Friday Wierd Science: Mopey Mice Pee their Feelings

Jul 19 2013 Published by under Friday Weird Science, Uncategorized

...or, in fact, they DON'T.

Anyone who has ever held a mouse has, honestly, probably been peed on. If you've held a lot of mice, you've been peed on a lot. Everywhere you put a mouse, that mouse WILL pee. It's part of the game and one of the things you get used to (probably one of the things we should warn new grad students about, too. "Congratulations! Be prepared to be peed on!"). So most people who work with mice don't really think anything of it.

But what if we should? ...and what if you could get some art out of the deal?

Lehmann, et al. "Urine scent marking (USM): A novel test for depressive-­‐like behavior and a predictor of stress resiliency in mice." PLoS ONE, 2013.

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(Oh, it looks so innocent. It's just waiting to pee on you. Source)

Scientists who study depressive behaviors are always on the lookout for better behavioral tests. Initial tests for "depression" in animals, tests like the tail suspension test (where you hang a mouse up by its tail for 6 minutes and measure how much it wiggles), and the forced swim test (where you put a mouse in water for 6 minutes and see how long it swims vs floating. Don't worry, mice are extremely good swimmers), are not tests for "depression" per se. Rather, they are tests that were developed to show whether or not antidepressants WORKED. Give an antidepressant just once to a mouse, and he will struggle more in the tail suspension tests and swim more in the forced swim test. Every antidepressant currently available on the market works in these tests, so they were good screens for antidepressants.

But are they good screens for depressive behavior in mice? That's less certain. We're still not sure what the behavior being measured in these tests really is. Is it escape behavior? Coping behavior? It's tough to say, and you can't really ask the mouse. So people who study depression in mice are always looking for better tests, both to induce depressive like behavior, and to measure it.

And one of the best ways to do this is to look to a mouse's normal behavior. Preference for sweet things, fear of open, bright spaces, fights for hierarchy. By knowing how mice behave, you can take advantage of natural behaviors, and use them to look at "depression" in mice.

But sweet things, big spaces, and mouse fights are one thing. It seems a little gross to look at the urine.

But it also seems SMART. After all, mice communicate with each other through scent, and urine is one of the best ways to spread a scent around. Males use it to mark their territory, to hook up with lady mice, etc. So any change in urine marking (say, marking less), is probably not a good thing. But can it be used as sign of depressive-like behavior in mice?

To look at this, the authors of this paper used one of the best ways to induce "depression" in mice: social defeat, aka, mouse bullying. A mouse is put into the home cage of a bigger, stronger, more aggressive mouse. The aggressive mouse resents this intrusion into his territory and will beat up the poor invader mouse. Usually the combatants are separated after about 5 minutes to prevent the invader mouse from becoming hurt, but the invader mouse is kept nearby, behind a partition, where he can see the "bully" mouse, and where the bully mouse can see him, smell him, and threaten him. After about 10 days of this social defeat, the poor invader mouse isn't very happy. If tested in an open field with a new mouse to interact with, he will stay away, and he drinks less sucrose than his non-bullied counterparts.

He behaves differently...but does he pee differently? The authors of the study took white paper and laid it down in the middle of an open field. On it, they put a dab of urine from a female mouse in proestrous. This is when the female mouse is fertile, and male mice love to smell the pee of a lovely lady. Not only do they love to smell it, they like to pee around it. So all you have to do, is put the mouse in the open field with the dab of lady urine, and let have at. After a few minutes, take up the paper, dry it out (it'll STILL smell), and then spray it to turn the urine purple.

mouse pee normal
(Image provided by the author. I call it "Pollock in Purple")

Above you can see a mouse I would have nicknamed "the dragger". He doesn't sprinkle it around, he DRAGS it around, and he is letting that lady know that he is HERE and READY.

...but what if that mouse goes through social defeat?

mouse pee depressed
(Image courtesy of the author. I call it "Clean Sheets")

Ouch. You can see the dot in the one quadrant, that's where the lady's urine was. But the male's? He's not letting ANYBODY know he's there. Poor guy's just holding it. This goes well with a particular aspect of depressive-like behavior: anhedonia, this avoidance of things that usually make you happy. Lady mouse pee definitely makes male mice happy, and avoidance of it might constitute anhedonia.

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(Figure 4E from the paper)

Here you can see the overall results. The normal mice are on the left, and show lots of preference for making in the area with the lady mouse pee. In the middle, however, are the mice susceptible to social defeat. Overall they marked WAY less. On the far right, there's another group: the socially resilient mice. These are mice that, when exposed to social defeat, don't give up and don't show "depressive-like" behaviors. A good number of mice when you socially defeat a group will always be resilient, and they are as important to study as the more susceptible mice, not only allowing us to study what makes a mouse subject to "depression", but what can protect them as well, findings that could help us study similar behaviors in humans.

But how does the urine marking compare to other tests? The authors performed a large number of other behavioral tests that have already been established for depressive-like behavior. They found that the urine marking correlated well with all of them. Not only that, the lack of urine marking in socially defeated mice could be REVERSED with treatment of the antidepressant fluoxetine (Prozac). And mice also marked more when you gave them enriched environments, something thought to protect against depressive-like behavior in mice.

While this test probably can't be used for studies in females (though social defeat is also difficult in females, as they usually don't fight), it's a great way of taking advantage of a mouse's natural behaviors to study things like depression. At least, it is if you're willing to tolerate vast piles of what is probably very smelly purple paper.

This is where the art comes in. I love the way these urine marked papers look, like Pollock paintings! Not only that, they represent the "mood" of the mouse that made them, "depressive-like", or normal, enriched, or even with fluoxetine. It's like mousey feelings on paper. And in times of short science funding, we can't let this opportunity pass us by. I say, get the smell out, frame them up, and sell mouse art (maybe with the pay prints of the mouse who made it)! I would definitely have one of those on my wall. I think it'd be a great way to raise science funding. Not only does it produce art, it teaches people important things about how we study depression using mice. Art and education! Now, if only we could get the SMELL out first...

Lehmann et al. "Urine scent marking (USM): A novel test for depressive-­‐like behavior and a predictor of stress resiliency in mice." PLoS ONE, 2013. The study is available open access.

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