Light-sensitive neurons and transparent brains: How a visionary changed neuroscience forever

Karl Deisseroth

Standford neuroscientist Karl Deisseroth discusses the techniques he has developed to study the brain. Credit: Emiliano Rodríguez Mega

By Rodrigo Pérez Ortega

SAN JOSE, Calif. — In recent years, Karl Deisseroth has revolutionized neuroscience research. Through the development of ingenious techniques, he has brought researchers closer to understanding how the brain works and how neurons determine behavior. During a plenary talk at the recent annual meeting of the American Association for the Advancement of Science in San Jose, Calif., he shared some of that research journey.

Hints about where research by Deisseroth — a Stanford professor and Howard Hughes Medical Institute investigator — and others could lead date back almost 40 years. That’s when Nobel laureate Francis Crick suggested that the major challenge in neuroscience was the need to control only one type of neuronal cell in the brain while leaving others untouched. Crick proposed using light as a way to achieve this, but scientists at the time had no idea how you could do that. Deisseroth’s later research would prove Crick was on the right track.

With millions of neurons taking part in one specific behavior it is not an easy task to elucidate which neurons do what. Neuroanatomy can give us some clues, but Deisseroth is certain that the key to understanding how the brain works is to dissect how individual neurons connect and interact with each other. Such work ultimately elucidates specific neuron networks, or neuronal maps.

One method is to use non-invasive brain imaging to see brain activity as a whole. That’s key, but the resolution is not very good. While researchers know a lot about neurons in petri dishes, they know much less about how neurons behave naturally within these neuronal maps, says Jack Gallant from the University of California at Berkeley.

For this reason, Deisseroth and his team had the unconventional idea of working with bacterial or algal opsins — proteins embedded in cell membranes that, when stimulated by light, can cause neurons to fire. He reasoned that these opsins could control specific neurons in conjunction with optic fibers. “It was unlikely to work. There were problems, but we were able to overcome them,” Deisseroth said during his AAAS talk. A proof-of-concept experiment came in 2007, when they were able to control a mouse’s motor activity using blue light. They named this new technique optogenetics.

This technique has since been used widely by neuroscientists all over the world to understand the neuronal maps involved in depression, drug abuse, social dysfunction, fear memory, and Parkinson’s disease, among other conditions. Anxiety, for example, is a mental state that involves several behavioral and physiological outputs, such as risk-avoidance and respiratory alterations. In 2013, Deisseroth and his team were able to dissect how a particular subregion of the brain was able to control these outputs by orchestrating different parts of the brain to perform in unison, giving rise to some of the classic symptoms of anxiety.

In order to go beyond control of individual neurons and make it possible to observe natural brain activity patterns, in 2014 Deisseroth went on to develop a new technique called fiber photometry. This involves inserting a calcium sensor in specific neurons, allowing detection of which cells are firing in real time to decipher which neurons respond to which stimuli.

The final piece of the puzzle was understanding the wiring that underlies the behavior. Until two years ago, the only way to track the connections for a single neuron was to slice the brain, image it, and then reconstruct all the acquired images. Even when done carefully, this method wasn’t sufficient for mapping very small structures. Deisseroth attacked this problem by developing CLARITY, which involves a chemical treatment that makes brain tissue transparent. This lets light from a microscope through, allowing 3D high-resolution images of neurons. Labs in other parts of the world have been using this technique to understand a diverse range of diseases, including Alzheimer’s and multiple sclerosis.

The techniques Deisseroth has helped develop have led to answers to numerous questions neuroscientists had been trying to solve for many years, such as how memories are stored and recalled in the brain and how some neurons drive cocaine addiction.

Eventually, optogenetics might even be a treatment for some psychiatric disorders by enabling control of errant neuronal maps. “I think we have a ways to go,” says Deisseroth, “We need to understand the wiring a little better … but more important is just the basic science understanding, because that could enable any kind of new treatment: better drugs, better brain stimulation.”

Rodrigo Pérez Ortega is a senior neuroscience student at the Universidad Nacional Autónoma de México and also a freelance science writer. He enjoys scuba diving, traveling and learning new languages. You can contact him directly at rpocisv@gmail.com.