A landmark study exploring a little-researched area of the hippocampus made an unexpected discovery about how memory is retrieved. The scientists found, surprisingly, that memory retrieval and memory formation depend on very distinct mechanisms.

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A new study reveals that there are different pathways for memory retrieval and memory formation.

Research on memory formation and memory retrieval is abundant and ongoing, as there is still so much we are yet to learn about how our brain works. For instance, Medical News Today have recently reported on a study that sought to understand how long- and short-term memory is formed.

Memory, in general, has long been associated with an area of the brain called the hippocampus, but although a lot of progress has been made in understanding what takes place in this brain region, there are still aspects of hippocampal functioning that remain unclear.

Previous research suggested that the hippocampus and surrounding cerebral areas are responsible for both memory formation and memory retrieval, but some studies pointed to an enigmatic part of the hippocampus, called the subiculum, as specifically involved in recalling memories.

However, until now, it remained unclear to what extent the subiculum is important in how we remember.

A study conducted by neuroscientists from the Massachusetts Institute of Technology (MIT) in Cambridge, MA, now suggests that the subiculum is central to the memory retrieval process, and that recalling memories follows a different neural circuit to forming memories.

According to the researchers, this recall circuit had not previously been identified in vertebrates, although a similar mechanism was spotted by scientists in the roundworm Caenorhabditis elegans.

Senior study author Susumu Tonegawa – Picower professor of biology and neuroscience, and the director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory at MIT – highlights the importance of the scientists’ findings:

This study addresses one of the most fundamental questions in brain research – namely how episodic memories are formed and retrieved – and provides evidence for an unexpected answer: differential circuits for retrieval and formation.”

The results of the study are reported in the journal Cell.

Prof. Tonegawa and his team investigated the subiculum using laboratory mice that they had genetically engineered for this purpose. The mice were conditioned to react to light changes, so that subiculum neurons would be inhibited as a reaction to green light.

Fear-conditioning events were thus used to manipulate memory formation and recall, determining the mice to make more or less pleasant associations with particular situations.

According to existing research, a region of the hippocampus referred to as CA1 is stimulated by this kind of memory-encoding process. CA1 interacts with the entorhinal cortex, which functions as a communication area between the hippocampus and other brain regions.

Thus, certain clusters of neurons are activated, and these become “engrams,” also known as “memory traces.” These are permanent changes in the brain that record an association that can later be recalled.

“It’s been thought that the circuits which are involved in forming engrams are the same as the circuits involved in the re-activation of these cells that occurs during the recall process,” says Prof. Tonegawa.

Yet, previous experiments conducted by the team of scientists had noticed that successful memory recall correlated with a bypath that deviated from the CA1 region, went through the subiculum, and reached the entorhinal cortex. This distinct pathway for memory retrieval was a surprising discovery for the scientists.

When conducting their in vivo experiments for the current study, the researchers split the mice into two groups. The subiculum neurons of mice in the first group were inhibited as the animals were submitted to the fear conditioning process. This did not impact the mice’s ability to recall the experience later.

Conversely, the subiculum neurons of the mice in the second group were inhibited after they had undergone the fear conditioning process. It was observed that these mice could not properly recall the experience, as they did not exhibit a successful fear association when appropriate.

Prof. Tonegawa and his team suggest that this confirms that the neural bypath involving the subiculum is necessary for memory retrieval, but not required for memory formation.

Further tests also indicated the reverse: that the direct neural pathway from the CA1 region to the entorhinal cortex is key for memory formation, but unnecessary for memory retrieval.

“Initially, we did not expect th[is] outcome […] We just planned to explore what the function of the subiculum could be,” Prof. Tonegawa confesses.

The researchers hypothesize that these distinct pathways might facilitate memory updates and “edits.” They suggest that, as the recall bypath is activated, the memory formation pathway is also triggered, which allows fresh information to be recorded in the brain.

“We think that having these circuits in parallel helps the animal first recall the memory, and when needed, encode new information. It’s very common when you remember a previous experience, if there’s something new to add, to incorporate the new information into the existing memory,” explains Dr. Dheeraj Roy, one of the lead authors of the study.

Another possible explanations for the necessity of two distinct memory circuits include the stimulation of stress hormone release, which happens after distressing memories are recalled.

Although the two pathways were found via experiments linked with emotional memory formation and recall, related to both pleasant and stressful events, the researchers suggest that the same mechanism may be relevant to all types of episodic memory.

Prof. Tonegawa and his team stress the importance of their discovery to understanding how memory works, and even hint that the new information might be relevant to the study of Alzheimer’s disease, although that is an avenue yet to be explored.