Tiny Worms Get the Munchies, Too | Science

Nematode Worm With Fluorescent Markers

This worm is genetically engineered so some neurons and muscles are fluorescent. Green dots are neurons that respond to cannabinoids, while magenta dots are other neurons.
Stacy Levichev

Those celebrating the decidedly unofficial holiday of 4/20 on Thursday might experience a phenomenon known to scientists and the lay public as “the munchies.” Cannabis’ ability to stimulate appetite is one of its many medically useful properties, but it can also lead recreational users to plow through pints of ice cream, devour mountains of Cheetos or gnaw a log of raw cookie dough down to a stump.

These feats of gluttony showcase one of the hallmarks of the munchies, says University of Oregon neuroscientist Shawn Lockery, which is not just a nearly insatiable hunger but an increased drive to inhale the yummiest, highest-calorie foods within reach.

But it turns out the munchies are not limited to humans or even mammals. Lockery and his colleagues show, in a study published Thursday in Current Biology, that even the millimeter-long nematode worm Caenorhabditis elegans chows down on its favorite foods with extra gusto while under the influence of cannabis molecules called cannabinoids.

These similar responses to cannabinoids are unexpected, because the evolutionary lineages that produced humans and nematode worms split off in different directions more than 500 million years ago, and because C. elegans has just 302 neurons compared to our roughly 86 billion.

“Surprisingly, over 500 million years of evolutionary distance, the worm’s cannabinoid signaling system and that of humans have not diverged that much,” says Lockery. This similarity could allow studies of nematode worms like this one to eventually offer insights into how more complex brains like ours work on a fundamental level.

Scientists have long known that humans and nematode worms both have receptors throughout their bodies that respond to cannabinoids. These cannabinoid receptors evolved to bind with molecules that are naturally produced inside the body called endocannabinoids—compounds that are structurally similar to the cannabinoids found in the cannabis plant.

Together, endocannabinoids and cannabinoid receptors form the endocannabinoid system, which in humans is involved in regulating a huge range of biological functions including learning and memory, sleep, pain, inflammatory and immune responses, and, of course, eating.

The inspiration for studying how C. elegans responded to cannabinoids stemmed partly from the legalization of recreational marijuana in Oregon in 2015. That same year, Lockery and his team were studying decision making using food choice in nematodes. Lockery says one day, almost as a gag, someone wondered aloud, “What would happen if you soaked the worms in cannabinoids?”

Prior research had shown that C. elegans prefers food that will help it grow fastest and that these nematodes can track down food, primarily bacteria, through chemical cues that approximate smell and taste.

From the very first cannabinoid experiment, Lockery says the effect was clear: Dose the nematodes with the endocannabinoid anandamide, and it makes them eat faster, amplifies their preference for their favorite foods, depresses their consumption of their least favorite foods and has no effect in their feeding on neutral foods.

The researchers showed the worm’s increased feeding rate using a device that can electrically measure how many times an individual worm swallows inside a tiny tube, and they recorded how much each test subject ate within a time span of one minute. To see how C. elegans responded to different foods, the team presented single worms with a menu of five different species of bacteria. The bacteria in the experiments contained two species known to be nematode delicacies, one neutral species and two non-preferred species.

Nematode Worms GIF

More worms under the influence of endocannabinoids in a T-shaped maze are drawn to favored food in the left arm, while some try inferior food on the right before moving to the left. The video is sped up to show 15 minutes of real time behavior in 5 seconds.

Aaron Schatz

In further testing, the researchers placed a group of worms in a T-shaped maze with patches of different bacteria at each end. The researchers then counted the number of worms in each bacteria patch at 15-minute intervals for one hour and found that endocannabinoids also made the worms more likely to seek out their favorite foods, less likely to track down foods they don’t care for and not any more or less inspired to sidle up to the patch of neutral bacteria.

The team then introduced a paralytic agent to the bacterial buffet to prevent the worms from switching patches of food once they made their initial choice. The results were unchanged: More of the anandamide-dosed worms clustered around the patches of the preferred bacteria, and fewer worms paid any attention to the least preferred bacteria.

“This told us that the worm’s odor detection system was involved,” says Lockery.

To test this further, the team used a strain of mutant worms that were missing olfactory neurons known as AWC neurons. Lockery and his colleagues found that for these mutant worms the effect of the endocannabinoids disappeared—the dosed test subjects showed normal levels of feeding on all five species of bacteria. The results suggested an increased sensitivity to food odors was behind the changes endocannabinoids caused in eating behavior.

Drilling down another layer of complexity, the team also used mutant worms missing a cannabinoid receptor called NPR-19 to show that the behavioral shifts required this receptor. The team then manipulated these mutant worms by restoring the NPR-19 receptor, and the nematodes got the munchies again. Surprisingly, the researchers got the same result when they replaced the worm’s NPR-19 cannabinoid receptor with the version present in humans, called CB1.

“This same functional pathway in the endocannabinoid system is present in this simple animal with just 302 neurons,” says Sreekanth Chalasani, a neuroscientist at the Salk Institute for Biological Studies who was not involved in the study. “This shows a commonality across a huge biological and evolutionary distance. When nature finds something good it often uses the same thing again and again, which I think is beautiful and fascinating.”

Lockery and his co-authors looked for the NPR-19 cannabinoid receptor on the AWC olfactory neurons but didn’t find it there, suggesting the true mechanism is more complex.

“This gives us a whole bushel of hypotheses to test,” says Lockery. The NPR-19 cannabinoid receptor is present on 28 different neurons in the worm’s head, and Lockery says future experiments can just delete them one by one to figure out where the cannabinoids are kicking off their behavioral effects.

In humans this list of potential neurons to test would be a lot longer than 28, yet Lockery’s research presents evidence of striking similarities in how the endocannabinoid system functions despite the worm’s relative simplicity.

“The more similar we are, the better we can learn about the human endocannabinoid system from studying these worms,” says Martine Skumlien, a psychopharmacologist at the University of Bath who was not involved in the study. “The endocannabinoid system regulates loads of other neurotransmitters in the human brain.”

Skumlien says she’s studied the endocannabinoid system’s role in reward processing during activities like eating or using recreational drugs. “If we really deepened our understanding of how all this fits together,” she says, “you could imagine medications that acted on the endocannabinoid system to make drugs of abuse less appealing.”

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