How optogenetics works is quite unique. First, the desired neurons for research are genetically modified to express a light sensitive protein, opsin, which can take the form of an ion channel, for example. Optogenetics works with Channelrhodopsins (ChRs), which are light-gated ion channels. Light-gated ion channels like ChRs are activated only when struck by a specific frequency of light. When the correct frequency is used to illuminate these neurons, it leads to an ion channel opening. When these channels are open, it allows the passage of positively-charged ions, which causes depolarisation, also known as an action potential. The ability to control specific neurons by manipulating their activation and deactivation using light has led scientists to better understand mood disorders, addiction, and even Parkinson’s disease. The key to understanding why and how such disorders and diseases occur: to first find the path in which it takes place, and then figure out what exactly goes wrong in that path.

The proton ‘starter’ that was recently discovered is known as nanohalosarchaeon Nanosalina (NsXeR), and it belongs to the class of proteins called xenorhodopsins. Xenorhodopsins functions have been better understood because of the discovery of NsXeR.

NsXeR is a powerful pump that’s been shown to induce action potentials in hippocampal neuronal cells to the perfect frequency which opens those frequency gated channels in rat brains. They’ve been characterized as inward opening pumps that are an alternative to the ChRs that have been used in research until now. NsXeR is very selective and only pumps protons into the cell, regardless of the cells concentration. Due to its selectivity and unique features, it is considered to be much more advantageous than ChRs. For instance, NsXeRs selectivity makes it safer to use during research, because unlike ChRs, only one specific positive ion is being transported, lowering the risk of possible cellular side effects during research trials.  

Optogenetic techniques have only ever been used in one clinical trial in 2016. A blind Texan woman underwent the first human clinical trial using optogenetic techniques. This has been the only human trial done so far because the methods are quite invasive. First, the brain needs to be genetically altered, and then a light delivering device must be implanted into the brain. However, research in the field is rapid, and hopes of continuing human clinical trials are high. The discovery of NsXeR brings researchers closer to the possibility, which in turn brings them closer to advancements in treatments for various diseases and disorders researched in the field of neuroscience. This field of research may be the key we’ve been waiting for to unlock the answers to treatments for millions of people around the world.

The paper on the finding of the NsXeR protein was published in Science Advances by an international team of researchers from Moscow Institute of Physics and Technology, Forschungszentrum Jülich, and Institut de Biologie Structurale. Vitaly Shevchenko, the lead author of the paper and a staff member at the MIPT Laboratory for Advanced Studies of Membrane Proteins stated, “So far we have all the necessary data on how the protein functions. This will become the basis of our further research aimed at optimizing and adjusting the protein parameters to the needs of optogenetics.”

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This year’s annual Beatty Memorial Lecture was held on October 16 at the Centre Mont-Royal, and featured Karl Deisseroth, a professor of bioengineering, psychiatry, and behavioural sciences at Stanford, as the speaker. Aside from his clinical work as a psychiatrist, he is an active researcher and a pioneer of optogenetics. This technique first took form in his lab just over a decade ago, and ever since, Deisseroth has continuously sought to improve neuroscience research by engineering better optogenetic methods and addressing classic questions in neuropsychiatry in new ways.

Optogenetics is a combination of genetics and optics to control the behaviour of certain cells. In neuroscience, optogenetics is used to control neurons by turning them on and off by exposing them to a certain colour of light. The opsins are inserted into the neurons using either microinjections or transgenic techniques. These opsins are light-sensitive pores, also referred to as light-sensitive ion channels, that form on the membrane and are sensitive to varying wavelengths of light. When the affected neurons are exposed to light, the pores either open, allowing ions to cross the membrane (exciting the neuron), or close, stopping ions from passing (inhibiting the neuron). This mimics the natural behaviour of these neurons and the way they connect with other neurons in the brain.

As a psychiatrist and a clinician, Deisseroth understands the importance of studying mental disease. During the lecture, he told the audience that “psychiatric disorders are not only chronic and fatal, but also still poorly understood.” Through his clinical work, he has learned that though there are distinct patterns in psychiatric disease that can be studied through patients’ subjective reports, measuring biological changes is a much more difficult task.

Is it possible then for optogenetics to help us understand neurological and psychiatric problems? The answer is yes. By exclusively activating a particular group of cells and thus the brain circuit they belong to, we can look at how they influence changes in behaviour patterns. By mapping these circuits and seeing what happens when they’re on and off, we can get closer to understanding how brain activity becomes affected by certain pathological conditions.

“Psychiatric disorders are not only chronic and fatal, but also still poorly understood.” – Karl Deisseroth, professor of bioengineering, psychiatry, and behavioural sciences at Stanford.

Deisseroth provided some examples of how this technique can give us insight into disorders like depression, Parkinson’s, and anxiety, by opening and closing circuits that researchers believe may be impaired. Previous research pointed toward a pattern of neural activity that may be altered in anxiety disorders. In a study published in Neuron, researchers were able to reduce anxiety in mice using optogenetics. They were able to insert the opsins into a specific subset of neurons, and when light was shone directly onto the brain to activate these opsins, animal tests showed reduced anxiety. Once the light was turned off, the animal went back to normal. These results show us how we can activate very specific cells and circuits in an animal’s brain and study what happens when they are turned on and off.

Deisseroth also went on to describe a second visualization technique called CLARITY that can make the brain transparent by taking away its fats, which block light from passing. Its novelty comes from the fact it does not require the brain or a sample block of tissue to be sliced into several thin slices to be imaged, and because antibody labels can also be viewed in the images. Additionally, the three-dimensional images produced are more detailed. However, this imaging technique requires either brain tissue to be extracted or has to be conducted post-mortem.

Neurons activated by mere flashes of light, entire brains made perfectly transparent ­— one can only be amazed at the innovative ideas springing up this millennium. In fact, the technique of optogenetics fits perfectly with the name of the talk: Illuminating the Brain, we illuminate the brain with different wavelengths of lights, but we also shine light on what may be actually happening inside of it. These techniques and the work of these researchers is definitely bringing us one step closer to understanding what’s happening inside the brain of the people that suffer poorly understood diseases. The hope is that this will one day allow us to create new treatments that target the specific circuits responsible for the brain abnormalities, instead of using chemical cocktails that affect the entire brain.

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