Unraveling Intricate Behaviors Through the Lens of a Simpler Organism | MIT News

The roundworm C. elegans is a straightforward organism possessing precisely 302 neurons within its nervous system. The intricate connections among these neurons have been thoroughly mapped, enabling researchers to investigate how they collaborate to produce the varied behaviors of the creature.

Steven Flavell, an associate professor of brain and cognitive sciences at MIT and a researcher with the Picower Institute for Learning and Memory at MIT and the Howard Hughes Medical Institute, utilizes the worm as a model to analyze motivated behaviors such as feeding and navigation, with the aim of illuminating the fundamental mechanisms that may also govern similar behaviors in other species.

Recent research from Flavell’s lab has revealed neural systems that underpin adaptive modifications in the worms’ feeding behavior, alongside mapping how the activity of each neuron in the organism’s nervous system influences the various behaviors of the worms.

Such investigations could assist scientists in understanding how brain activity produces behavior in humans. “Our goal is to uncover molecular and neural circuit mechanisms that may apply across various species,” he states, emphasizing that numerous significant biological breakthroughs, including those related to programmed cell death, microRNA, and RNA interference, were initially identified in C. elegans.

“Our lab primarily focuses on motivated state-dependent behaviors, such as feeding and navigation. The mechanisms involved in regulating these states in C. elegans—for instance, neuromodulators—are fundamentally the same as those in humans. These pathways are evolutionarily conserved,” he explains.

Attracted to the laboratory

Flavell was born in London to an English father and a Dutch mother, relocating to the United States in 1982 at the age of 2, when his father assumed the role of chief scientific officer at Biogen. The family resided in Sudbury, Massachusetts, while his mother worked as a computer programmer and mathematics instructor. His father subsequently became a professor of immunology at Yale University.

Although Flavell was raised in a scientific household, he contemplated majoring in English upon entering Oberlin College. A musician as well, he took jazz guitar courses at Oberlin’s conservatory and also plays the piano and saxophone. However, after attending courses in psychology and physiology, he realized that the discipline that captivated him the most was neuroscience.

“I was instantly enamored with neuroscience. It blended the precision of the biological sciences with profound inquiries in psychology,” he shares.

During his college years, Flavell participated in a summer research project focused on Alzheimer’s disease in a laboratory at Case Western Reserve University. He continued examining post-mortem Alzheimer’s tissue throughout his final year at Oberlin.

“My initial research centered on mechanisms of disease. While my research interests have evolved over time, those early experiences truly ignited my passion for laboratory work: conducting experiments, observing brand-new results, and striving to comprehend their significance,” he notes.

By the conclusion of his undergraduate studies, Flavell labeled himself as a lab enthusiast: “I just adore being in the laboratory.” He applied to graduate programs and ultimately attended Harvard Medical School for a PhD in neuroscience. Collaborating with Michael Greenberg, Flavell investigated how sensory experiences and resulting neural activity influence brain development, specifically focusing on a family of gene regulators known as MEF2, which are crucial for neuronal development and synaptic plasticity.

Although all of this research utilized mouse models, Flavell shifted his focus to studying C. elegans during a postdoctoral fellowship under Cori Bargmann at Rockefeller University. His aim was to explore how neural circuits regulate behavior, which appeared to be more manageable in simpler animal models.

“Investigating how neurons throughout the brain dictate behavior seemed nearly unmanageable in a large brain—comprehending all the intricacies of how neurons engage with each other and ultimately induce behavior appeared overwhelming,” he asserts. “However, I rapidly became excited about studying this in C. elegans because, at that time, it was still the only organism with a complete blueprint of its brain: a diagram of every brain cell and their interconnections.”

This wiring schematic includes around 7,000 synapses in the complete nervous system. In contrast, a single human neuron can create over 10,000 synapses. “In comparison to those more extensive systems, the C. elegans nervous system is astonishingly simplistic,” Flavell explains.

Despite their significantly simpler structure, roundworms are capable of performing complex behaviors such as feeding, movement, and egg-laying. They can even sleep, develop memories, and select suitable mating partners. The neuromodulators and cellular mechanisms that prompt these behaviors are analogous to those found in humans and other mammals.

“C. elegans has a relatively well-defined, modest set of behaviors, making it appealing for research. You can effectively measure nearly everything the organism does and examine it thoroughly,” Flavell states.

The emergence of behavior

Early in his career, Flavell’s investigations into C. elegans disclosed the neural systems that underpin the creature’s consistent behavioral states. When worms search for food, they switch between consistently exploring their surroundings and pausing to eat. “The rates of transition between these states rely heavily on various environmental cues. How favorable is the food environment? How hungry are they? Are there odors signaling a more rewarding food source nearby? The organism integrates all these factors and subsequently modifies its foraging strategy,” Flavell explains.

These persistent behavioral states are regulated by neuromodulators such as serotonin. Through examining the effects of serotonergic regulation on the worm’s behavioral states, Flavell’s lab has been able to uncover the organization of this crucial system. Recently, Flavell and his team published an “atlas” of the C. elegans serotonin system, identifying every neuron that synthesizes serotonin, every neuron with serotonin receptors, and the ways in which brain activity and behavior alter throughout the organism as serotonin is released.

“Our investigations into how the serotonin system functions to regulate behavior have already disclosed fundamental aspects of serotonin signaling that we believe should generalize all the way to mammals,” Flavell remarks. “By examining how the brain executes these enduring states, we can tap into these fundamental characteristics of neuronal function. With the level of detail achievable when studying specific C. elegans neurons and their role in behavior, we can reveal essential features of neuronal activity.”

Simultaneously, Flavell’s lab has also been charting how neurons throughout the C. elegans brain govern various behavioral aspects. In a 2023 study, Flavell’s lab investigated how modifications in brain-wide activity correlate with behavior. His team employs specialized microscopes that can track the worms as they explore, enabling them to concurrently monitor every action and gauge the activity of every neuron in the brain. Leveraging this data, the researchers constructed computational models that accurately reflect the connection between brain activity and behavior.

This line of research necessitates proficiency in numerous areas, Flavell emphasizes. When seeking faculty positions, he aspired to find an environment where he could collaborate with researchers from diverse neuroscience fields, as well as scientists and engineers from various departments.

“Being at MIT has allowed my lab to be significantly more multidisciplinary than it could have been elsewhere,” he states. “My lab members come from undergraduate backgrounds in physics, mathematics, computer science, biology, and neuroscience, and we utilize tools from all of these domains. We design microscopes, construct computational models, and develop molecular techniques to manipulate neurons in the C. elegans nervous system. I believe that utilizing all these varied tools leads to groundbreaking research outcomes.”