Nematodes, minuscule worms that are partial to rotting fruit, haven't been blessed with a lot of brain cells to rub together. But even with the few neurons they do have, these worms do amazing things: find food, avoid danger.
Killing off even a single brain cell can prevent a worm from turning environmental cues into a coherent picture of its surroundings. When scientists damage a neuron at the center of a worm's odor-sensing circuit, it wanders aimlessly, unable to move toward a pleasing scent even though its neuron that detects the smell still works.
Every animal must turn sensation into perception. How our neural circuits perform this magic is mostly mysterious, but nematodes are helping scientists pull back the curtain. As a first step, scientists at Fred Hutchinson Cancer Research Center and the Hebrew University of Jerusalem are breaking and rewiring neural circuits to better understand how they shape an animal’s understanding of its world.
In new work published Jan. 19 in the journal Cell Systems, they showed that in nematodes, researcher-created connections between nerve cells can form new routes to bypass neural damage by turning minor paths of neural information flow into major roads. The team also found that the new synapses could be used to amplify weak signals and strengthen the damaged circuit even when it wasn’t bypassed.
“If you have a broken [neural] circuit, there are many ways that you can bypass that lapse,” said Dr. Jihong Bai, a Hutch neuroscientist who led the study.
The work focused on molecular connections, called electrical synapses, that pass electrical impulses between neurons without relying on a chemical intermediate. Bai’s team can create new, highly specific electrical synapses in nematodes by using the proteins that vertebrates use to form these connections, which differ from those that have evolved in invertebrates like worms. His lab is one of only a few in the world genetically engineering worms to produce these synthetic electrical synapses.
The results also show the feasibility of repairing neural circuits using genetics to create new connections, he said. (It only works when neurons are in very close proximity, making it unlikely that the strategy could be applied to critically damaged neural circuits in humans any time soon.) Of greatest interest to Bai, the tool could also be used to ask more fundamental questions about how animals process information in neural circuits to create their perception of the world around them.
The study was co-led by Bishal Upadhyaya, a former technician in Bai’s lab, and Dr. Ithai Rabinowitch, previously a postdoc on Bai’s team and now a faculty member at the Hebrew University of Jerusalem in Israel.
Nematodes are a brain-mapper’s dream come true: Each tiny worm has exactly the same number of cells, including nerve cells. Because of this, scientists have been able to create an incredibly detailed map of nematodes’ neural networks: They know how many nerve cells there are, which other neurons each connects to, as well as each neuron’s primary function.
Neuroscientists like Bai use nematodes to understand the link between brain and behavior because their neural circuits are as simple as they come. In people, whole brain areas work to create perception and behavior based on incoming sensory information; in a worm, the same circuit is made up of just a few neurons, making it much easier to study.
Information flows along neurons in the form of electricity, and connections between neurons come in two flavors. Electrical synapses are simple connections between neurons that allow an electrical pulse to flow from one nerve cell to another. Chemical synapses convert chemical information, transmitted between neurons in the form of molecules like neurotransmitters, into electrical information.
Bai’s team chose to use the simpler electrical synapses to forge new connections between nerve cells. They took advantage of the fact that a protein called innexin forms electrical synapses in invertebrates like worms, while a completely different protein, called connexin, forms these synapses in vertebrates like humans. Worms can be genetically reprogrammed to produce vertebrate connexin; if the neurons expressing connexin are close enough, they form new electrical synapses.
Rabinowitch had previously shown that neural information can flow between nematode neurons connected by vertebrate connexin. Using these synthetic synapses to link previously unconnected neurons, Bai and his team had been able to modify worm behavior, including making worms move toward chemicals they usually avoid.
Now, he, Rabinowitch and Upadhyaya wanted to see if their synthetic electrical synapses would allow neuronal information to bypass a damaged point in a neural circuit. Other strategies to circumvent damage in a neural circuit, such as to improve motor rehabilitation in paralyzed patients, have used connections to computers to reroute information flow. Instead, the team wanted to try a genetic approach, prompting specific neurons to forge new connections with each other.
