As a medical resident specializing in psychiatry, Karl Deisseroth was tired of being served neurotransmitter soup. Brains are intricate, electrical structures, so why is mental illness so often framed as a chemical imbalance? To him, it made more sense to think in terms of circuits. "Talking to a patient that's depressed," he says, "you get a sense that activity is not flowing appropriately."
Deisseroth wanted to know how signals move through interconnected cells, but common techniques to study living brains - PET and functional MRI - were too slow and imprecise to study neural networks effectively. They take measurements in seconds and millimeters rather than in milliseconds at the level of individual cells.
As a graduate student and postdoc, Deisseroth dissected the molecular interactions that occur as neurons respond and adapt to stimuli. In particular, he and colleagues found that repeated stimulation in neurons stabilize the MAP kinase pathway to allow new dendritic growth, helping to explain how neurons forge new, stable connections.
When applying for faculty positions, Deisseroth realized that research questions he'd been asking about individual neurons could spawn tools to study higher-order brain functions. Now an assistant professor with joint appointments in Stanford University's bioengineering and psychiatry departments, Deisseroth and his group have developed a process that removes a thin slice of living brain tissue from a mouse and places it under a microscope attached to a very fast, high-resolution digital camera. When they add stimuli, voltage-sensitive dyes fluoresce and darken with neuronal activity. Researchers use algorithm-hunting software to uncover circuit dynamics.
Deisseroth's techniques can manipulate brain cells as well as monitor them. Recently, his team engineered lentiviruses with an algal gene coding for ion channels to create brain cells that respond to light, a fast, nontoxic stimulus that can go where electrodes can't.
Most intriguing is observational evidence that electrical activity encourages hippocampal stem cells to become neurons and hook into existing brain circuitry, a phenomenon known to occur in most successful treatments for depression. And with his joint appointment, Deisseroth can also explore this phenomenon as a psychiatrist. He is part of a 16-site clinical trial to see whether high-speed transcranial magnetic stimulation has an antidepressant effect.
Rob Malenka, Stanford professor of psychiatry and behavioral sciences and Deisseroth's former postdoctoral advisor, recalls how Deisseroth came to lab every day after seeing patients. "He had a vision of what he wanted to accomplish and never seemed to get discouraged." Deisseroth has a different recollection. "I had the frustration and background to say, 'We can make something.'"