Nature (2012) doi:10.1038/nature11436
Received 13 May 2011Published online 19 September 2012
Stressors motivate an array of adaptive responses ranging from ‘fight or flight’ to an internal urgency signal facilitating long-term goals1. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments2. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal3. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry4. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors5 and other arousing environmental stimuli6, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF’s capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.
Stress and depression linked in the brain
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.