Interview with Optogenetics Expert Prof. Anatol Kreitzer

Anotol Kreitzer, PhD, is a senior investigator at the Gladstone Institute of Neurological Disease and an Associate Professor of Physiology and Neurology at the University of California, San Francisco. Dr. Kreitzer’s research focuses on the disordered physiological processes associated with Parkinson’s disease. He is an expert in the emerging field of optogenetics—the application of genetic and optical techniques to remotely control brain cells in animals. Using optogenetics, Dr. Kreitzer has identified key neural circuits that are disrupted in Parkinson’s disease. He has also discovered brain circuitry that restores normal behavior in mice modified to model Parkinson’s disease. In addition, he uses sophisticated electrical-recording techniques to probe brain activity at a cellular level. These methods led to seminal discoveries linking changes in motor behavior in Parkinson’s disease with the inability of specific brain cells to be modified.

Dr. Kreitzer serves as a regular reviewer for prominent scientific journals, including Nature, Neuron, Nature Neuroscience and Journal of Neuroscience, and is on the scientific advisory board of Circuit Therapeutics. In 2011, he was honored with the Young Investigator Award from the Society of Neuroscience.

Watch this video from Neuro Transmissions for an introduction to optogenetics…

The following has been paraphrased from an interview with Prof. Anatol Kreitzer on April 13th, 2018.

(Click here for the full audio version)

Do you believe it will one day be possible for us to fully understand our brains?

There are aspects of the brain that we will probably be able to understand fairly well, but I don’t think we will ever be able to really understand things like consciousness, or emotion. The complexity of the brain is on a scale that is very hard to comprehend, there is a limit to what we can conceptualize. We will probably be able to understand perception, sensory transduction (the conversion of a sensory stimulus from one form to another), hearing, how the spinal cord works, etc. But, when it comes to the inner core of the brain, the deep layers of integrated neural networks, things become a lot more mysterious and I am skeptical we will ever be able to fully comprehend them.

Let’s say our understanding of the brain was a hundred yard dash, where are we in that race?

There are too many unknown unknowns to answer that, we don’t even know where the finish line is, we are racing in dense fog. Relative to where we started in the late 1800’s, when Ramon y Cajal and Camillo Golgi figure out we have cells in the brain that communicate using electrical signals, we have come a long way. A lot of that has been driven by new technologies that have given ways to measure and image brain activity.  Then there are other tools that have allowed us to record and manipulate certain brain activities. But, if I had to guess I’d say we are about 5 yards in to this 100 yard dash.

How do you define optogenetics and how was this technique discovered?

I think of optogenetics as genetically encoded proteins that are light sensitive and can change the function of neurons. The prototype of this is a protein called channelrhodopsin-2, which was cloned from bacteria in 2002 and inserted into neurons in 2005, it allowed researchers to control neural activity in tissue. Over the past decade, this was expanded to include control over neurons in live animals, and lately the possibilities for using this to control the brain have really exploded. We can now excite or inhibit neurons with different colors of light, and across a range of timescales. But, the real potential of optogenetics is in the ability to selectively target and change the behavior of specific cell types in the living brain. We can now turn different cell types on and off and really figure out what each cell type does.

How did you come to understand that you could control basal ganglia circuitry (the area of the brain impaired in Parkinson’s disease) using optogenetics?

It goes back to a lecture I heard while at graduate school in Harvard on the direct and indirect pathways in the basal ganglia, which are critical for motor control and also for the dopamine related deficits in Parkinson’s disease. Then, for my post doc, I really started to focus on these two pathways. Initially, I was perplexed as to how to target these pathways because they originate in the striatum, and if you look at the cells in the striatum they all look identical. Then I saw another lecture during my post doc where the investigators had figured out how to get certain cells to express green fluorescent proteins to light up the direct or indirect pathway neurons. It was really cool to see that it could be done in living tissue.

Right around this time, a former postdoc in the lab I was working in, Karl Deisseroth, started using channelrhodopsin-2 to turn neurons on or off with light. He also figured out how to inject viruses into the mice so that they would express channelrhodopsin-2 in any cell type that you wanted. That was a major breakthrough and I jumped at the opportunity to use these tools in the basal ganglia.

The next step was to figure out how to deliver light deep into the brain, and Karl had the insight to use very thin optical fibers for this. We stuck them into the basal ganglia, and it was one of those experiments that worked the first time we tried it. We turned on the direct pathway and the mice immediately started running around, we then turned on the indirect pathway and the mice completely froze. It was really remarkable to see that we could change the motor behavior of the animal in an instant.

What are the biggest obstacles to translating this work into humans?

If you want to do optogenetics in humans, the first thing you need to do is deliver proteins from algae and bacteria into human cells, which could lead to an immune response. Then we encounter another problem of how to get the virus into the right place. In mice we do it by genetically engineering different strains of mice, so we need to figure out another way of doing it in humans. There are strategies that people are thinking about, but we are still a long way from being able to deliver specific proteins to specific types of brain cells in humans safely and effectively. The third challenge is delivering the light, because the human brain is so much bigger than a mouse brain, we will need new ways to deliver the light over a larger area. There are some ideas, but the technology is not quite there.

Is there any possibility of one day being able to use optogenetics to modify a person’s consciousness or cognition?

I think there is, we obviously know that there are drugs that can already do this by targeting neuromodulatory systems. The brain has all these cells that talk to each other using various neurotransmitters that either excite or inhibit neurons. But there are another class that release neuromodulators, which are similar to neurotransmitters, but send out slower moving signals over a larger area. A lot of the promise for controlling cognition or consciousness relates to the control of these neuromodulators, like dopamine and serotonin.

One drug that does this is Adderall for ADHD, people also use it to improve focus, cognition and attention. It works by targeting neuromodulator systems, in this case the dopamine system. You could imagine that if you target specific types of dopamine neurons using optogenetics, you could have much finer control and really improve specific aspects of cognition without as many side effects. Another example is ecstasy, or MDMA, which is now used for post-traumatic stress disorder. Same for psilocybin and LSD, so-called micro dosing leads to increased cognitive abilities and consciousness. But, all these drugs are blunt tools, the real power of optogenetics is that we might be able to target specific aspects of consciousness and cognition.

What do you see as the far future potential of optogenetics?

We are already seeing the integration of various technologies with our bodies in everyday life through mobile devices and wearable sensors. This trend will probably continue and our ability to manipulate our bodies is going to improve through more non-invasive devices. One day we’ll be able to read out oscillations from our brains and use that to change our brain state or modify consciousness. That is not too far into the future.

Are we ever going to have the ability to implant electrodes into our brains and use that to precisely tweak and control consciousness? It is hard to say. We have these visions of the future and some of them are silly in retrospect. I think the brain is so vastly complex that the changes that are really going to be effective are going to be technologies that are non-invasive, like focused ultrasound. I am skeptical of anyone claiming to stick wires into your brain to control a variety of cognitive abilities.

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