lab

This study illustrates how functional connectivity with other brain regions allows cortical engram cells to mature and become permanent long-term memories in PFC neurons over the course of about 12 days. Specifically, the researchers labeled memory cells in three parts of the brain: the prefrontal cortex, the hippocampus (HPC), and the basolateral amygdala (BLA). Notably, they found the BLA stores both positive and negative emotional associations to a memory in conjunction with the PFC and HPC. 

The findings suggest that traditional theories of long-term memory consolidation may only be partially accurate. Memories appear to be formed rapidly and simultaneously in both the prefrontal cortex and the hippocampus on the day an initial memory is created. Then, the memory is consolidated in the PFC over time. 

Historically, the hippocampus has been considered by most experts to be the "memory hub" and the prefrontal cortex was considered the seat of "executive functions" such as planning, emotional regulation, impulse control, cognitive flexibility, etc. These new findings challenge traditional views of the role that the hippocampus and cerebral cortex play in memory consolidation. 

Kitamura and colleagues also discovered that engram cells linked to both positive and negative emotional events were encoded in the amygdala, which is connected to the hippocampus and the prefrontal cortex as part of a neural network. The latest MIT findings may debunk another popular myth that the amygdala is the brain's "fear center." 

Interestingly, once a memory was formed in the engram cells of the basolateral amygdala, it remained unchanged throughout the course of the experiment. Engram memory cells in the amygdala appear necessary for the communication of a spectrum of emotions linked to a particular memory. The amygdala acts as a type of emotional relay station between the hippocampus and prefrontal cortex.

Technological Advances in Tonegawa's MIT Lab Advance Our Understanding of Engram Cells and Brain Circuitry Necessary for Memory Formation

In 2012, Tonegawa's lab developed a technological breakthrough that allowed them to label specific engram cells in various parts of the brain that contained specific memories. This allowed the researchers to trace the brain circuitry involved in memory formation, storage, and retrieval. Using state-of-the-art optogenetics, Tonegawa’s team was then able to turn target cells on and off using bursts of light. Turning these cells "on" artificially reactivated memories held in specific engram cells.

For their latest study, the MIT researchers labeled memory cells in mice during a fear-conditioning event—which was a mild electric foot shock delivered when the mouse is in a particular chamber. Optogenetics allowed them to observe the subsequent fear-conditioned behavior of freezing in place when specific engram cells were reactivated. These findings were also corroborated by placing the mice back in the original chamber where the foot shocks had first been delivered to observe a natural recall of the fear-based memory.

More research is necessary to determine if memories fade completely from hippocampal cells or if some traces remain in hippocampal engram cells. Currently, researchers in Tonegawa's lab can only monitor engram cells for a few weeks. But they’re working on advances in their technology that will allow them to monitor these cells for longer periods.

Kitamura has a hunch that some trace of a memory remains in the hippocampus indefinitely and that details are retrieved and updated occasionally if a memory is triggered. "To discriminate two similar episodes, this silent engram may reactivate and people can retrieve the detailed episodic memory, even at very remote time points," Kitamura said.

Moving forward, the MIT researchers also plan to investigate how the maturation process of a memory engram in the prefrontal cortex evolves. Stay tuned for follow-up research from Tonegawa's lab and others that will help us better understand how engram cells and complex neural circuitry work together to consolidate memories.

References

Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, Redondo RL, Tonegawa S (2017). Engrams and circuits crucial for systems consolidation of a memory. Science. doi: 10.1126/science.aam6808

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