One gene turns low-ranking mice into alpha-rodents

By Ed Yong | September 30, 2011 9:09 am

Two mice run headfirst into one another in a narrow plastic tube that isn’t wide enough for both of them. One of them must give way. In their earlier encounter, the first mouse exerted its dominance by forcing its rival to reverse down the tube. This time, things are different; the second mouse pulls rank and the first one backs down.

Mouse hierarchies don’t change this readily, but the second mouse has been given a boon by Fei Wang at the Chinese Academy of Science. By injecting a single gene into one part of its brain, Wang turned the subordinate animal into a dominant one.

The gene that gave the mouse a burst of social mobility is GluR4. It creates part of a protein called the AMPA receptor, which allows signals to flow quickly between two neurons. By injecting extra GluR4 into a mouse’s brain, and producing more AMPA receptors, Wang strengthened the connections between its neurons. The effect is like building expressways between two cities overnight – you can have a much larger and faster flow of traffic between them.

Wang injected the extra GluR4 into a part of the rodents’ brains called the medial prefrontal cortex (mPFC), which has been linked to social rank. As early as 1986, scientists showed that rats lose their social status if they suffer injuries to their mPFCs. Wang himself found that the mPFC’s neurons signal more strongly to one another in dominant brains than in subordinate ones.

By manipulating this signalling, he could push mice up or down the social ladder. With an extra dose of GluR4, the mice gained social standing. When they confronted other mice in a cramped plastic tube, they were more likely to force their rivals to retreat, even if they had previously given way. With their new rank, they were also more likely to court female mice with high-pitched ultrasonic songs.

On the flipside, Wang managed to lower the rodents’ rank by injecting them with just a small fragment of GluR4 (GluR4Ct). On its own, this fragment scuppers AMPA receptors and weakens the communication lines between the mPFC’s neurons. This time, the newly subordinate mice were more likely to give way to individuals that they had previously bested, and they were less likely to sing to females.

How could changes in the brain of one animal affect its standing among its peers? Wang thinks that the answer lies with the mPFC. Among other roles, this region has been linked to social behaviour and hierarchies, in humans as well as mice. When computer gamers think about players who are better than they are, their mPFCs light up.

The mPFC acts like a control centre for social interactions. It exerts influence over other parts of the brain that release hormones and signalling chemicals, which affect everything from aggressiveness to fear. If you change the strength of the signals in the mPFC, the effects would ripple out across the brain. Perhaps the mice become more aggressive; maybe they become less fearful. Wang is now looking at which of these effects accounts for the rise and fall of the rodents’ ranks.

We’ve known that animals form dominance hierarchies for around a century. In 1921, Norwegian scientist Thorleif Schjelderup-Ebbe discovered one of the first examples of these hierarchies in chickens, which is why they’re more commonly known as pecking orders. They’re a vital part of animal life. An individual’s rank can drastically affect its access to mates, food and shelter. These ranks emerge very early (you can see them in two-year-old children) and they change very slowly, if at all.

But very few people have looked at how different social ranks are manifested in the brain. Wang has not only started to do that, but he has shown that manipulating the brain can actually change a mouse’s rank. It would be fascinating (and probably experimentally tricky) to see if the same trick would work in humans. It is unlikely though, especially since our social structures are much more complex. For a mouse, it’s enough to give it an extra gene that makes it pushier. We have wealth, reputation, contacts, education and discrimination to contend with.

Wang, F., Zhu, J., Zhu, H., Zhang, Q., Lin, Z., & Hu, H. (2011). Bidirectional Control of Social Hierarchy by Synaptic Efficacy in Medial Prefrontal Cortex Science DOI: 10.1126/science.1209951


Comments (6)

  1. In any bar you will easily spot evidence that manipulating the brain (with ethanol or other compounds) can change a human’s rank, drastically affecting dominance hierarchies. Under the influence of such compounds – willingly taken – some humans become more aggressive, and others become more likely to indulge in courting behaviour. The effect is temporary, as the compounds – unlike gene therapy – wear off after a day or so.

  2. Mike B

    Interesting; I wonder if effects in the mPFC in humans do have some role in social anxiety disorders. Stress or other factors changing development in the brain could logically make some people feel more anxious during social interactions, resulting in “submissive”/avoidance responses to avoid the anxiety. Might be a treatment target in there somewhere.

  3. Steve Moxon

    This is highly interesting research that is not akin to the effects of having a drink in a bar (as Richard Van Noorden imagines): simply getting more aggressive does not change relative status.
    That an individual’s rank in a reproductive-group can be artificially increased or decreased solely by manipulating a specific area of the dorsal medial pre-frontal cortex, shows that an individual’s rank in effect is in the control of the individual rather than it simply being forced from behavioural interaction with same-sex conspecifics. Others react behaviourally in a sub-dominant manner to an individual changed in no other way than specifically how rank is registered in that individual’s brain.
    If the individual effectively self-calibrates rank, then unless the whole dominance-based social system is anyway in the close mutual interest of all participants, the free-rider problem would lead to scramble competition and thence the evolution of dominance hierarchy as normally understood.
    So what pertains in these mice looks like a diluted form of cooperative-breeding, where, rather than a single breeding pair, there is breeding by many or most males, along a breeding gradient (and, more obviosuly, a sexual-access gradient) of differential reproductive outcome through autonomous differential reduced sexual motivation.
    This is the dominance-hierarchy with integral reproductive-suppression I theorised. [Moxon 2009]

  4. Richard Van Noorden

    Steve Moxon – behind my flippant comment, I am interested to know why this experiment (running down tubes) proves a change in relative status. Couldn’t it just be the mice getting more aggressive? would be interested to learn more about how you define that distinction.

  5. Steve Moxon

    Hi Richard

    The authors state in the paper that they considered just such possibilities and tested to exclude them.
    They write: “To confirm that viral manipulations in mPFC affected dominance instead of other variables that could alter tube-test behavior (fig. S3), we performed an additional dominance measure, the ultrasonic vocalization test.”

  6. Richard Van Noorden

    Thanks Steve – glad to know they checked!


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