Animals don't handle stress well. I'm not talking about acute stressors, the predator charging at you through the brush, you run away and it's over. We handle that stress very well indeed. But severe stress, losing a job, a divorce, a death in the family, these can really wear us down. Severe life stressors can not only impact your physical health, they also often occur before the onset of mental illness, particularly major depressive disorder.

Depression takes many forms (lack of interest in activities, sleep changes, eating changes, severely depressed mood), but one of the most debilitating ones is the way that it impacts motivation. While some stressors (like, say, a deadline), might before have been a motivator, making you work to get it done, during depression, these stressors become insurmountable obstacles. Things you did before you couldn't possibly get done now. You'll never make the deadline. You can't run the race. Stress can't motivate you any more. What has changed?

To look at this, Lemos et al at the University of Washington, Seattle, looked at one of the signals in response to stress in the brain: corticotropin releasing factor (CRF). CRF is the first step in the process that eventually allows cortisol to be released into the bloodstream, the molecule we usually associate with stress.

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You can see at the top of the chain there CRF being released from the hypothalamus. From there the next step in the chain is the anterior pituitary, and from there adrenocorticotropic releasing hormone (ACTH) is released, and stimulates the adrenal glands (sitting in little pads of fat above your kidneys) to release cortisol. But in the brain, it's more complicated than that. CRF isn't just released from the hypothalamus to the pituitary, it's released to other regions, too.

Lamos et al wanted to look in particular at the nucleus accumbens (NAc). This is an area of the brain that we usually associate with things like drug addiction, but the nucleus accumbens is associated with the motivational properties of many things, from cocaine to sex to...stress?

That's right, stress can be very motivating in the accumbens. Lemos et al showed that this is due to CRF. CRF release does project to the accumbens, and there are receptors for it there (the CRF1 and CRF2 receptors, this may sound uncreative, but believe me you'd never remember it if they were all named funny things like "The motivator"). And they showed that when you add CRF to the nucleus accumbens, you get increases in dopamine, a chemical messenger associated with reward and motivation.

What you can see above are signals from a technique called voltammetry. In voltammetry, you use a very tiny carbon fiber electrode, encased in glass, and inserted into a brain (or brain slice, as shown here). When you apply an electrical potential elsewhere in the brain or on the slice, dopamine will be released, and the carbon fiber will allow it to, very, briefly, oxidize. And scientists can detect that signal, and produce the heatmaps you see above, where the dark purple is the dopamine signal. Using that, you can quantify just how much dopamine you have.

And you can see that increasing CRF in the brain slice increases dopamine as well. Dopamine is usually thought to be a good clue as to whether something is motivating, the more dopamine, the more motivating (if you think those signals are big, you should see cocaine!). But to really find out if CRF is motivating, you need to perform a behavioral task.

What you can see here is a task called conditioned place preference. You give an animal (in this case, a mouse) a choice between two compartments. At first, they are pretty much the same. But then you give the mouse saline and put him in one side. Then, you give him CRF and put him in the other side. Repeat this for several days, so that the mouse learns to associate one side with the "feeling" of saline and the other side with the "feeling" of CRF. Then you put him in between the two compartments, with nothing at all, and see which side he prefers. If he "prefers" the feeling of CRF over the feeling of saline, he will spend more time in the CRF -paired compartment.

And you can see above that this is what happened. When you give a single dose of CRF, the mouse prefers the CRF paired compartment. CRF, and acute stress, is a motivator under these conditions.

But what about after chronic stress? Lamos et al exposed the mice to a severe stress. This stress was a two day swim task. On the first day, they swam 15 minutes, and one the second day, they swam four bouts of 6 minutes, with 6 minutes in between each bout. Mice are very good swimmers and it's not dangerous, but it is still very stressful. The authors then looked again to see how dopamine in the accumbens, and their conditioned place preference, responded.

What they found that the exact OPPOSITE of the acute stress response. When animals got acute CRF, they saw an increase in dopamine signal. But after a chronic stress, there was no change at all. And when they looked at how they responded behaviorally, they found a totally opposite response. While animals showed place preference for a single injection of CRF, after chronic stress, CRF was very aversive. The authors were able to show that severe stress can SWITCH how mice (and possibly, humans), respond to stress, making the formerly motivating signal highly aversive.

How is this happening? Well that's not certain, though it looks like feedback with glucocortocoid receptors (the receptors that respond to cortisol, the stress chemical at the end of the line) might play a role. But it's amazing to see how sever stress could change the way we respond to stress in future, and how it might really make future stress a much harder problem to deal with.

Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, & Phillips PE (2012). Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature, 490 (7420), 402-6 PMID: 22992525