Dr. Deisseroth is also the D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University. He was an HHMI early career scientist from 2009 to 2014.
Discovering Neural Circuits That Control Behavior
Karl Deisseroth has created innovative optical tools that enable researchers to manipulate neurons with unprecedented precision and visualize neural circuits in fine detail. Deisseroth and others around the world are using these techniques to further their understanding of how the brain controls behavior, and to explore how neural activity is disrupted by mental illness.
Deisseroth pioneered optogenetics, a technology that uses light to control the activity of specific cell types in the brains of mammals. His original technology genetically introduced a light-activated protein called channelrhodopsin into neurons, allowing the cells to be turned on instantly with the pulse of a laser. His team later created many engineered versions of channelrhodopsin that can act as different kinds of light-activated switches. With this array of tools, researchers can now switch multiple sets of neurons on or off with millisecond precision.
In 2007, Deisseroth’s team used optogenetics to wake sleeping mice by activating specific neurons in the hypothalamus region of their brains. Since then, the researchers have used the technology to investigate how the brain implements different behavioral states and transitions between them. As a practicing psychiatrist, Deisseroth focuses much of his research on understanding brain circuits involved in clinically relevant symptoms and behaviors, including anxiety, depression, and social dysfunction.
To improve observation of the brain’s structure, Deisseroth created CLARITY. The method removes light-scattering fats from biological tissue and introduces a permeable hydrogel as support, generating an optically transparent sample that retains the tissue’s original structure and molecular information. CLARITY is complemented by fiber photometry, an imaging method Deisseroth developed to quantitatively detect traffic along fine connections deep within the intact brains of freely behaving mammals. Deisseroth’s team and labs worldwide are using these techniques – often in combination with optogenetics – to obtain high-resolution information about biological systems while maintaining a global perspective.
Additional support from NIH, DARPA, NSF, and many philanthropic donors and foundations.
“If you asked 100 psychiatrists if we know enough about the brain to devise truly specific treatments,” says Karl Deisseroth, “all 100 would probably say no.” That’s why Deisseroth, a practicing psychiatrist himself, is working to elucidate the detailed form and function of the brain’s neural circuitry.
He has developed ways to study how groups of neurons influence each other, and is using those techniques to explore how brain circuitry works, and how it goes awry in disorders such as depression, anxiety, and Parkinson’s disease.
When he started his lab at Stanford University, in 2004, Deisseroth launched a high-risk project. Some algae make a protein that opens a gate in cell membranes when the protein absorbs light. Deisseroth thought that by slipping the gene for that kind of protein into specific neurons, he could use these gate-opening properties to stimulate or inhibit neurons with flashes of light.
His research team succeeded between 2004 and 2009, developing an approach that Deisseroth calls “optogenetics.” For example, in the first mammalian behavioral experiment in 2007, his group used optogenetics to wake sleeping mice, using patterns of pulsed light to control a genetically targeted specific kind of neuron in the hypothalamus. In 2009, they reported a series of versatile advances for targeting genes and light as well, to control behavior even more specifically, in an integrated approach applicable to virtually any type of cell in the brain.
Since then, Deisseroth has shared optogenetics methods and tools with thousands of other laboratories, and an avalanche of discovery has ensued. His own lab has used optogenetics to make many surprising discoveries, including identifying how anti-anxiety and anti-depression circuits work within the brain, and demonstrating how these conditions can arise from shifted balance among circuit populations.
In another major advance, Deisseroth’s team developed a way to make an intact, isolated brain transparent, so that its inner structure and wiring is visible and accessible. The technique links the brain to an internally constructed hydrogel, which makes it possible to dissolve away the organ’s fat. That fat normally scatters light and obscures scientists’ view into the tissue. With a clear view, researchers can chart long-distance connections between neurons and probe the fine details of individual cells with standard molecular tools.
Deisseroth calls the approach CLARITY. He has shared the tools with hundreds of other neuroscientists, as well as researchers who are using it to study organs other than the brain. His own team has used CLARITY to build brain-wide maps of cells involved in signaling with dopamine, a chemical messenger associated with movement, cognition, and pleasure. They visualized the global input and output wiring of distinct populations of cells deep within the brain that receive inputs from different subpopulations of dopamine neurons. Optogenetic tools have already worked well together with CLARITY to help define the role of such specific neuronal populations.
Deisseroth’s primary goal is to help the research community understand as much as possible about basic principles of brain circuitry. Secondarily, that knowledge might eventually be harnessed to create better treatments for brain disorders. “The brain is a complicated place, and will take a long time to sort out,” he says. “But in the last four years, the revolution in understanding has been thrilling.”