For Stress Resiliance, thank DeltaFosB

Sci’s not gonna lie, the past several days have been, to say the least, incredibly stressful.  I have no idea when blogging went from something that was fun and interesting to something that took up my entire life, but WHOA DUDES.  The end result is stress, and Sci has been eating junk food, not sleeping, and getting decidedly snappish.  Mr. SiT requests your sympathies.

And Sci is having another stress response.  Because she likes this paper and wants to blog it.  But it’s REALLY complicated.  As a side note, one of the things about blogging and trying to explain things to people outside of your field is that you often need to pick the more simple papers.  This one is THICK and it’s chock full of STUFF.  But.  She’s going to try this anyway, and is going to stick with the first half.  Because the finding is cool, and it has implications.  So here we go.

So Sci has what is probably the normal reaction to stress.  But there’s not REALLY a normal reaction to stress.  people who are under stress (which would be a lot of us) show really widely differing responses.  Some people make it through times of extreme stress relatively unscathed, while others develop depression or PTSD, and right now, we’re still not sure what makes the difference.

Some people have thought that the brain’s reward circuits could play as role of how we adapt to stress, by influencing things like self-esteem  and optimism (Sci’s not so sure what she thinks of the psychological ideas that underlie this theory, but it’s what the paper is based on, so we’re going with it for now, and the science backing up the role of the reward system in things like depression is some very good stuff).  And so this paper investigates the way changes in certain parts of the mesolimbic dopamine system, a system connected with the rewarding and reinforcing properties of stuff, like drugs, is affected by stress, and what that means in terms of behavior.

Vialou et al (et al is right, there’s like 20 authors on this thing!) “DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses” Nature Neuroscience, 2010.

Now, this study was done in mice.  And Sci has blogged a little before on how to look at depression in mice.  What she hasn’t really blogged about much is what MAKES for a stressed or depressed (or both) mouse (For some posts on depression, and treatment for depression, which we’ll also be talking about, you can see my tutorials here , here, and here).

So for this study, they used mice, and to create some stress, they used a method called social defeat.

Take a male mouse.  Give it a home.  Have him hang out there, get it decorated like he likes, and have him put all his favorite snacks in the fridge.

Now dump in an intruder mouse.  It’s the intruder mouse we’ll be worry about here.  The first mouse (the resident) has made this his home.  You put an intruder mouse in there, and the resident mouse is going to pull a “my home is my castle” and go nuts.  These episodes usually end in less than 5 minutes, with the intruder being “socially defeated” which basically means on his back pleading for mercy, or otherwise huddled in a corner.

But how do you tell how much that stressed out the mouse and how the mouse reacted?  Well, you subject the intruder mice to social defeat for a specific length of time, usually 10 days, each time having the mouse’s butt get kicked by a different resident.  Then you perform something called social avoidance.  You take the intruder, and you put him an entirely new situation with an entirely new mouse, who is ALSO new to the situation.  The new mouse is in a little box which allows the intruder mouse to explore him without worry.  You then see how long the intruder mouse takes to make friends with the other mouse.  Mice that are fraying at the edges from social defeat are not going to try and make friends, while those who are resilient to the stress will still make an effort.  About 30% of the mice who go through social defeat end up pretty resilient to the effects when tested for social avoidance.

Now the great thing about this social defeat idea is that not only does it produce these groups of mice who are both stress resilient and not stress resilient, it ALSO responds to antidepressant treatment in the non-resilient mice.  Social defeat which produces social avoidance can be helped with chronic treatment with an antidepressant, but not with acute treatment.  This is what we think makes it such a good model, because it is relatively similar to the human condition.

So for this paper, the authors were looking at a protein called DeltaFosB, wherein Delta normally is a nice little triangle shaped sign that I cannot seem to get on this blog.  Boo.  Anyway, DeltaFosB is a transcription factor that controls the expression of other genes, and it can be induced by the presence of rewarding stimuli (like drugs, sex, rock and roll) in an area of the brain called the nucleus accumbens.  The nucleus accumbens is part of the mesolimbic dopamine system, a system using the neurotransmitter dopamine (more basic posts about neurotransmission here, and about dopamine specifically here), and which is involved in rewarding and reinforcing properties of stuff.  You know, pizza, sex, the stuff I mentioned before.   DeltaFosB is ALSO activated by things like stress.

So the authors took a bunch of mice.  They put them through social defeat, and then looked at their social avoidance.  They THEN looked at DeltaFosB.  Both the resilient and the stressed out mice had increases in DeltaFosB, but the BIGGEST increases were in the resilient mice!  Interesting.

