Stress and depression, linked in the brain

Los Angeles Times

Scientists have taken a big step toward solving a longstanding riddle, identifying a key molecular pathway that leads from stress to depression.

It may come as no surprise that stressful life events often precede episodes of major depressive disorder. But what might surprise you is that, in general, scientists have had little understanding of exactly why that is.

The new study, carried out in mice and published this week in the journal Nature, makes significant progress toward that goal. The researchers, from the University of Washington, identified the missing link: a peptide called corticotropin-releasing factor, or CRF. CRF, they discovered, plays a nuanced role in an area of the brain called the nucleus accumbens, a region well known for its role in motivation, pleasure and social behavior.


Normally, the brain signaling pathways in the nucleus accumbens work like this: When something exciting or motivating happens, such as entering a new environment or receiving a new toy to play with, CRF arrives and binds to a receptor. This causes an increase in the release of dopamine-a neurotransmitter that plays a major role in making you feel rewarded or aroused by something interesting in your environment.

The researchers demonstrated this with a standard experimental design called “conditioned place preference.” They put a mouse in one of two connected cages and infused its nucleus accumbens with CRF. Then, the researchers moved the mouse to the other cage, and infused their nucleus accumbens with a placebo liquid. After that, they let the mouse choose which cage it preferred. If CRF was leading to dopamine release -- and thus to a strong feeling of reward -- the mouse should prefer the cage where it received CRF, even though in reality the cages are identical. That is exactly what they found.

The scientists then carried out the central experiment: They stressed the animals out by forcing them to swim in water numerous times over a two-day period, which has been shown in the past to not only be stressful but to lead mice to have symptoms of depression. Then they tested the ability of CRF to cause dopamine release in the brains of the stressed-out mice.

Incredibly, they found that the effect was completely gone: CRF no longer had an impact on the release of dopamine after stress. In fact, when the scientists repeated the cage test, they found that CRF actually caused the mice to want to spend less time in the cage, meaning the molecule had actually become aversive. The effect lasted for more than 90 days, suggesting it mirrors the long time-course of depressive disorder.

In other words, a chemical cascade that normally makes you feel good had been twisted to make you feel bad.

You can read a summary of the study here.


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