The idea that organisms can stably inherit characteristics they acquire during their lifetimes was discarded a long time ago; the fact that it doesn't seem to happen was a big strike against the pre-Darwinian idea about evolution. But over the last few decades, that idea has been making a bit of a comeback. We've identified a few forms of epigenetic inheritance—primarily chemical modifications of DNA—that can be changed during the life of an organism but can still be passed down to its progeny. There's clear evidence that this sort of inheritance is used in plants, and there are a few hints that it could influence significant traits in animals.

Yesterday, Nature Neuroscience published a paper that provides the strongest evidence yet that an acquired trait can be passed down for several generations in mice. Animals that were trained to associate a specific smell with pain produced progeny that also were sensitive to the smell—even when their entire role in producing the next generation was limited to being a sperm donor.

The paper itself inadvertently indicates just how radical this idea is. Early in its introduction, the authors (Brian Dias and Kerry Ressler) write, "An important, but often ignored, factor that influences adult nervous systems is exposure of parents to salient environmental stimuli before the conception of their offspring." Well, yes, it has been ignored. But that's largely because nobody had any evidence that it actually happens.

To generate some evidence, Dias and Ressler turned to a very simple environment-behavior interaction: learned fear. Mice can be taught to fear the smell of a specific odorant simply by giving them electric shocks whenever they're exposed to it. It's then simple to read out the strength of this through a startle response. When they hear a loud noise, mice tend to freeze for a short period of time. If you hit them with both a loud noise and the odor they fear, they'll freeze for even longer.

Rather than testing the mice themselves, however, the researchers decided to test their offspring. And they found that mice in the next generation, as well as the generation after that, also showed an enhanced startle effect when exposed to the same chemical. They ruled out the simplest explanation for this—researcher bias—by making sure that the person measuring the response was blinded to whether the mouse they were testing was an experimental animal or a control.

That result seems a bit odd, as the extensive contact among the parents and offspring (mice will care for their young for three weeks or more) gave ample opportunity for some form of social learning. But Dias and Ressler did several experiments to rule that theory out. In one, they trained females but then had their pups raised by foster mothers. Those baby mice still responded to the same odorant. They then trained males and used them as sperm donors, with females fertilized in a completely different animal facility. The offspring still showed an enhanced fear response when the odorant was present.

How could this possible work? The authors chose their odorant (acetophenone) very carefully, because it was one where the receptor that perceives its presence had been identified. So they looked in the olfactory nerve cells and found that the sensitive mice had more neurons that expressed this receptor. In other words, the parental exposure and training seemed to prime offspring to be able to perceive the odor much more easily.

Looking at the gene itself, the authors found that the training process resulted in changes to the chemical modifications of the DNA nearby that were present in the sperm of the animals. (They also checked for changes in the proteins that package the DNA, but they found none.) Thus, they conclude that epigenetic inheritance is indeed passing the fears of the father onto at least two generations of offspring.

Overall, the behavioral and mouse work seem sound; it's tough to find a flaw that would lead you to question the author's overall conclusions. That said, there are a couple of issues in the details. To begin with, the chemical changes to the DNA don't show up in the nerve cells of the olfactory area of the brain, where the changes in the receptor's expression take place. So there's a big gap between the epigenetic changes in the DNA and the brain.

The gap exists in the other direction as well. It's not clear how a learning process that takes place in the brain ends up affecting the DNA of the germ cells. The authors suggest that odorant receptors could be present on the cells that produce sperm and eggs, which could mediate part of the effect. But the implication of this work is that the animals also have to be trained to associate it with fear for the changes to take place (although that hasn't been demonstrated). All of which would imply that the germ cells are very busy doing lots of things that don't necessarily involve the production of the next generation.

Still, the initial results seem solid and very, very interesting, so these follow-up studies are very likely to get done.

Nature Neuroscience, 2013. DOI: 10.1038/nn.3594 (About DOIs).

Editorial note: I normally avoid reading other coverage of a research paper that I'm going to cover. In this case, I read coverage by Virginia Hughes before deciding to cover this. Her piece is worth reading for a different perspective, and it quotes a researcher who works on DNA methylation who is skeptical that the changes seen in this paper can alter gene expression.