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.
The researchers had previously shown that neurons in the reward circuit hub deep in the brain, called the ventral tegmental area (VTA), fire at normal rates in social stress-resilient mice, but at high rates in social stress-susceptible mice. So they embedded an LED-lit optical fiber aimed at the VTA circuitry of genetically modified resilient mice to convert them into susceptible mice by triggering high firing rates.
Normally, it takes 10 days of repeated encounters with a dominant animal an experimental procedure called social defeat stress to induce depression-related behaviors. Even after that, some mice emerge seemingly unscathed. But these resilient animals in which the reward circuit had been genetically modified for optogenetic control instantly succumbed to a long-lasting depression-like syndrome after light pulses triggered neural activity mimicking the high firing rates seen in the susceptible animals.
In subsequent experiments, using similar optogenetic strategies, the researchers discovered that inhibiting the reward circuit activity pattern in stress-susceptible mice instantly converted them into stress-resilient animals. The reward circuit projects from the VTA to an area in the center front of the brain, called the nucleus accumbens. This study suggests that dopamine neurons firing at high rates in this specific circuit projection encode a signal for susceptibility to depression induced by acute, severe stress. By contrast, a circuit projectio
|Contact: Jules Asher|
NIH/National Institute of Mental Health