A Worm Peptide Picks Which Smell Memory to Erase

HOW does a brain decide which memories to throw away? In worms, a peptide released by one smell-sensing neuron triggers a chain of signals that erases the memory of one odour and spares another. That’s the finding of a study in the roundworm Caenorhabditis elegans (C. elegans), published in Current Biology by a team led by Takeshi Ishihara at Kyushu University in Japan.

Forgetting gets a bad rap. Most memory research asks how memories form and last, and Ishihara’s group notes that how they’re lost has had far less attention. Yet losing the right things is part of coping with a changing world, and holding on to everything is no gift, as the case of a teen with exceptional life recall, whose memories pop up unasked, suggests. A worm turns out to be a great place to test that idea.

A worm with 302 neurons and a short memory

C. elegans is a nematode with 302 neurons, every one of them identified. It is blind but smells well, which makes it a good subject for tracing a memory to individual cells. The team trained worms to ignore diacetyl, an odour they normally head towards, by exposing them to it without food. After about four hours back on food, the worms regained their interest. In effect, they had forgotten the lesson.

The memory sits in a sensory neuron that detects diacetyl. Its calcium response to the odour drops after training and returns after the rest on food, so the team could watch the trace fade in the cells themselves. Each behavioural test used about 100 animals per plate and was repeated at least four times.

In 2013 the same lab had worked out which neurons were involved, but not which molecule carried the order to forget. To find it, the researchers searched for peptide genes active in a neighbouring smell neuron and found nine. They used CRISPR (a gene-editing tool that cuts out a chosen gene) to knock out each in turn. Eight made no difference. Knocking out the ninth, a gene for a peptide labelled NLP-47 from the neuropeptide-like protein family (NLP), left worms still ignoring diacetyl four hours later. Worms lacking the matching receptor behaved the same way. A worm missing both did no worse than one missing either, which suggests the two work as a pair.

The signal chain, one hop at a time

The peptide doesn’t talk to the memory neuron directly. Cell-specific knockouts placed its source in the neighbouring smell neuron and its target in a relay neuron sitting between the two. That relay neuron then releases glutamate, a common chemical messenger, onto the memory-holding neuron, where a glutamate receptor picks it up. Worms without that receptor failed to forget. Restoring it in the memory neuron alone brought forgetting back. Calcium imaging agreed: in each mutant, the odour response never recovered.

Timing matters too. The team switched off the peptide-releasing neuron with light-controlled proteins, a technique called optogenetics. Doing so during the rest on food hurt the forgetting process. Doing so at other times did not. The relay neuron followed the same pattern, since silencing it during the rest period impaired forgetting and silencing it during training did not. The erasing happens after the lesson, not during it.

The selective part came from teaching the worms two odours at once, diacetyl and isoamyl alcohol. Normal worms forgot both. Worms lacking the peptide, its receptor, the glutamate receptor or glutamate release from the relay neuron kept the diacetyl memory but lost the isoamyl alcohol one on schedule. The circuit erases one memory and leaves its neighbour alone.

What this does not show about worms or people

Everything above comes from worms, and from one odour the pathway targets and one it spares. Why it picks diacetyl is unknown. The sensory neurons that detect each odour differ, which may matter, or the difference may lie in the memories themselves. Testing other odours would help settle it.

There are gaps in the chain as well. Worms without the relay neuron did not head for diacetyl even before training, so their forgetting could not be tested by behaviour. The relay neuron’s role rests on imaging, targeted knockouts and light-based silencing instead. The knockout that removed glutamate from the relay neuron alone had a modest effect, which the authors put down to the limits of their gene-editing tool. The route from relay neuron to memory neuron uses sparse connections, so a middleman cannot be ruled out.

The human angle is a possibility, not a result. The worm receptor is a relative of the human receptor for gonadotropin-releasing hormone, and its relatives turn up in memory-related brain regions, including the hippocampus in rodents, where what they do is unknown. The authors suggest forgetting pathways of this kind may be shared across species, mammals included. The study did not test that.

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