NEUROLOGY/OPTOGENETICS: Optogenetics studies show that different stressors induce depression in distinct ways

Two recent studies funded by the NIH's National Institute of Mental Health (NIMH) have used optogenetics to shed new light on the operation of reward circuits in the brain, and how depression is triggered.

Researchers the Mount Sinai School of Medicine (New York, NY) and colleagues have shown for the first time that "split-second control of specific brain circuitry can switch depression-related behavior on and off with flashes of an LED light," said Ming-Hu Han.1 Previous work had led Han's team to think that a specific pattern of rapid neuron firing in a reward circuit heightens susceptibility to depression in the face of acute severe stress—and that slower firing promotes resilience. Optogenetics offered the first evidence in support of their hypothesis.

In the study, resilient animals with reward circuits modified for optogenetic control instantly exhibited signs of a long-lasting, depression-like syndrome after exposure to the light pulses. By comparison, the natural stressor they sought to mimic, social defeat, requires 10 days of exposure to take effect and doesn't work 100% of the time. Subsequent experiments showed that inhibiting the reward circuit activity pattern in stress-susceptible mice instantly made them stress-resilient. The results suggest that dopamine neurons firing at high rates in a specific circuit encode a signal for susceptibility to acute, severe stress, whereas a different circuit serves an opposite function.

Meanwhile, Kay Tye of the Massachusetts Institute of Technology (MIT; Cambridge, MA) and Karl Deisseroth of Stanford University (Stanford, CA) used the approach to investigate the depression that often results from long-term exposure (up to 10 weeks) to mild stressors like white noise, crowded housing, or continuous darkness or illumination. Their study reveals that the same reward circuit neuronal activity pattern had the opposite effect when the depression-like behavior was induced by chronic, unpredictable mild physical stress.2 In contrast to the other study, optogenetically inducing high firing rates instantly reversed depression-like behaviors and vice versa. Also opposite to the social defeat stress findings, optogenetically inhibiting these neurons induced depression-like states.

"The variable effects that stressors of different types induce in the dopamine system may point to the need for distinct treatment strategies for patients whose depressions stem from different types of experiences," said Tye, who is leading a research group studying the neural underpinnings of motivational and emotional processing.

1. D. Chaudhury et al., Nature, doi:10.1038/nature11713 (2012).

2. K. M. Tye et al., Nature, doi:10.1038/nature11740 (2012).

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