Researchers Control Rodent Depression With Optogenetics

Imagine if you could switch your depression off like a light. Researchers did it in mice. They used optogenetics to gain more insight into how brain circuits work in cases of depression, and discovered that different types of stress trigger different activity patterns in the same brain circuit.

Two papers published recently in the journal Nature describe how neuronal activity in specific brain circuits in mice can be turned on and off to control depression-like behavior. Both studies used optogenetics, a research method pioneered by one of our customers, Dr. Karl Deisseroth that combines fiber optics and genetic engineering to control the activity of specific neurons. Dr. Deisseroth, a neuroscientist and psychiatrist at Stanford University contributed to both papers.

In the first paper, “Rapid regulation of depression-related behaviors by control of midbrain dopamine neurons,” a team led by Dr. Dipesh Chaudhury and Dr. Jessica J. Walsh at the Han Laboratory at the Mt. Sinai School of Medicine in New York identified a specific pattern of dopamine neuron firing in a key reward circuit that renders mice vulnerable to depression-like behavior. Mice resilient to social stress have neurons that fire at normal rates, while the neurons of social stress-susceptible mice fire at rapid rates, according to an NIH press release. The researchers used an LED-lit optical fiber to trigger neurons to fire faster in the brain circuit of resilient mice. The light triggered the neurons to fire more rapidly, and the mice became depressed. Inhibiting the circuit activity pattern in stress-susceptible mice instantly made them resilient.

Interestingly, the second study seemed to contradict the first one. Led by Dr. Kay Tye, researchers at the Massachusetts Institute of Technology used optogenetics to make the dopamine neurons in the ventral tegmental area (VTA) fire rapidly, just like in the first study. But instead of becoming more depressed, the mice stopped displaying depression-like behaviors. Conversely, when the researchers prevented the neurons from firing so quickly, the mice became depressed.

There was, however, one major difference between the mice in the first study and the mice in the second study: the type of stress experienced. The mice in the Mt. Sinai study had been genetically modified so that their reward circuits mimicked that of mice exposed to “social defeat stress,” a type of experimental procedure where mice are exposed to repeated encounters with a dominant animal over a ten-day period. That type of stress is considered “acute severe stress.” In contrast, Dr. Tye’s mice experienced milder stresses over longer periods of time, a pattern more closely related to the types of experiences that can spark depression in humans. They were exposed to white noise, crowded housing, or continuous darkness or illumination for periods of up to ten-weeks, according to the NIH press release.

“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,” Dr. Tye said in the press release.

References:

Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai H-C, Pomeranz L, Christoffel DJ, Nectow AR, Ekstrad M, Domingos A, Mazie-Robison M, Mouzon E, Lobo MK, Neve RL, Friedman JM, Russo SJ, Diesseroth K, Nestler E, Han M-H. (2012) Rapid regulation of depression-related behaviors by control of midbrain dopamine neurons. Nature. 2012 Dec 12. doi:10.1038/nature11713

Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai H-C, Finkelstein J, Kim S-Y, Adhikari A, Thompson KR, Andalman AS, Gunaydin LA, Witten LB, Deisseroth K. (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2012 Dec 12. doi:10.1038/nature11740