I encountered Nest making and oxytocin comparably promote wound healing in isolation reared rats  while reading about how stress affects wound healing, and it drew me in with its lure of drawing connections between nest making and oxytocin. Oxytocin does a lot of things in the body, but what this paper was interested in was its participation in social bonding. You all must already know the coolest story about oxytocin, the story about the two species of voles. The species are almost identical. One species mates for life, one doesn’t. The one that does has more receptors in its brain for oxytocin than the one that doesn’t.
Because of the promise of learning more about oxytocin, I chose this paper for my second and final journal club presentation. The second time is a lot less scary than the first, I learned, and preparation goes faster.
This paper took a while to get to oxytocin, so let me start at the beginning. The authors had run three separate experiments which the paper covered. In the first study, Assessment of wound healing due to Nestlet treatment, they gave some rats a burn on their backs. (It was a pretty serious burn; two of the rat pups died of shock after receiving it.) Then they put them into three groups. One group of rats lived in sets of three (“group housed”). One group of rats lived alone (“isolation housed”). And one group of rats lived alone, but were given Nestlets, which are little cotton squares which can be used to make nests. They compared the healing rates of the three groups. The group housed rats healed the fastest; the isolation housed rats which had Nestlets to use to make nests healed almost as fast (statistically there was no significant difference); and the isolation housed rats without Nestlets healed most slowly.
They asked themselves: why does nest making help rats heal better? It seems like the mechanism has to be central (in the brain, rather than in the rest of the body), since a nest is really environmental enrichment. In their second experiment, Time series analysis of wound healing and comparison of wound healing with Nestlets to wound healing with oxytocin, they repeated their first experiment, but this time with a fourth group of rats: isolation housed rats who were injected with oxytocin once a day for several weeks. Why oxytocin? The idea seemed to be that rats build nests together, and if a rat lives alone, building a nest is still somehow a social act. Since oxytocin is released during social bonding, a dose of oxytocin might theoretically substitute for having other rats around or for nest building. And indeed, the rats given oxytocin healed faster, with rates similar to the rates of rats given Nestlets.
Finally, in Assessment of behavior and brain changes due to Nestlet administration, they had four groups of rats: group housed rats without Nestlets; group housed rats with Nestlets; isolation housed rats with Nestlets; isolation housed rats without Nestlets. No rats were burned in this experiment. They demonstrated gene expression changes (mRNA changes) in the brains of rats given Nestlets, and demonstrated behavior changes (decreased hyperactivity in an “open field test”).
They conclude by suggesting that Nestlets do affect wound healing rates; these changes seem to happen because of changes in the brain (though that isn’t proven); and this particular model of wound healing and Nestlet administration might be a good model for studying stress impairment of physical health in humans.
I had gone into this paper enthusiastically, because oxytocin is probably my favorite hormone. I came out the other end bothered on several levels, but decided to present the paper at journal club anyways, because it seemed like a good exercise. The attendees seemed as bothered by the paper as I was, and contributed more issues with it than those I’d come up with; actually, the presentation felt really enjoyable to me as a result.
What bothered me? To start, why were the rats not given any analgesics at all? Perhaps the researchers felt that pain killers would have confounded their study design in some way, but I would have been interested to know what way. As it stood, I wondered if they simply hadn’t thought of it.
Can you really say that the effects of nest making are centrally mediated (take place in the brain) just because they are similar to the effects of oxytocin? Can you even say that the effects of nest making are related to the effects of social interactions? No, you cannot. Perhaps the tool used here for measuring rate changes in wound healing was so insensitive that any number of changes would look similar. Perhaps the changes were in fact very similar but caused by very different things. (One possibility proposed by someone at journal club: the rats which were able to nest improved because the nests helped them keep warm better, something which group housed rats use each other to do.) To their credit, the authors of this paper did state that they hadn’t proven that the effects of Nestlets were centrally mediated or even related to the effects of oxytocin administration. But if they knew that their study wasn’t going to answer that question, why include the oxytocin group at all? Or, if they really were interested in comparing the two mechanisms, why not include an oxytocin group in the experiment in which they looked at behavior changes and mRNA changes in the brain?
