The researchers traced every neuron in small worms to create a diagram that other experts described as the "gold standard" connectome: the neural map responsible for senses and behaviors.
A connectome is a wiring schematic, like a circuit diagram, that shows how nerve cells link to each other and to organs. Building a human connectome is a long-sought goal among neuroscientists. It remains out of reach, despite investments such as the BRAIN Initiative, which the National Institutes of Health funded at more than $400 million in 2018.
But researchers behind the worm connectome say maps such as this could help explain the biology of mental disorders that affect humans. Schizophrenia and bipolar disorder "may be connectopathies. That is, they're due to abnormal or faulty or incorrect wiring somewhere in the nervous system," said study author Scott Emmons, an expert in the nervous system at Albert Einstein College of Medicine. If scientists better understand when wires malfunction in the worm, "that could well lead to insights into mental disorders in a rather direct way," he said.
The worm in question is Caenorhabditis elegans. Thin and translucent as a glass noodle, the microscopic animal lives in dirt and eats bacteria. Bench biologists like C. elegans because the animal is easy to raise, with a simple body plan, yet behaves just complexly enough to be interesting. More scientists study the worm than it has cells in its body - it has about 1,000, all of which have been mapped. The worm's whole genome was the first of any animal sequenced. In December, several thousand worms were flown to the International Space Station to observe how muscles react to spaceflight.
"The C. elegans nervous system has made a massive contribution to neuroscience," Emmons said. Nerve cells exchange signals, like relay runners handing off batons, at connections called synapses. Key proteins in synapses were first discovered in the worms, before scientists knew to look for similar proteins in mammals.
The Nobel Prize-winning biologist Sydney Brenner, who died in April, championed C. elegans research beginning in the 1960s. Brenner and his colleagues submitted the first C. elegans connectome for publication in 1984. Microscope images and the wiring diagram, completed by hand, filled six paper notebooks.
"There were still regions in the animal that hadn't been looked at. And those gaps are sealed," said Rockefeller University biologist Shai Shaham. "This will be the main reference point to which everything else will now be compared."
Rochester University biologist Douglas Portman, who studies sex differences in C. elegans and was not involved with this research, called this connectome the "version 2.0" of what Brenner and his colleagues accomplished.
"There's cool stuff that's going on that we didn't even know about," Portman said. The worms' organs, such as intestines and gonads, are more heavily innervated than some biologists had predicted. The system is very tightly connected. Signals from a sensory neuron can reach nearly any cell within two passes of the electrochemical baton.
Emmons and his team digitized some of the same microscope images used by the original workers. Their reconstructions on a computer allowed the scientists to count many more synapses for the new connectome. Brenner's team had mapped only one of the worm sexes, the hermaphrodite, which can self-fertilize its own eggs or use a male's sperm. The new report includes the connectomes of both sexes.
The male worm has 385 neurons and the hermaphrodite has 302. Add in muscles, organs and synapses, and the connectome is a web of nodes laced together by several thousand strands.
(Humans have approximately 86 billion neurons and trillions of synapses. For perspective: Scale the Statue of Liberty and you've traveled upward about 300 feet. An 86-billion-foot journey could take you to the moon and back 35 times.)
In the part of the worm analogous to its brain, some connections are "considerably stronger" in the male than the hermaphrodite, Portman said. That may stem from different priorities. Alone in an environment filled with food, hermaphrodite worms will stay put and eat. Male worms, however, eventually slither away from the food in search of mates.
In the future, "the ability to link specific neurons with specific behaviors will also allow us to really establish the extent to which wired and wireless circuits contribute to specific behaviors," said Piali Sengupta, a biologist at Brandeis University who was unaffiliated with this research.
There are still frontiers left to map. "The field needs to go and do this in other species," Portman said. The published connectomes are reconstructions, stitched from images of several animals. "We need to have many more examples of individual C. elegans."
Other laboratory groups are developing the connectomes of larval stages of the worm. Efforts are also underway to map the 100,000 neurons in the fruit fly connectome, and all of the connections in a cubic millimeter of a mouse brain.
"The field of connectomics is in its infancy," said Emmons, who likened it to the early days of genetic sequencing. "It has an enormous future ahead of it."