Scientists' hunt for the cause of depression has implicated so many suspects and found so many treatments with different mechanisms that the condition remains an enigma.
Now researchers at the Stanford University School of Medicine have identified one unifying principle that could explain how a range of causes and treatments for depression converge.
They found that in rats the differing mechanisms of depression and its treatment in the end appear to funnel through a single brain circuit. Changes in how the electrical signals spread through the circuit appear to be the cause of depression-related behavior, according to their study. Their findings will be published July 6 in Science Express, the advance online publication of the journal Science.
"I think this will help us make sense of how there can be so many different causes and treatments of depression," said senior author Karl Deisseroth, MD, PhD, assistant professor of bioengineering and of psychiatry and behavioral sciences. "It also helps us understand conceptually how something that seems as hard to get traction on as depression can have a really quantitative, concrete basis."
The work also may have implications for the search for new treatments for depression. "You can use that common pathway as the most efficient, most direct targeted way to find truly specific treatments," he said.
Deisseroth, who sees many depressed patients in clinic, said he has come to appreciate how the bumps in the road that most people see as normal obstacles in life become insurmountable hurdles to depressed people, causing them to lapse into helplessness.
Reasoning that the brain is essentially a complex electrical circuit, Deisseroth's team set out to test the theory of whether brain circuitry malfunction could be at the root of depression. To explore the idea in a precise, quantitative way, they needed to develop a visualization tool that was faster and sharper than brain imaging systems currently available, such as MRI or CT scans.
Raag Airan, an MD/PhD student in Deisseroth's lab and co-first author of the study, led the development of a technique called voltage-sensitive dye imaging for this model. This technique allows intact brain circuits to be viewed in real time, enabling the researchers to watch living neurons in action, across entire brain networks.
The system uses a fluorescent dye, sensitive to brain circuit activity, which the researchers introduce into the animal brain tissue. As dyed circuits light up and darken again in response to electrical activity, very fast high-resolution cameras capture the action. The researchers can observe how different stimuli received by the animal, such as a dose of an antidepressant drug, affect circuit operation.
The researchers used slices of rat brain, Deisseroth said, "like a computer repair technician would take out a circuit board" to test its functional properties. The brain slices, which remain active for many hours, came from parts of the hippocampus, a region long implicated in depression. They also tested slices from rats treated with the antidepressant medications fluoxetine and imipramine.
The team carried out the study using a standard rat model of depression. Even though the rats do not mimic the entire complexity of genetic and environmental causes of human depression, Deisseroth explained, the animals exhibit similar symptoms and also get better from the same medications that work on humans.