The billions of neurons that make up our brains are linked together to form intricate networks. Synaptic transmission is the method by which they communicate with one another by exchanging chemical and electrical signals known as neurotransmitters and action potentials.
Chemical neurotransmitters are produced from one neuron, diffuse to the others, and then reach the targeted cells, producing a signal that stimulates, inhibits, or modifies the activity of the cellular level. When processing sensory data, making judgments, and producing behavior, the brain depends on the strength and timing of these signals.
Controlling the connections between neurons might enable us to better understand and cure neurological ailments, restructure or fix damaged neural circuit failures, enhance our capacity for learning, or broaden our repertoire of behaviours.
Neuronal activity can be controlled in a variety of ways. Using medications that change the concentrations of chemical neurotransmitters in the brain and impact neuronal activity is one option. Another strategy is to activate or inhibit the neurons by electrically stimulating particular brain areas. A third option is to regulate brain activity with light.
Using photons to control the neuronal activity
It has been attempted to use light, a relatively recent method, to control neural activity. It entails genetically altering neurons to make the target cells express light-sensitive proteins, ion channels, pumps, or certain enzymes. Researchers can more precisely control the activity of certain populations of neurons using this method.
But there are some restrictions. As light scatters within the brain tissue, it must be given very close to the neurons in order to acquire sufficient resolution at the level of the synapsis. As a result, it often necessitates outside interventions and is intrusive. Additionally, the level of intensity required to reach the targeted cells may be damaging to them.
In order to address these issues, a group of ICFO researchers present in Nature Methods a system that regulates neural activity by using photons rather than chemical neurotransmitters.
The ICFO researchers Montserrat Porta, Adriana Carolina González, Neus Sanfeliu-Cerdán, Shadi Karimi, Nawaphat Malaiwong, Aleksandra Pidde, Luis Felipe Morales and Sara González-Bolívar led by Prof. Michael Krieg together with Pablo Fernández and Cedric Hurth, have developed a method to connect two neurons by using luciferases, light-emitting enzymes, and light-sensitive ion channels.
They created and put to the test a system called PhAST, or Photons As Synaptic Transmitters, in the Caenorhabditis elegans roundworm, a popular model organism for studying many biological processes. PhAST uses the enzymes luciferases to send photons, rather than chemicals, as communicators between neurons, simulating how photons are used by bioluminescent animals.
The team had previously created a new microscope by streamlining a fluorescence one, removing all the unnecessary optical components like filters, mirrors, or the laser itself, assisted with machine learning to reduce the noise coming from the external sources of light. This allowed them to study bioluminescence and see the photons.
Replacing chemical neurotransmitters with photons
The team genetically altered the roundworms to have defective neurotransmitters, rendering them unresponsive to mechanical stimuli, in order to investigate if photons could encode and convey the activity status between two neurons. They sought to use the PhAST method to fix those flaws.
Second, they created luciferases, which are light-emitting enzymes, and they chose ion channels that were light-sensitive. They created a device that applied mechanical stress to the animal’s nose while also monitoring the activity of calcium, one of the most significant ions and intracellular messengers, in the sensory neurons, in order to track the information flow.
The PhAST system was then put to the test in a number of studies, and it was successful in using photons to convey neural states. They were able to repair a damaged circuit by establishing a new transmission between two disconnected cells. Additionally, they altered the animals’ responses to olfactory stimuli, turning attractive behaviour into unpleasant behavior, and analysed the dynamics of calcium during egg-laying.
These findings show that the PhAST system enables the synthetic alteration of animal behaviour and that photons can actually behave as neurotransmitters and enable communication between neurons.
The potential of light as a messenger
Future potential applications for light as a messenger are numerous. It has wide-ranging implications for both basic research and clinical applications in neuroscience because photons can be used in different kinds of cells and by various animal species.
With new techniques for imaging and mapping brain activity with higher spatial and temporal resolution, the use of light to control and monitor neuronal activity can aid researchers in better understanding the underlying mechanisms of brain function and complex behaviors, as well as how different brain regions communicate with one another. Additionally, it might aid in the development of novel therapies and, for instance, aid in the mending of harmed brain connections without the need for intrusive operations.
The technology still has some drawbacks, though, and future advances in the engineering of bioluminescent enzymes and ion channels, or in the targeting of molecules, would enable non-invasive optical control of neuronal function with greater specificity and accuracy.
