Stress-Resilience/Susceptibility Traced to Neurons in Reward Circuit

A specific pattern of neuronal firing in a brain reward circuit instantly rendered mice vulnerable to depression-like behavior induced by acute severe stress, a study supported by the National Institutes of Health has found. When researchers used a high-tech method to mimic the pattern, previously resilient mice instantly succumbed to a depression-like syndrome of social withdrawal and reduced pleasure-seeking – they avoided other animals and lost their sweet tooth. When the firing pattern was inhibited in vulnerable mice, they instantly became resilient.

“For the first time, we have shown that split-second control of specific brain circuitry can switch depression-related behavior on and off with flashes of an LED light,” explained Ming-Hu Han, Ph.D., of the Mount Sinai School of Medicine, New York City, a grantee of NIH’s National Institute of Mental Health (NIMH). “These results add to mounting clues about the mechanism of fast-acting antidepressant responses.” Han, Eric Nestler, M.D., Ph.D., of Mount Sinai, and colleagues, report on their study online, Dec. 12, 2012, in the journal Nature.

In a companion article, NIMH grantees Kay Tye, Ph.D., of the Massachusetts Institute of Technology, Cambridge, Mass., and Karl Deisseroth, M.D., Ph.D., of Stanford University, Stanford, Calif., used the same cutting-edge technique to control mouse brain activity in real time. Their study reveals that the same reward circuit neuronal activity pattern had the opposite effect when the depression-like behavior was induced by daily presentations of chronic, unpredictable mild physical stressors, instead of by shorter-term exposure to severe social stress.

Prior to the new studies, Han’s team suspected that a telltale pattern – rapid firing of neurons that secrete the chemical messenger dopamine in a key circuit hub – makes an animal vulnerable to the depression-like effects of acute severe stress, and that slower firing supports resilience. But they lacked direct, real-time evidence.

To pinpoint cause-and-effect, they turned to a research technology pioneered by Deisseroth, called optogenetics. It melds fiber optics and genetic engineering to precisely control the activity of a specific brain circuit in a living, behaving animal. Genetically modified viruses are used to inject light-reactive proteins, borrowed from primitive organisms like algae, to make the circuitry similarly light-responsive.