In order to remember, we must forget. Recent research shows that when your brain retrieves newly encoded information, it suppresses older related information so that it does not interfere with the process of recall. Now a team of European researchers has identified a neural pathway that induces forgetting by actively erasing memories. The findings could eventually lead to novel treatments for conditions such as post-traumatic stress disorder (PTSD).
We’ve known since the early 1950s that a brain structure called the hippocampus is critical for memory formation and retrieval, and subsequent work using modern techniques has revealed a great deal of information about the underlying cellular mechanisms. The hippocampus contains neural circuits that loop through three of its sub-regions – the dentate gyrus and the CA3 and CA1 areas – and it’s widely believed that memories form by the strengthening and weakening of synaptic connections within these circuits.
The dentate gyrus gives rise to so-called mossy fibres, which form the main ‘input’ to the hippocampus, by relaying sensory information from an upstream region called the entorhinal cortex first to CA3 and then onto CA1. It’s thought that the CA3 region integrates the information to encode, store, and retrieve new memories, before transferring them to the cerebral cortex for long-term storage. Exactly how each of these hippocampal sub-regions contribute to memory formation, storage, and retrieval is still not entirely clear, however.
Previously, Cornelius Gross of the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, and his colleagues used genetic engineering to develop a new way of inhibiting the activity of specific cell types in the brain. When they used the technique to inhibit granule cells in the dentate gyrus of live mice, they found that the animals could not learn to avoid a part of their cage that gave them mild electric shocks.
Their latest study, led by Noelia Madroñal, combined this technique with several others to learn more about the function of the dentate gyrus. First, they trained some of their genetically engineered mice to associate mild electric shocks with particular sounds, and found that inhibiting the activity of dentate gyrus granule cells during, but not after, the learning procedure, prevented them from learning the associations.
Using microelectrodes implanted into the brains of live mice, they showed that inhibition of dentate gyrus granule cells during learning prevents memory formation by weakening synaptic connections between the dentate gyrus and the CA3 regions, and that this inhibition depends on incoming signals from the entorhinal cortex. Thus, the dentate gyrus seems to be required for memory formation, but not for retrieving existing memories.
Finally, the researchers mined a comprehensive atlas of genes expressed in the mouse brain to identify a cell surface receptor, called Npy1, which is expressed exclusively in dentate gyrus granule cells, and found that activating this receptor in normal mice with a synthetic peptide that selectively binds to it caused the same learning-induced memory loss seen in the other experiments.
“This is the first time that a pathway in the brain has been linked to forgetting, to actively erasing memories,” said Gross, a co-senior author of the study. “One explanation for [our findings] is that there is limited space in the brain, so when you’re learning, you have to weaken some connections to make room for others. To learn new things, you have to forget things you’ve learned before.”
The finding that memory loss can be induced by Npy1 receptor activation alone could one day help researchers to treat conditions involving intrusive traumatic memories. “A patient suffering from intrusive traumatic memories would take a pill containing a drug that would enter the brain and activate Npy1 receptors and then be exposed to a virtual experience of the trauma,” says Gross, “and we predict that the combination of receptor activation and trauma exposure and recall would promote the selective erasure of the relevant memory.”
He adds, however, that any such treatment is still a long way off: “We have been trying to test drugs that can be delivered systemically rather than directly into the brain. When we identify such molecules, we can start thinking about pre-clinical and clinical testing.”
Madroñal, N., et al. (2016). Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells. Nat. Commun. DOI: 10.1038/ NCOMMS10923 [Full text]