Researchers at The Institute of Photonic Sciences (ICFO) demonstrated that photons, acting as neurotransmitters, can enable communication between neurons. The researchers developed an all-optogenetic, synaptic transmission system that enabled synthetic signaling between unconnected neurons and the generation of synaptic circuits. The team’s findings could lead to therapies that use light instead of chemicals or drugs to restore communication between nerve cells in the treatment of diseases such as Alzheimer’s and Parkinson’s. In addition to treating neurological disorders, the team’s approach could potentially be used to rewire damaged neural circuits and improve learning. The Photons as Synaptic Transmitters (PhAST) system connects two neurons by using light-emitting enzymes and light-sensitive ion channels. The researchers tested the PhAST system on the roundworm model C. elegans and showed that photon-based synaptic transmission can facilitate the modification of animal behavior. After genetically modifying the roundworms to have faulty neurotransmitters, which made the worms insensitive to mechanical stimuli, the researchers engineered a luciferase enzyme to generate light inside the worms and a specially designed microscope for viewing the light being emitted by the worms. They also selected ion channels for the postsynaptic cells. The channels are highly sensitive, so that very little light is needed to open them. A single worm in which the flavor of chemical neurotransmitter has been replaced by the color of the photon. The cyan neuron is presynaptic to the yellow and red and thus controls their activity using cyan-colored light. Courtesy of ICFO. The genetically engineered enzyme introduced into the worms as a light source requires calcium and the binding of a co-factor to emit light. The calcium increase occurs when the presynaptic cell activates, so the light is only on when the presynaptic neuron is on as well. When the light source and the presynaptic cell are activated, blue light is emitted from the presynaptic cell. The ion channel in the postsynaptic cell senses the blue light and activates the postsynaptic cell, which then transmits the information to the downstream pathway. To follow the information flow, the researchers developed a device that delivered mechanical stresses to the animals’ noses, while at the same time measuring the calcium activity in the sensory neurons. To acquire the dim light signals coming from the neurons, they built a microscope with a sensor that is strong enough to detect a faint signal from just a few photons. The researchers then took a default model of an existing microscope and removed the optical elements that were not needed for bioluminescence and that could interfere with imaging. The researchers also used artificial intelligence to enhance the bioluminescence imaging capabilities of the microscope. In experiments, the researchers established a new transmission between two unconnected cells, restoring neuronal communication in a defective circuit. They also suppressed the worms’ response to a painful stimulus, and they switched the worms’ response to an olfactory stimulus from attractive to aversive behavior. The researchers also used PhAST to study the calcium dynamics of the temporal pattern generator in a motor circuit for ovipositioning. The experimental results showed that the PhAST system can facilitate the modification of animal behavior. Further, the PhAST system could help researchers better understand the underlying mechanisms of brain function and complex behaviors, and how different brain regions communicate with each other. It could lead to new ways to image and map brain activity with higher spatiotemporal resolution. Limitations to the widespread use of the technology remain. Further improvements in the engineering of the bioluminescent enzymes and the ion channels and in the targeting of molecules would allow greater optical control of the neuronal function, with higher specificity and precision. However, the ICFO study demonstrated that chemical neurotransmitters can be replaced with light to overcome malfunctioning in neural circuits and help neurons communicate again. Now that the technology has been shown to work in vivo in worms, a potential next step could be use of the PhAST system for the study of more complex neural circuits. The research was published in Nature Methods (www.doi.org/10.1038/s41592-023-01836-9).