LA JOLLA (August 27, 2026)—Our brains constantly integrate information about both our internal state and our surroundings to determine how we behave. Much of this coordination depends on neuromodulators—chemical messengers that establish how neurons communicate and function. Understanding how these signals produce distinct responses to different social contexts is crucial to understanding how the brain works.
Remarkably, many of these fundamental molecular mechanisms are conserved across evolution, including in the tiny brain of a fruit fly. That makes fruit flies powerful models to study how neuromodulators influence complex social behaviors such as aggression. One such neuromodulator, octopamine—the functional counterpart of noradrenaline in humans—can regulate a wide range of processes, from aggression and feeding to wakefulness and memory.
But how can one chemical messenger perform so many functions?
Scientists have long suspected that a different set of neurons using the same neuromodulator may be specialized to a specific process, but they lacked the tools to study them separately. As Valentina Fajner, PhD, the co-first author of the study and staff scientist at Salk, describes, "It's like trying to isolate a single instrument within an orchestra."
Now, Salk researchers have developed a genetic toolkit that allows them to do just that. The study, published in Current Biology on August 27, 2026, shows that distinct neuronal subtypes, identified using the genetic toolkit, can produce different—and even opposing—effects, including pinpointing neurons that suppress aggression.
How can one brain chemical perform so many different jobs?
Octopamine provides an ideal system for exploring neuronal function in fruit flies because it regulates a wide range of behaviors, including aggression. According to Fajner, "Socially, aggression can be beneficial—for defending territory or accessing resources—but it can also be risky."
Octopamine itself presents a paradox in that regard. Prior work has linked octopamine to increased aggression, while other evidence suggests it can also decrease aggression. This intriguing phenomenon led Salk scientists to hypothesize that, rather than all octopamine-associated neurons performing the same job, different subgroups may contribute to different functions.
Until now, the researchers couldn't test this hypothesis because they lacked the tools needed to distinguish individual neuronal subgroups within the octopamine system. "Virtually, no single gene is sufficient for specifying one single cell type," says Kenta Asahina, PhD, associate professor at Salk and senior author of the study.
To overcome this limitation, the team first screened several hundred genetically engineered fruit flies to identify common expression patterns. Then, they developed a genetic toolkit that uses overlapping genetic markers to pinpoint specific groups of neurons. By narrowing down where those markers overlap, the researchers could manipulate distinct subgroups of the octopamine system—in some cases, targeting just a single pair of neurons.
"Before, it was like trying to isolate a single instrument within an orchestra," says Fajner. "Now, we can listen to one instrument at a time."
What can individual neurons tell us about aggression?
Using their new toolkit, the researchers deconstructed what individual groups of neurons within the octopamine system do, and began to unravel the apparent paradox—how can the same neuromodulator (octopamine) both promote and suppress aggression?
They identified one neuronal subgroup, called ASM4, that helps suppress aggression in fruit flies housed in groups. After identifying ASM4 neurons, the researchers looked for a potential chemical explanation for their ability to suppress aggression. Octopamine is produced from another neuromodulator called tyramine. They found ASM4 neurons appear unable to convert tyramine into octopamine. Because octopamine and tyramine can have opposing physiological effects, the researchers hypothesize that ASM4's unique role may depend on both the type of neuron and the chemical signal it releases.
Fajner was particularly intrigued by another finding: ASM4 suppressed aggression in both male and female fruit flies, despite aggression typically differing between the sexes. "This neuron itself is important for both," says Fajner. "So, it's a more universal control of aggression."
The toolkit also identified another group of neurons with a completely different role—helping flies track visual motion during flight. Together, the findings show how neurons within the same neuromodulatory system can perform very different jobs. Or, as Fajner puts it, "one modulator, but distinct neurons, distinct jobs."
What could a fruit fly's brain teach us about the human brain?
Many fundamental nervous system mechanisms are conserved across many species. The neuromodulator octopamine in a fruit fly is functionally related to noradrenaline, an important human neuromodulator associated with fight-or-flight and other behavioral responses.
However, human systems are far more complex, which is precisely why Salk researchers see value in starting with the simpler fruit fly nervous system; first, uncover the fundamental principles of neuromodulation, then ask whether those principles extend to more complex organisms.
The next step in their research is to map the input and output signals in the octopamine/tyramine system in fruit flies to understand the larger neuronal circuit and how different social stimuli promote or suppress aggression. Ultimately, dissecting these mechanisms in flies could provide a game plan for understanding the molecular organization of the human noradrenergic system and how signaling failures contribute to altered brain function.
"Almost every brain cell is different," says Asahina. "We can't really study precisely how the brain works if we are handling a group of neurons as a single unit. Now, we can begin asking what each specific neuron is actually doing."
Other authors and funding
Other authors include co-first author Lesly Palacio Castillo of UC Los Angeles, as well as Ezgi Yalbir and Shafana Shahul of Salk and UC San Diego; Bruce Ruff, Victor Junmyung Lee, Audrea Koger, Juliet Heller, Kenichi Ishii, Veronica Morad, and Max Trask of Salk; and Carter Warren, Giovanni Frighetto, and Mark Frye of UC Los Angeles.
This work was supported by NIH NIMGS R35GM119844 and NIH NINDS 530 R01NS120984.
This press release was written by Bhaswati Sinha, PhD.
About the Salk Institute for Biological Studies
The Salk Institute is an independent, nonprofit research institute founded in 1960 by Jonas Salk, developer of the first safe and effective polio vaccine. The Institute's mission is to drive foundational, collaborative, risk-taking research that addresses society's most pressing challenges, including cancer, Alzheimer's disease, and agricultural vulnerability. This foundational science underpins all translational efforts, generating insights that enable new medicines and innovations worldwide. Learn more at www.salk.edu .
