The Rockefeller University
Dr. Bargmann is also Torsten N. Wiesel Professor and head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior at the Rockefeller University.
Genes, Neural Circuits, and Behaviors
Cornelia Bargmann studies the relationships between genes, experience, the nervous system, and behavior, using the transparent, millimeter-long worm Caenorhabditis elegans. Although it has just 302 neurons, C. elegans shows considerable sophistication in its behaviors, and its defined neuronal wiring and genetic accessibility make it an ideal subject in which to study these interactions.
The most complex behaviors in C. elegans occur in response to smell, and these are the focus of Bargmann’s research. The animal can sense hundreds of different odors, discriminate among them, and generate reactions that are appropriate to the odor cue. These behaviors can be traced from molecules, to neurons, to circuits, to behavioral decisions. To study these different levels of information processing, Bargmann’s team uses quantitative analysis of behavior under well-defined conditions, genetic manipulation of animals and individual neuronal cells, and observation of neuronal activity in living animals.
C. elegans is also capable of learning the odors of different bacteria and avoiding the ones that previously caused illness. These learned olfactory behaviors result from specialized circuits that drive long-lasting behavioral remodeling. Other kinds of flexible behaviors are shaped by the integration of internal states with environmental context. Bargmann’s team has identified neuromodulators representing internal motivational states that change the flow of information through the nervous system, thereby changing behaviors to match different contexts.
Bargmann is also interested in how genetic and nongenetic variation between individuals can cause them to behave differently from one another. For example, natural wild isolates of C. elegans show substantial variation in foraging behaviors, aggregation, and exploration that can be traced to genetic differences. Bargmann’s team has discovered that genetic polymorphisms affecting sensory and neuromodulatory receptors are sources of this variation, suggesting that the interaction between environmental cues and internal states is a central source of behavioral variability.
Grants from the National Institutes of Health, the Ellison Medical Foundation, and the G. Harold and Leila Y. Mathers Foundation provided partial support for these projects.
When Cornelia Bargmann began studying the relationship between neural circuits and behavior in 1987, a powerful new resource had just become available: a complete wiring diagram of the Caenorhabditis elegans nervous system. The diagram mapped the connections between each of the tiny roundworm’s 302 neurons, and had the potential to guide neuroscientists to a new understanding of brain function.
Bargmann has been studying that deceptively simple nervous system ever since, using C. elegans to investigate the genes and molecules that enable animals to sense and respond to their surroundings and modify their behavior based on past experiences. “These are very big, complex questions,” she says. “I study them in C. elegans because [unlike in larger animals] I can try to think about all of these problems at once.”
Bargmann’s research focuses on C. elegans’ sophisticated sense of smell, which she says impacts every aspect of its physiology and behavior. As a postdoctoral researcher and later in her own lab at the University of California, San Francisco, she started with the basics, focusing on the odors worms can smell and how they detect them. Her genetic studies revealed how the worms recognize and distinguish between hundreds of odors. That work laid the foundation for mapping C. elegans’ innate odor preferences, as well as identifying the neurochemical changes that help the worms learn to avoid certain smells, such as that of bacteria that once made them ill.
Bargmann, who moved her lab to Rockefeller University in 2004, is now seeking a new level of understanding of the relationships between genes, behavior, environment, and experience. The big questions about how neurons and circuits generate behavior haven’t changed, she says. “But with more sophistication, more quantification, and more advanced tools, we are reaching deeper answers.”
Understanding what underlies the variability of worms’ behavioral responses to odors is a priority in the lab. Why do worms respond to some odors differently at different times? What causes them to change their behavior? What are the genetic variations that cause individual worms to behave differently from one another?
With the availability of new tools for monitoring and perturbing neural activity, there is plenty of opportunity. “The thing that limits our understanding is our creativity,” explains Bargmann. Interactions between the “smart, creative, and curious” members of her research team and collaborators are vital for identifying important questions and allowing the best ideas to emerge, she says.
Today, C. elegans is still the only organism whose neuronal connections have been fully mapped. But neuroscientists admit that even in the worm’s simple system, a neural connectivity map leaves a lot of nervous system function unexplained. Even so, the wiring diagram is a critical tool for neuroscience discovery. “If you can’t explain a behavior based on the wiring diagram, there must be something outside the wiring diagram – and you need to find it,” Bargmann says. “The beauty of C. elegans for neuroscience is that you have nowhere to hide.”