In the famous song by The Clash, “Should I Stay or Should I Go,” the lyrics wrestle with one of the more complicated decisions people make — whether to end a difficult love affair or try to make it work. We aren’t likely to understand exactly how specific genes affect such momentous choices anytime soon. But when a microscopic worm ponders whether to stay on a patchof bacteria it is eating or leave for greener pastures, the biology of primitive decision-making is much more accessible. A recent study by Rockefeller University researchers identified natural variations in several genes that influence this behavior, including one, tyramine receptor 3 (tyra-3), that produces a receptor for an invertebrate’s version of adrenaline, a hormone involved in the ‘fight or flight’ response in mammals.
“What’s encouraging to us about this story is that molecules related to adrenaline are implicated in arousal systems and in decision-making across a lot of different animals, including humans,” says Rockefeller University’s Cori Bargmann, who oversaw the work led by graduate student Andres Bendesky.
The research, published by Nature April 21, focused on the famous nematode Caenorhabditis elegans, a model organism whose simple nervous system of 302 neurons — and all of their connections — have been completely mapped. Researchers in Bargmann’s Laboratory of Neural Circuits and Behavior and in Leonid Kruglyak’s lab at Princeton interbred two different strains of the worm to create about 100 distinct genotypes. Using a statistically powered genetic screen, the researchers were able to zero in on variations in genes that appeared to have an outsize impact on the worms’ decisions to “exploit” an existing food supply or “explore” new areas.
The impact of the gene variants on the worms’ foraging behavior was the most significant in borderline decisions, when the amount of available bacteria was in a middling range. Where the bacteria were especially bountiful, or especially scarce, the effects diminished.
Bendesky and colleagues wanted to know not just what genes are involved but how. A variant of one gene, npr-1, was previously known to affect the worms’ foraging behavior, among other things, but it does not occur in native nematodes, which are often found in agricultural settings, feeding on the bacteria in rotting fruits and vegetables. Rather it arose in a strain bred for laboratory use. A natural variant of tyra-3, however, opened up a new line of research, says Bargmann, Rockefeller’s Torsten N. Wiesel Professor and also an investigator with the Howard Hughes Medical Institute.
To find out where in the nervous system tyra-3 was active, the scientists labeled the tyramine receptor with a green fluorescent protein. The gene expression pattern spread through about a dozen cells, but the researchers determined that the primary effect on foraging behavior was the gene’s expression in two sensory neurons that detect environmental cues. More research could provide details about the neural circuits that coordinate the worms foraging behavior with the environment.
Tyramine is related to mammalian noradrenaline, which is involved in a variety of arousal behaviors, and its release is implicated in switching between different tasks, “a cognitive function with analogies to the exploration-exploitation decision,” the authors observe.
“It suggests these molecules have been used in different branches of the animal kingdom to solve similar problems,” Bendesky says.
This fundamental description of the mechanisms underlying a behavior, which combines genetic studies with neuronal analysis, grows increasingly difficult with the complexity of the animal being studied — the human brain has billions of neurons compared to C. elegans’ 302, for instance – and the environmental variables involved. Still, similar work has made inroads in understanding what genes are behind the foraging behavior of fruit flies and even of anxiety in mice, although the neural mechanisms have not been spelled out in these cases. Bendesky hopes to expand this type of research in rodents.
The work also illustrates the monumental difficulty of providing a similarly detailed understanding of the mechanisms that might tilt a person one way or the other in The Clash’s classic stay-or-go conundrum.
|Nature 472: 313–318 (April 21, 2011)
Catecholamine receptor polymorphisms affect decision-making in C. elegans
Andres Bendesky, Makoto Tsunozaki, Matthew V. Rockman, Leonid Kruglyak and Cornelia I. Bargmann