The nematode C. elegans is a basic organism whose nervous system consists of precisely 302 neurons. The entirety of the connections among these neurons has been meticulously charted, enabling scientists to examine how they collaborate to produce the various behaviors of the organism.
Steven Flavell, an associate professor at MIT in brain and cognitive sciences as well as a researcher with The Picower Institute for Learning and Memory at MIT and the Howard Hughes Medical Institute, employs this worm as a model to investigate motivated behaviors like feeding and navigation, with the goal of illuminating the essential mechanisms that may also influence how such behaviors are regulated in other creatures.
Flavell’s laboratory has recently discovered neural mechanisms that drive adaptive alterations in the feeding behavior of worms, and it has also mapped how the action of each neuron within the organism’s nervous system impacts its diverse behaviors.
Such investigations could provide valuable insights into how brain activity leads to behavior in humans. “Our objective is to pinpoint molecular and neural circuit mechanisms that could be applicable across various organisms,” he mentions, highlighting that numerous fundamental biological breakthroughs, such as those related to programmed cell death, microRNA, and RNA interference, were initially identified in C. elegans.
“Our lab has primarily focused on motivated state-dependent behaviors, like feeding and navigation. The mechanisms controlling these states in C. elegans — for instance, neuromodulators — are essentially the same as those in humans. These pathways are evolutionarily ancient,” he states.
Attracted to the laboratory
Born in London to an English father and a Dutch mother, Flavell moved to the United States in 1982 at the age of 2, when his father took on the role of chief scientific officer at Biogen. The family settled in Sudbury, Massachusetts, where his mother worked as a computer programmer and a mathematics instructor. His father later became a professor of immunology at Yale University.
Although Flavell was raised in a science-oriented family, he considered majoring in English upon arriving at Oberlin College. Also a musician, Flavell participated in jazz guitar classes at Oberlin’s conservatory, and he plays the piano and saxophone as well. Nevertheless, courses in psychology and physiology led him to realize that neuroscience was the field that captivated him the most.
“I was immediately enthralled by neuroscience. It combined the rigor of biological sciences with profound questions from psychology,” he remarks.
While attending college, Flavell engaged in a summer research project related to Alzheimer’s disease at a lab in Case Western Reserve University. He continued this project, which entailed analyzing post-mortem tissue from Alzheimer’s patients, during his final year at Oberlin.
“My initial research centered on disease mechanisms. Although my research interests have progressed since then, those early experiences cemented my passion for benchwork: conducting experiments, examining new results, and comprehending their implications,” he reflects.
By the conclusion of college, Flavell described himself as a lab enthusiast: “I simply enjoy being in the lab.” He applied to graduate schools and ultimately attended Harvard Medical School for a PhD in neuroscience. Collaborating with Michael Greenberg, Flavell investigated how sensory experiences and resultant neural activity influence brain development, particularly focusing on a group of gene regulators known as MEF2, which play critical roles in neuronal development and synaptic plasticity.
All that research was conducted using mouse models, but Flavell shifted to studying C. elegans during a postdoctoral fellowship working with Cori Bargmann at Rockefeller University. He aimed to explore how neural circuits dictate behavior, which appeared more manageable in simpler animal models.
“Investigating how neurons across the brain regulate behavior seemed almost insurmountable in a complex brain — understanding all the intricate details of neuronal interactions and how they ultimately produce behavior seemed overwhelming,” he explains. “But I quickly became enthusiastic about studying this in C. elegans because, at that moment, it was the only organism with a complete neural map: detailing every brain cell and the wiring that connects them all.”
This wiring diagram contains around 7,000 synapses within the entire nervous system. In contrast, a single human neuron can form over 10,000 synapses. “Compared to those larger systems, the C. elegans nervous system is astonishingly straightforward,” Flavell points out.
Despite their much simpler construction, nematodes can perform intricate behaviors like feeding, movement, and laying eggs. They even exhibit sleep, form memories, and seek appropriate mating partners. The neuromodulators and cellular mechanisms responsible for these behaviors are akin to those found in humans and other mammals.
“C. elegans has a fairly well-defined, limited array of behaviors, which makes it very appealing for research. You can practically measure everything the organism does and study it,” Flavell shares.
The emergence of behavior
Early in his career, Flavell’s studies on C. elegans unveiled the neural mechanisms that are responsible for the animal’s stable behavioral states. When foraging for food, the worms oscillate between exploring their surroundings and pausing to feed. “The transition rates between these states truly depend on various environmental cues. How favorable is the food environment? How hungry are they? Are there scents suggesting a better food source nearby? The organism comprehensively integrates all these aspects and then modifies its foraging strategy,” Flavell explains.
These stable behavioral states are modulated by neuromodulators such as serotonin. By examining serotonergic regulation of the worm’s behavioral states, Flavell’s lab has been able to reveal how this critical system is organized. In a recent investigation, Flavell and his team published an “atlas” detailing the C. elegans serotonin system. They cataloged every neuron that produces serotonin, every neuron with serotonin receptors, and tracked how brain activity and behavior fluctuate throughout the organism as serotonin is released.
“Our research on how the serotonin system functions to manage behavior has already disclosed fundamental aspects of serotonin signaling that we believe should extend up to mammals,” Flavell asserts. “By investigating how the brain enacts these enduring states, we can tap into core features of neuronal function. With the precision available when studying specific C. elegans neurons and their role in behavior, we can uncover essential elements of neuronal action.”
Simultaneously, Flavell’s lab has also been detailing how neurons throughout the C. elegans brain influence various behavioral aspects. In a 2023 study, Flavell’s lab investigated how alterations in brain-wide activity correlate to behavior. His lab employs specialized microscopes that can move alongside the worms as they navigate, enabling them to simultaneously track all behaviors and assess the activity of every neuron in the brain. Using these findings, the researchers have crafted computational models that accurately represent the connection between neuronal activity and behavior.
This type of research necessitates expertise across diverse fields, Flavell notes. In searching for faculty positions, he sought out an environment that would allow him to collaborate with researchers from various branches of neuroscience, alongside scientists and engineers from different departments.
C. elegans nervous system. I believe that being able to implement such a diverse array of tools results in exciting research findings.”