The studies certainly did demonstrate that oxytocin administration improves wound healing in isolation reared rats. But does this have to do with the fact that oxytocin is associated with bonding? It might have been interesting to see if oxytocin administration improved wound healing in group housed rats as well.
The studies also demonstrated that providing Nestlets does improve healing rates in isolation housed rats. However, one rat researcher at journal club pointed out that, in fact, they couldn’t even say that “nest building” caused the improvement. Perhaps it was just the exercise of moving the Nestlets around the cage. She suggested a control group which was given exercise wheels.
The suggestion that this model could be useful to study the physical effects of stress in humans gave me pause, as well. Different kinds of stress have different effects. This kind of social isolation stress isn’t necessarily going to affect a human the same way some other kind of stress might, like job-related stress. In fact, one journal club attendee pointed out that the slower wound healing rates in the isolation housed rats might have less to do with social isolation stress, and more to do with the fact that group housed rats are able to lick each other’s wounds. (None of us knew if rats actually did that, though.)
As a veterinary student, I was also a little saddened by the fact that this paper was never placed by its authors into the context of laboratory animal medicine. Though the purpose of the paper was to illustrate a model that is useful for human medicine, I felt at least a sentence could have been devoted to explaining the context of enrichment for laboratory animals and why it is important.
At the end of the paper, the authors explained some future directions for their research, including giving oxytocin antagonists to rats with Nestlets. This would prevent oxytocin from acting in those rats. If the effects of the Nestlets were blocked in those rats (i.e., if their wound healing slowed), then we might conclude that oxytocin had something to do with the mechanism of Nestlets’ effects. That would be an interesting next step and would definitely clarify the Nestlet/oxytocin relationship, if there is one. I wish that they had waited to publish this paper until they could include those findings; as it is, the paper felt somewhat incomplete.
We talked a little bit about the journal that this paper was published in: PLoS ONE, an open access journal. One attendee felt that open access journals are likely to publish lower quality papers. I hope that’s not actually true, since I believe open access to be important. If this paper weren’t open access, I wouldn’t be able to provide a link to its full text in this blog post!
Of course, the paper did have some interesting things to say. Nest making improves wound healing in socially isolated rats. That’s interesting! (But we don’t really have any idea why it does this, at least not based on this paper.) Oxytocin also improves wound healing in socially isolated rats, which I find even more interesting. I’m curious whether oxytocin has been used in wound healing experiments in the past. I know that research has suggested in the past that happily bonded people are healthier (though I don’t know anything about this field and therefore hesitate to try to find a reference for this assertion — if you have a good one, let us know in the comments). I’ve always wondered why. Do people living alone find taking care of themselves harder? They might be more likely to have trouble getting to the hospital, or lack caretakers when they’re ill, or just lack someone to tell them “You’re sick, go to bed.” This study suggests that loneliness might actually affect health more directly. Of course, the complete social isolation these rats experienced might have different effects from the milder isolation of someone who lives alone but works in an office. And healing from burn wounds is not the same thing as general health. It’s still food for thought.
I was definitely dissatisfied with this paper, but the presentation was fun. The attendees felt engaged and interested. I hadn’t realized before how useful it can be to present a paper that you have some issues with. It’s not something I’d do every time, but it’s a useful trick to know.
 Vitalo A, Fricchione J, Casali M, Berdichevsky Y, Hoge EA, Rauch SL, Berthiaume F, Yarmush ML, Benson H, Fricchione GL, & Levine JB (2009). Nest making and oxytocin comparably promote wound healing in isolation reared rats. PloS one, 4 (5) PMID: 19436750 [Free full text]
 Young, L. (1998). Neuroendocrine bases of monogamy Trends in Neurosciences, 21 (2), 71-75 DOI: 10.1016/S0166-2236(97)01167-3 [Abstract at oxytocin.org] [Pop-sci summary]