Summary: Scientists turned to the tiny roundworm Caenorhabditis elegans as a model organism to explore how neural signals travel and are processed within the brain’s network.
Using advanced techniques such as optogenetics, they followed the signal flow in real time to trace their paths, neuron by neuron. Contrary to predictions from the worm’s connectome map, they discovered important “wireless signals” related to molecular release that influence neuronal dynamics. This important research takes a step towards understanding more complex brains.
Important facts:
- The team studied C. elegans, a transparent worm with 302 neurons, making it an ideal model for mapping signal flow in the brain.
- Using groundbreaking optogenetics, they visualized signaling in real time and discovered an unexpected ‘wireless signal’ using neuropeptides.
- Their results contradict current predictions based on the insect connectome and reveal molecular details for understanding neuronal responses.
Source: Princeton
Do we actually know how the brain works?
In recent decades, scientists have made great strides in their understanding of this incredibly complex organ. They now have a deeper understanding of the brain’s cellular neurobiology and a broader insight into its neural connections and components. Yet many important questions remain unanswered. This is why the brain is one of the great and fascinating mysteries of science. The team consisted of Francesco Randi, Sophie Divali, and Anuj Sharma and was led by Andrew Leifer, a neuroscientist and physicist.
The brain is fascinating and mysterious, Leifer said. “Our team is interested in how groups of neurons process information and produce actions.” The first step in answering the question of how information is processed by a network of communicating neurons was for Leifer and his team to find a suitable organism that could be easily manipulated in the laboratory.
It turned out to be C. elegans, a non-segmented, non-parasitic roundworm that scientists have studied for decades and is considered a “genetic model organism.” Model organisms are often used in laboratories to help scientists understand biological processes because their anatomy, genetics, and behavior are well known.
“These insects are therefore very easy to study. In fact, they are perfect for experiments because they strike the perfect balance between simplicity and complexity.” Importantly, Leifer added, C. elegans was the first organism to have its brain’s wiring completely mapped. That means scientists have compiled a complete diagram of all its neurons and synapses, the places where neurons physically connect and communicate.
In neuroscientific jargon, this field is called “connectomics.” The complete map of neural connections in an organism’s brain is called the “connectome.” One of the main goals of connectomics is to discover the specific neural connections responsible for specific behaviors.
This field of research, called “optogenetics,” has revolutionized many aspects of experiments in biological neuroscience. Instead of the more traditional approach of sending currents to neurons through electrodes, triggering a response, optogenetics uses light-sensitive proteins from specific organisms and implants those cells into another organism, allowing researchers to control that organism’s behavior or response using light signals.
Similarly, other proteins can be used to light up one neuron and send a signal to another. This suggests two important things for laboratory experiments: an organism responds to the presence of light, and one neuron lights up when it receives a signal from another. This has allowed researchers to study neuronal interactions visually.
These optical instruments allowed Leifer’s team to begin the difficult task of understanding how information travels through the insect’s brain. The goal was to understand how signals travel directly through the insect’s brain. Therefore, it was necessary to measure each neuron. This involved isolating one neuron at a time, shining light on it to ‘activate’ it, and then observing how the other neurons responded.
Leifer explained that the team examined the brain on a neuron-by-neuron basis, selectively activating or disrupting individual cells and then monitoring how the entire network responded. This approach enabled them to chart the pathways along which signals travel through the brain’s circuitry.
“This was an approach that had never been done before at a whole-brain level,” Leifer added.
In total, Leifer and his team performed nearly 10,000 stimulation events, measuring more than 23,000 pairs of neurons and their responses a task that took seven years from conception to completion.
Leifer and his team’s research provides the most comprehensive explanation yet of how signals travel through the brain. Scientists studying C. elegans have thus gained a wealth of knowledge about how specific signals work in the worm’s brain. The research is expected to yield new insights that will help advance basic research.
“We found that in many cases, many of the molecular details that are not visible in the wiring diagram are actually very important in predicting how the network should respond,” Leifer said.
Ultimately, the researchers believe their work will have an important impact in that other neuroscientists studying this and similar phenomena can develop better models for understanding the brain as a system.
“Through our research, we have provided a very important piece of the missing puzzle,” Leifer said.
Funding: This work was funded primarily by a National Institutes of Health New Innovator Award, a National Science Foundation Career Award, and a Simon Foundation Award. It also received funding from the NSF Frontiers in Physics Center, which supports Princeton University’s Center for the Physics of Biological Function.
Abstract
Atlas of neuronal signal propagation in Caenorhabditis elegans
Determining how neuronal functions arise from network properties is a fundamental problem in neuroscience.
To explore how the structure of the nervous system relates to its function, the researchers examined signal transmission across 23,433 neuron pairs in the head region of the nematode Caenorhabditis elegans. They achieved this by combining direct optogenetic activation of individual neurons with simultaneous whole-brain calcium imaging, allowing them to track neural activity patterns in unprecedented detail.
The researchers mapped a functional atlas of neural communication by measuring the direction (excitatory or inhibitory), strength, timing, and causal flow of signals between neurons. They found that actual signal propagation patterns differed from predictions made by standard physiological models.
By studying mutant organisms, they discovered that extrasynaptic signaling—communication occurring outside traditional synaptic connections—was a key factor in these differences. In several cases, signaling relied on dense-core vesicles to release neuropeptides, sometimes within fractions of a second, producing strong calcium responses even without direct synaptic contact. The team suggests that in such scenarios, these neuropeptides act much like classical neurotransmitters. Their atlas more accurately predicted spontaneous neuronal activity than physical models, highlighting that both synaptic and extrasynaptic signaling shape brain dynamics on short timescales, and that tracking these signals is essential for understanding neural function.
