Transcriptional changes are essential for converting new experiences into memories but may not be required to make memories last, a new study suggests.
The findings, published in eNeuro in March, conflict with a model proposing that positive feedback loops of transcription can help maintain long-term memories, says study investigator Irina Calin-Jageman, professor of biological sciences at Dominican University. But they open up a set of hypotheses about how transcription maintains long-term memories and indicate that the handful of genes whose regulation persists for up to two weeks could be “really key,” she adds.
The results, obtained in the sea slug Aplysia californica, are “one small step on our way to understanding this very important question of: What is the role of transcription in forming long-term memories?” says Wayne Sossin, distinguished James McGill professor of neurology and neurosurgery at McGill University, who is listed as a reviewer for the paper. Disproving models doesn’t “get the attention it deserves, I think, from the scientific community,” he says, but science is built on overturning theory.
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Even after behavioral responses go back to baseline, A. californica remains sensitive to shocks, Irina Calin-Jageman and her colleagues showed in a 2020 paper. The slugs exhibit few lasting changes to gene expression, except seven transcripts that “never seem to go away,” says study investigator Robert Calin-Jageman, professor of psychology at Dominican University.
This disconnect between gene expression and behavioral expression of the memory led the team to look at genes expressed when the memory has only partially faded, he says.
In their new study, they shocked their slugs four times—every 30 minutes for two hours—on one side of the animal’s body. One day later, they gave the animals a weak shock on both sides of the body, and the slugs withdrew their siphons for nearly twice as long on the sensitized side. In addition to the seven long-lasting transcripts, the remaining 1,198 genes were either up- or downregulated in the pleural ganglia on the sensitized side of each slug compared with the non-sensitized side.
When given another weak shock five days later, the slugs retracted their siphons for less time than they did after their second shock, but for longer than a non-sensitized slug would, suggesting the memory had partially faded but wasn’t forgotten. Both sensitized and non-sensitized ganglia, however, showed that transcription had fallen back off, except for the long-lasting transcripts.
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Irina Calin-Jageman says she is planning to examine that very question to see if the transcriptional program “settles into a smaller subset of cells, rather than being as widespread as it is one day after training.”
Some researchers are not surprised by these findings, however. Cell-wide responses such as transcriptional regulation are unlikely to explain synapse specific changes underlying memory maintenance, says Harel Shouval, professor of neurobiology and anatomy at the University of Texas Health Science Center at Houston, who wasn’t involved in the new study. He says he thinks neurons can maintain memories by regulating how transcripts are translated.
There are some indications of non-transcriptional mechanisms, Irina Calin-Jageman admits, “but those are harder to prove, to some extent, because we don’t know what they are.”
There is currently no way to causally link continuous transcriptional or translational changes to memory maintenance, says Eric Klann, professor of neuroscience at New York University. To do that, the field needs to move toward single-cell multiomics, targeting putative engram cells directly involved in storing specific memories, he says.
