Synthetic rewiring of damaged neural circuits

From the Bai lab, Basic Sciences Division

Neural circuits control all aspects of thought, sense, and behavior. The networks of neurons that make up these circuits, carefully linked to one another by synaptic connections, serve to transmit information throughout the body. In this sense, the neurons within a circuit can be considered as a sort of cellular bucket brigade – a series of stationary cells, arranged one after the other. Neuron A hands information to nearby neuron B, which hands information to nearby neuron C, and on down the line until it gets where it ultimately needs to go. Or perhaps, if you prefer, consider these neurons as engaging in a high stakes game of telephone – neuron A whispers in the ear of neuron B, who then whispers in the ear of neuron C, et cetera. In either case, consider, then, what happens if one individual (say, neuron B) is removed from the line. The chain is broken. Neuron A cannot reach neuron C to bridge the gap. Information transfer stalls and circuit function is lost. This thought experiment is far from hypothetical. Neuronal loss, due to injury or disease, is a common occurrence, and it can cause breaks in circuits and significant impairments. Dr. Jihong Bai, associate professor in the Basic Sciences Division at Fred Hutch, is interested in how neural circuits are constructed, damaged, and repaired. In new research published in Cell Systems, Dr. Bai’s Lab, led by former postdoctoral fellow Ithai Rabinowitch (now a principal investigator at the Hebrew University of Jerusalem), successfully repaired a damaged circuit by genetically rerouting the flow of information between cells.

As a model for this project, the lab used a simple and well-defined chemosensory circuit in the nematode worm, C. elegans, which is used by the worm to sense chemicals in the environment and migrate towards them in a process known as chemotaxis. Central to this circuit is a neuron called AIA; this neuron receives information for the odor-sensing neuron AWC, and then passes that information on to the downstream AIB neurons to elicit movement (AWC  AIA AIB). The authors found that genetically killing AIA neurons impaired AIB activation and chemotaxis, indicating a failure to convey information properly through the circuit. However, they hypothesized that, if they could connect AWC and AIB, they could circumvent the need for AIA and restore the broken circuit. Electrical synapses are a type of cell-cell connection formed by gap junctions, which act essentially as a molecular skybridge to connect two cells. These structures are formed by well-defined interactions between connexin proteins in the two cells. Thus, the authors expressed an exogenous connexin gene in AWC and AIB, hoping that the connexin proteins in the two cells would find each other and establish a new gap junction. Indeed, this approach was enough to restore information flow through the damaged circuit, and animals with this synthetic bypass exhibited a restoration of chemotaxis, in fact even exceeding that of wild-type worms. In synthetically manipulating these circuit connections, however, the authors got a bit more than they intended. The first indication that something unexpected was going on was that expressing connexin in just one of the neurons – AWC or AIB – restored chemotaxis, even though this condition could not lead to an AWC-AIB connection. The answer to this conundrum arose from the fact that, in this bilaterally symmetric animal, two copies of this circuit, and all its component neurons, are present – one on the left side, one on the right.  Thus, connexin expression in one of these pairs generated new gap junctions between the left and right neurons. This so-called lateral coupling served to amplify the weakened signal that was able to make its way through the damaged circuit enough to restore function. This observation also explained the enhanced chemotaxis they observed when they synthetically connected AWC and AIB: by bypassing the break within the circuit, and further amplifying the signal through lateral coupling, they likely expanded the gain control of a circuit to allow enhanced chemotaxis.

In some cases, the brain is capable of rewiring broken circuits all on its own. “Remarkably”, Dr. Bai notes, “occasionally, the brain is capable of spontaneous recovery from such damages through mechanisms of synaptic plasticity.” He explains that, in the past, most work in this area has focused on helping the brain perform this self-repair. But the brain’s natural plasticity has its limits. With their current work, Bai says, “Our study shows another way. We found that we could recover the functionality of damaged circuits in vivo by designing new synaptic connections, acting as a synaptic bypass for rerouting information flow in the circuit”. And perhaps, in so doing, also bypass our brains’ own limitations. Now the lab is working to generate additional functional synaptic bypasses in order to identify general design principles, and to establish whether these principles can be applied to similar ends in animals with more complex nervous systems.

synthetic bypass circuit schematic
An illustrative representation of the normal (left) and damaged (right) chemotaxis circuit, and the synthetic synapse engineered to bypass the damage, in the C. elegans nematode worm.

This work was supported by the Hartwell Innovation Fund, the National Institutes of Health, and the Israel Science Foundation.

Fred Hutch/UW Cancer Consortium member Jihong Bai contributed to this work

Rabinowitch I, Upadhyaya B, Pant A, Galski D, Kreines L, Bai J. (2021) Circumventing Neural Damage in a C. elegans Chemosensory Circuit Using Genetically Engineered Synapses. Cell Systems 12, 1-9.