Can a protein found in a mosquito lead to a better understanding of how our own brain works? Professor Ofer Yizhar and his team at the Department of Neurobiology at the Weizmann Institute of Science took a photosensitive protein derived from mosquitoes and used it to design an improved method to study messages transmitted from neuron to neuron in the brains of mice. . This method, reported today in Neuron, could potentially help scientists solve age-old brain mysteries that could pave the way for new and improved therapies to treat neurological and psychiatric conditions.
Yizhar and his lab team are developing so-called optogenetic methods – research techniques that allow them to “reverse engineer” the activity of specific brain circuits in order to better understand their function. Optogenetics uses proteins called rhodopsins to control the activity of neurons in the brain of mice. Rhodopsins are light sensitive proteins – they are best known for their role in organs like the retina rather than in dark areas inside the body. But the rhodopsins in Yizhar’s mouse brains allow him to control the activity of specific neurons when he and his team shine a tiny beam of light into the mouse’s brain. He is particularly interested in communication between neurons: what signals pass through synapses, these gaps on which brain signals move? “We can detect the presence of different neurotransmitters, but different neurons ‘read’ these neurotransmitters differently,” he says. “Optogenetics allows us not only to see ‘the ink’, but also to actually decipher the ‘message’.”
Although optogenetic methods have produced a number of groundbreaking results in laboratories around the world in recent years, they can be a bit finicky. In particular, the rhodopsins used for optogenetic studies tend to be imperfect when it comes to controlling the activity of synapses, the tiny junctions between neurons.
Yizhar and a large team of his trainees, including Dr Mathias Mahn, Dr Inbar Saraf Sinik and Pritish Patil, believed they could create a better version of rhodopsins than are currently available. “We decided to look around and see what natural solutions exist,” Yizhar says. And nature, it turns out, contains a multitude of variations on the rhodopsin molecule – not only in the eyes of animals, but also fish, insects and even mammals carry them in various parts of the body; some possibly to regulate their circadian cycles, others for purposes as yet unknown. So the team started with a long list of potential rhodopsin proteins, and their first job was to assess which ones were most likely to meet their experimental needs, which mainly included light-dependent proteins capable of modulating l synaptic activity. Eventually, the researchers narrowed their list down to two – one taken from a pufferfish and one from a mosquito.
The most suitable is the rhodopsin mosquito. To assess the effectiveness of the new mosquito-derived tool, the researchers tested their method against a drug known to reduce the strength of communication between neurons in the brain. They found that the interference was just as effective and much more stable with mosquito rhodopsin.
More than that: Unlike a conventional drug that affects many parts of the brain and is difficult to control, the researchers found that since only the neurons that produce the mosquito sensor are affected by light, the modulating effect on synapses of the brain can be controlled with precision. both in space and time – simply by turning the light on or off in specific regions of the brain. They then validated the usefulness of the new tool by using it to block the release of the neurotransmitter dopamine from only one side of the brain: lighting the hemisphere expressing the rhodopsin mosquito with a green light led to a one-sided bias. in the behavior of the latter. mouse. In other words, they had created a precise, selective and controllable tool.
“One of the main advantages of mosquito rhodopsin is that it is bistable – that is, it does not need to be refreshed – and is potentially very specific, so that we can only control the precise synapses that interest us, ”says Yizhar. “This is a very exciting technology because it will allow us to discover the roles of specific pathways in the brain in ways that were not possible before. We believe that this mosquito protein could pave the way for the development of a whole family of new optogenetic tools for use in neuroscience research. “These scientific efforts will be given a strong impetus within the framework of the new Institute for Brain and Neural Sciences – the flagship project of the Weizmann Institute, which is expected to bring together leading research groups in various fields, who will unite their efforts to unveil the mysteries of the brain.
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