Lighting up Mechanisms of the Brain

It was late 2005, and Dr. Ofer Yizhar was busily conducting neurobiology research at Tel Aviv University for his doctorate, unaware that his life plans were about to change, when a fellow doctoral student burst into the lab, a scientific paper in hand.

“You won’t believe what they did in this paper,” he told Dr. Yizhar, who was surprised to read that scientists were able to genetically modify a neuron – a brain cell – to make it sensitive to light.

Why was this so revolutionary? Because neurons, aside from the ones in our retinas, do not respond to light.

That paper was a turning point for Dr. Yizhar. “You always remember a specific day in your life where things changed,” he says. And so after receiving his PhD with distinction, he moved to California to conduct his postdoctoral research with the paper’s author: Dr. Karl Deisseroth at Stanford University. There Dr. Yizhar became a pioneer, helping develop a powerful, promising, truly revolutionary new field of neuroscience: optogenetics.

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Dr. Ofer Yizhar

Optogenetics brings together techniques from the fields of optics (a branch of physics devoted to the behavior and properties of light) and genetics (the study of genes) to control and monitor the activities of neurons in living tissue.

First, scientists choose a cell that they suspect is involved in the condition or behavior they wish to study. Using genetic engineering, they then insert a photoreceptor, which responds to light, into the selected cell – all without negative effects. According to Dr. Yizhar, “the cell won’t be affected in any way, but now it will contain one additional gene that makes it sensitive to light.”

“We all want to help people. Understanding the physiological basis of psychiatric diseases would be a dream for me.”

The technique lets researchers very precisely control neural activity – in fact, they are able to manipulate single neurons and measure the effects of those manipulations in real time with an extraordinary degree of accuracy.

This is where the power of optogenetics becomes literally visible: it enables the study of a living, active animal. Dr. Yizhar can actually turn a neuron on or off and watch the immediate effect to see how its activity – or lack thereof – contributes to the animal’s behavior. This has been particularly useful in studying a variety of brain functions, including learning, memory, and social behavior, and how these functions might be altered in autism.

After completing his postdoc, Dr. Yizhar established his own optogenetics lab at the Weizmann Institute of Science in 2011. He soon began collaborating with colleagues who were expert in the genetics of psychiatric disease. Together, the group developed an invaluable research tool: a group of special mice with mutations similar to psychiatric diseases in humans, including autism.

Working with the engineered “autistic” mice and using ever-more-refined optogenetics tools, Dr. Yizhar devised a system that allows him to activate individual neurons, one by one, to see their effect on the mouse’s behavior. This method also lets his team examine the connections between neurons – by “stimulating this neuron and that neuron, we can start to see where the connections are formed,” he says; this is critical because communications breakdowns are behind a host of neurological and psychiatric disorders.

Most remarkable, though, is Dr. Yizhar’s discovery that by activating or deactivating certain neurons, autistic behaviors could actually be turned on or off, effectively reversing autistic behavior. Turn the neuron off, the mouse behaves in an autistic manner. Turn it on, and it behaves normally again.

Optogenetics is already being applied to the study of depression, autism, schizophrenia, addiction, narcolepsy, epilepsy, Parkinson’s disease, blindness – even to the mechanisms of how memories are formed and saved.

In other research, Dr. Yizhar was able to “trigger a mouse to be reminded of a particular place by just shining light and activating the neurons that were active when the mouse was in that place” – in effect, summoning a memory. This means the reverse is true: the memory can also be silenced.

“Think of, for example, PTSD [post-traumatic stress disorder], where you really want or need to extinguish a particular bad memory,” he says. “Today, that’s possible in mice.”

Collaboration is a byword at Weizmann, and Dr. Yizhar’s optogenetics expertise is in high demand. He and Prof. Alon Chen were able to pinpoint anxiety neurons, a finding with considerable potential for treating a range of anxiety-related disorders, including PTSD; the two also found that stress-response molecules in the brain can help mice make new friends. With Dr. Tali Kimchi, Dr. Yizhar helped find ways to increase maternal instinct in mice and make males less aggressive. He also has a major collaboration underway with scientists at Japan’s RIKEN Brain Science Institute; they hope “to discover how autism spectrum disorders develop in the brain and what neural mechanisms are involved in the behavioral impairments associated with these disorders,” he says.

However, treating a neuropsychological disease is more complicated than simply switching a neuron on or off. As Dr. Yizhar points out, “we know a lot about the genetics of these diseases; there are several hundred genes that can contribute to autism or schizophrenia.”

But the benefits of such knowledge are limited; for example, virtually none of the genes involved in autism are known, with absolute confidence, to be directly responsible for producing an autistic child.

With optogenetics, Dr. Yizhar can turn autistic behaviors on and off in mice.

Thus, scientists still need to fill in the middle part of the equation. “Between mutation and behavior, there’s an entire brain,” Dr. Yizhar states. “And we need to understand what kind of changes in the function and structure and connectivity of the brain are taking place.”

“We all want to help people,” he says. “Understanding the physiological basis of psychiatric diseases would be a dream for me.”

While it is not yet clear if optogenetics will be a therapy on its own or help advance other interventions, the method has tremendous implications for understanding and treating brain-related diseases. In fact, optogenetics is already being applied to the study of depression, autism, schizophrenia, addiction, narcolepsy, epilepsy, Parkinson’s disease, blindness – even to the mechanisms of how memories are formed and saved.

And if, one day in the future, Dr. Yizhar looks back and sees that “optogenetics techniques allowed us to better understand and treat disease, then I would be really happy, and I’d feel that I accomplished at least some of what I came here for.”

The research of Dr. Ofer Yizhar is supported by Jean-Charles Schwartz and Marc-Antoine Schwartz; the Adelis Foundation; the Candice Appleton Family Trust; Paul and Lucie Schwartz; and the Georges and Vera Gersen Laboratory. Dr. Yizhar is the incumbent of the Gertrude and Philip Nollman Career Development Chair.