Cornelia I. Bargmann
As Cori Bargmann embarked on her research career, she found herself drawn to the neurobiology of behavior. “I’ve always been interested in behavior,” Bargmann said. “I remember reading about the work of the early 20th century neurobiologists, who showed that there were certain behaviors that were innate to all animals in a species, or behaviors that would be released by a specific event like imprinting.”
After finishing graduate school, where Bargmann focused on cancer biology, she decided to shift her focus to neurobiology, to try and understand the basis of behavior. At the time, molecular genetics and genetics were starting to become more broadly applicable, which Bargmann recognized could be applied to the question of understanding behavior. “When you have a really complex problem, and you have no idea how a system works, genetics is a good way to get a foothold,” Bargmann said.
After considerable debate about the best model organism that could help answer these questions, Bargmann decided to study behavior in C. elegans, due to the fact that the wiring diagram had recently been published, showing the 7,000 connections made by the 302 neurons found in C. elegans. “You’re trying to explore a new country, and here you have a map,” Bargmann said. “The strength of C. elegans is that you would be able to link together what molecules were important, what cells they were acting in, and what they were doing there.”
Having decided on C. elegans as a model system for studying behavior, Bargmann started her postdoc in the lab of Bob Horvitz at Massachusetts Institute of Technology, where she performed technically challenging laser ablation experiments to remove individual neurons from the worm to determine what behaviors these neurons were responsible for.
Following this cell-based approach with genetic screens, Bargmann and her colleagues were able to identify an odorant receptor in C. elegans, which sensed the molecule diacetyl, and connect this receptor with the behavior of crawling towards this molecule. “There were very strong candidates for odorant receptors that had been identified in mice a few years earlier, but this was the first time that a specific odorant was linked to a specific receptor,” Bargmann said. The next step was to perturb the system to establish causality: Bargmann and her colleagues expressed the odorant receptor in neurons that normally reacted only to noxious odors, which had the effect of changing the worm’s behavior. “The worms ran away from the diacetyl, instead of approaching it,” Bargmann said. “You could reprogram that innate sensory preference, just by moving the receptor from one cell to the next.”
This combined approach of looking at genes, cells and behaviors would come to define Bargmann’s career, as she would follow up these early experiments with many more, all seeking to define the ways in which behavior is determined by a complex mixture of environment and physiological factors. This included experiments to identify context-specific behaviors. “We studied how information is transmitted from sensory neurons to the next level of integrating neurons, and asked, how does that relate to the fact that sometimes the sensory stimulus does not elicit the behavior?” Bargmann said. “We saw that the integrating neurons are switching back and forth between different functional states. In some states, they are listening to the sensory input, and in some, they are not.”
Along the way, Bargmann developed a number of tools for observing or perturbing neuronal function, which she shared with the research community at large, including microfluidics devices for olfactory imaging and behavioral analyses, a transgenic histamine-gated chloride channel that silenced neurons, and a split protein called GRASP that labeled synapses between neurons. “In the C. elegans field, people had a mindset of developing resources the entire community could use,” Bargmann said. “That was the mindset that people walked in the door with.”