Here you can see the first study, with the purple mice showing social avoidance, and the green mice showing resilience.  They both showed increases in DeltaFosB, but the resilient mice showed increases in both parts of the nucleus accumbens (left and right b graphs showing the core and shell of the accumbens), while the stressed mice showed increases in only one area.

They then took a bunch of genetically mutated mice that expressed more than the usual levels of DeltaFosB, and put THEM through the same social defeat trials.  The mutants with high levels of DeltaFosB showed now stress effects following social defeat.

Above you can see the mutant mice on the left and the normal mice on the right.  While the normal mice showed social avoidance when there was a mouse present (grey bar on the left), the mice mutated to have high levels of DeltaFosB did not show any difference (blue bar on the right).

And THEN they did something elegant and used mutant mice that overexpress a transcription factor called cJun, which OPPOSES FosB activity.  Smart yes?  They found that these mice were more susceptible to social defeat.  You can see the control mice are still fine after only four days of social defeat (the light grey bars, it usually takes 10 days), but the cJun mice are already showing the stress.  By day 11, they both showed full stress results.

They did a ton of experiments to show they were on the right track.  They found that mice with lower levels of FosB (this time induced by isolation) were more susceptible to the effects of social defeat.  They found the mice could be rescued by artificially increasing their FosB levels.  They also found that BLOCKING FosB in normal mice by artificially increasing cJun ALSO increased their response to social defeat and made them display more signs of stress.

But of course, if FosB is REALLY part of this, and low FosB makes people less resilient in response to stress, then antidepressants should help with that, right?

Yes they do.

Up there you can see what happens when they treat mice with fluoxetine, which is an antidepressant marketed as Prozac.  You can see that they looked at social anxiety (graph on the left).  The animals exposed to defeat and no Prozac showed social avoidance (dark grey bars).  The animals exposed to social defeat and THEN treated with Prozac did NOT show social avoidance (black bars).  All of the animals that got fluoxetine did show increases in FosB, but the animals who got social defeat AND Prozac showed the biggest increase.  They even blocked this effect by treating socially defeated mice with Prozac and blocking the whole thing with Jun.  And they found that treatment with fluoxetine not only increased FosB, it ALSO increased time spent in social interaction after social defeat, and this behavior could be blocked by cJun, indicating that FosB was responsible in some way for the social interaction behavior changes associated with fluoxetine treatment.

Sci thinks it’s particularly interesting that FosB increases during social defeat and then increases MORE when Prozac is given.  This means to me that it’s the relative increase that is important, and that other things might be opposing the actions.  It also means that changes in FosB not ONLY could explain people’s reaction to stress, but may help explain why some people do not necessarily react well to antidepressants, if, say, their increase in FosB isn’t high enough (though even if this is the case, it’s probably only part of the truth).

Now, a lot of scientists talk about something called clinical relevance.  This is the idea that your findings will have something to do with diseases found in the population at large, and will either say something about the human condition, maybe something about just the way the body works, or maybe even find a new target to treat something.

These authors were so certain of their findings that they went to HUMAN brains.  Post-mortem brains.  Of people who had been clinically depressed. And they found that the humans, like the mice exposed to social defeat, had lower levels of FosB than people without depression.  In the humans, whether or not they were on antidepressant apparently didn’t matter.  So it appears that their findings of changes in FosB in mice really DO translate to humans, which is a cool thing indeed.  Though Sci finds the bit about antidepressants extremely interesting.

That’s actually only the first part of the paper.  The second part goes into detail about the targets of FosB, including the ratio of GluR2 to GlurR2, SCI, and numerous other things.  In Sci’s opinion, the GluR2/1 stuff is very interesting, but the rest of it is kind of a mishmash, and rather detracts from the elegance of the story.  But the message Sci liked was the more basic stuff,  DeltaFosB may play a role in how a mouse (or a human) reacts to stress, with resilience or not.   It’s a small piece of a story, but it’s also an interesting new target to explore what FosB is doing, with maybe new targets for treatment.

Vialou V, Robison AJ, Laplant QC, Covington HE 3rd, Dietz DM, Ohnishi YN, Mouzon E, Rush AJ 3rd, Watts EL, Wallace DL, Iñiguez SD, Ohnishi YH, Steiner MA, Warren BL, Krishnan V, Bolaños CA, Neve RL, Ghose S, Berton O, Tamminga CA, & Nestler EJ (2010). DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nature neuroscience, 13 (6), 745-52 PMID: 20473292