The team focused on a well-characterized neural circuit that nematodes use to smell and move toward attractive odors in their environment. To tantalize worms in lab dishes, scientists use chemicals that give almonds and bananas their characteristic scents. Once the circuit’s odor-sensing neuron detects one of these chemicals, it signals to several intermediary neurons. These intermediary neurons, or interneurons, ultimately direct the information that a scent has been detected to the motor neurons that tell the worm’s muscles to move toward the odor.
The odor information mostly flows from the odor-sensing neuron through a first interneuron called AIA and then to another interneuron called AIB. However, odor-sensing neurons do make some direct connections to AIB neurons.
Rabinowitch and Upadhyaya genetically manipulated worms to force the AIA neurons to die off. Worms whose AIA neurons have withered away become very bad at moving toward attractive odors. Next, the researchers wanted to see if strengthening the connection between the odor-sensing neurons and AIB interneurons could bypass damaged AIA neurons and restore worms’ ability to respond to appealing odors. They genetically manipulated worms such that the odor-sensing neuron and AIB neurons both produced vertebrate connexin. The connexin brought the neurons together in new ways, creating many new connections through which electrical information could pass between them.
The scientists found that when they added synthetic connections between the odor-sensing neuron and AIB interneurons in worms with damaged AIA interneurons, their ability to respond to the odors in their environment was restored.
Just as Bai commutes along a highway to get to his Seattle-area Hutch office, neural signals also travel along major routes.
“If I’m driving along I-5 to my office, if there’s traffic somewhere, I can’t get to the Hutch,” he said.
But like cars that exit the highway for side streets, neural information can also flow along minor routes. The synthetic connections that Bai’s team used helped turn these information byways into information highways, allowing the circuit to bypass a blockage.
Upadhyaya, Rabinowitch and Bai also discovered that the synthetic synapses can restore odor-sensing behavior in worms with damaged AIA neurons even when neural information flow continues along its usual routes.
Unexpectedly, Bai and his team found they could restore some odor-sensing behavior in worms by making either the odor-sensing neuron or the AIB neuron produce connexin. But how could the circuit be circumvented if the synapses weren’t creating a new information highway between the odor-sensing neuron and AIB?
As it happens, though worms have no arms or legs, they do have right-hand and left-hand versions of each neuron (a phenomenon also seen in many animals and humans). The team found that connecting a neuron to its mirror self (either odor-sensing neuron to odor-sensing neuron or AIB to AIB) amplifies weak electrical signals in those neurons.
This makes it possible for connected odor-sensing neurons to send a strong-enough signal to AIB neurons to make up for loss of AIA neurons. And if AIB neurons are connected to each other, they can amplify the weak signal received from odor-sensing neurons. In these cases, amplifying the electrical signals passing along neurons can correct the worms’ damaged odor-sensing behavior even if the signals are still moving along informational byways.
While the study’s results show the feasibility of bypassing neural damage by forging new connections between nearby neurons, Bai is interested in even more basic questions.
“The most fundamental question in the field is, 'How do you generate perception?'” Bai said. “If we think about the human mind, it's a bridge between our environment and all things. But that's so fundamental to all animals: They all have to make decisions based on the information that they collect.”
His synthetic synapses could allow researchers to manipulate how worms sense — and respond to — anything from odor to temperature, and provide insights into how neural circuits process incoming information. Right now, the electrical synapses allow electrical signals to flow in both directions between neurons. To understand information processing in neural circuits, researchers will first have to develop synthetic synapses that only allow information to flow in one direction, he said.
Neuroscientists have done a lot to identify the molecules that carry information along neural networks, Bai said.
“But if you ask somebody how our mind really generates what is attention, what is distraction — I think it's very hard for anyone to have any explanation for that,” he said.
The ability to engineer synthetic synapses in living animals expands scientists’ toolbox as they seek answers, and, Bai said, "may eventually help us understand how the brain produces behavior, and what we understand to be the mind."
The study was funded by the National Institute of General Medicine, the National Institute on Deafness and Other Communication Disorders, the Hartwell Innovation Fund and the Israel Science Foundation.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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