Terror Mouse!

Building a better fight-mouse through brain injections of genes.

Much of our economic and political discussions are sublimated social dominance psychology ... who "deserves" to stand higher on the totem pole, who deserves what pay, which class should rule, which cultural myth should guide us into the future. These are not technocratic issues, but questions of value embedded in our social instincts. Up till quite recently, we were under the impression that our lives needed to be run by the nobilities of blood and church. And status archetypes like princess, knight, and king- reflected in popular literature like the Harry Potter series- continue to structure our political and social systems. For example, the king-like office of president.

Obviously, all this is extremly ancient and perhaps unavoidable. All animals with any kind of social system also have a social hierarchy so that most of the time, internal conflict can be avoided and members can get on with the common goals for which the social system exists. This includes mice, which are the subject of a recent paper in Science from a lab which investigated the neurological basis of their dominance hierarchy.

The tests of status were simple. In a tube test, two mice are put into opposite ends of a one-lane tube, and the one who backs out is the dominant mouse. The mice have been trained to run to the end of such tubes to get some food, and apparently were occasionally prodded along with sticks so that they met at the middle before deciding which mouse would back out.

A second test used a natural behavior where in nests, one mouse typically chews down the whiskers of the other mice, becomming the "barber" mouse. Other tests included measurements of weight gain after food was put in a common area in limited amounts, a urine marking assay of territory size, and a sound assay, where dominant males call out ultrasonically to females with more enthusiasm. The tests all correlated with each other, leading to a coherent score of social rank.

Previous clues had directed these researchers to the medial prefrontal cortex (MPFC) as an area that shows hightened activity during dominance-related behavior. So they looked for signs of social rank in their mice in this area of the brain by slicing up their research subjects and looking for electrical activty (live slices) and various molecular signatures (dead slices).

They found that the electrical activity of randomly tested neurons in this brain region, upon chemical stimulation of glutamate receptors, was somewhat higher in dominant mice vs the lowest ranked mice. Likewise, the c-Fos gene, which gets expressed after brain activity and is used as a marker for active brain regions, shows higher mRNA levels in higher-ranking mice (below). One wouldn't necessarily assume that the brains of dominant animals are more active than lower-ranking ones, but in any case, they would have different profiles of activity, so non-dominant mice may have higher activity elsewhere in the brain.

cFos gene expression in MPFC area of brain slices reflects social dominance.

Now for the exciting part. The researchers decided to test this correlation of brain activity with social status by direct action: increasing or decreasing glutamate receptor activity in the brains of living mice by injected gene therapy. Glutamate-sensitive neurons can be "tuned" by expression of proteins Ras or Rap,  which have opposite effects in the signalling cascade involved in recycling the synaptic vesicles that contain neurotransmitters. So the researchers injected the MPFC with a virus expressing either of these proteins. The affected neurons showed strong effects, with 179% of normal activity when infected by Ras-expressing virus, and 71% of normal activity when infected with Rap-expressing virus.

"Mice infected with the Ras virus moved upward in rank, starting a easrly as 12 hours after viral injection. In contrast, mice infected with the Rap virus moved down in rank. Infection of virus expression green fluorescent protein [GFP] alone did not result in any rank shift."

The average rank shift was only one unit, out of three possible units of rank from one end of the status scale to the other. So this treatment alone is not quite sufficient to produce the über-mouse. The treatment is also incredibly crude, perhaps providing an "injection" of confidence or slight craziness.

A small brain injection might do wonders for one's social status, if one wants to go beyond the steroid, testosterone and other injections people use currently. Less facetiously, it is another example of the brain basis of our thoughts, feelings, and behaviors.

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