To kill, or not to kill? A fight club for mice


School shootings. Sexual assault in the military and religious orders. Genocide. Terrorism. We live in an aggressive world, one that habitually confronts us with acts of heinous violence. But, as a behavior, aggression is an evolutionarily conserved natural instinct in all of us -- it helps us adjust to our environment and can protect us from threats to our safety. Problems arise, however, when the ‘brakes’ on aggression are dysfunctional and this instinct bleeds into the realm of pathology. The result is a degree of violence that can have lasting implications on society.

Now, consider a laboratory mouse cage as a microcosm of society today. A day in the life of male mice in Dayu Lin’s New York University laboratory usually boasts a pattern of cooperation within the habitat of their cage. If that cooperation falters and a mouse is provoked, the instinctual defensive behavior kicks in, and an abrupt, and often immemorable, fight results. One mouse admits defeat, backs down and retreats. No one is hurt and they’re back to their typical rodent politics.

But, much of what we know about aggression comes from seeing what happens when this delicate system breaks down, and anarchy ensues amongst these little citizens. Where does the governor of this undesirable outcome lie in the brain? Lin’s group was able to explore this question by achieving refined control of select cells using a technique known as optogenetics. With this method, they bioengineered mice that have one group of cells whose activity can be controlled in real time by light:  shining light on the cells 'turns on' a certain activity, and turning the light off stops the activity. These elegant experiments have confirmed the existence of a brain structure that regulates aggression, much like the brakes of a car. This region is known as the lateral septum (LS) [1], an area that has direct physical connections to the “attack area” of our brain, anatomically known as the ventrolateral part of ventromedial hypothalamus (VMHvl) [2].

“Our latest findings show how the LS in mice plays a gatekeeping role, simultaneously ‘pushing down the brake’ and ‘lifting the foot off the accelerator’ of violent behavior,” says the study’s senior investigator, Dayu Lin.

Historically, the LS debuted in its role as a mediator of aggression on the stage of early 1920s research done on cats. Lesioning the septum led to episodes of excessive rage expressed as violent hissing, paw striking, and attacking. Among other species, damaging the LS increases aggression in rodents as well as some types of birds. In humans, patients with brain tumors in the septal region display higher levels of unprovoked irritation and aggression. Colloquially, this phenomenon came to be referred to as “septal rage.”

Damaging the lateral septum increases aggression, called “septal rage.”

Lin’s team believes that by attempting to understand septal rage in mice, they might be able to map the brain circuits, or connections, between key regions controlling aggression. By inserting an optic fiber into the LS of a mouse, the group used optogenetics to excite a select group of LS cells with blue light. When the blue stimulation came on, the mice lost their appetite to fight. In controlling the activity of these ‘brake’ cells, they were able to start, stop, and re-start bouts of aggression in the mouse. Lin’s group points out that it is no surprise that “given the high risk associated with fighting, the central nervous system has evolved an active mechanism to modulate its expression." They thus refer to the LS as a shrewd arbiter of aggression.

While the establishment of this brain circuit connecting the LS to the “attack area” is a huge step forward in understanding aggression, it is important to note that this circuit doesn’t act alone. Environmental experiences may impact it and either ignite or help resist impulses of aggression. The LS is a region that receives messages from other parts of the brain that control emotion and cognition. Each of these factors could significantly influence how well the LS does its job. Researchers are focusing future efforts on nuancing their understanding of the LS in its control of aggression.

But for now, the process of manipulating the activity in the “attack area” provides tremendous insight into how aggression is hard wired in the brain. The more we know about the aggression circuit, the better our ability to try to prevent the travesties that occur through violence. In that vein, while the act of rodent bullying may seem far removed from the mass shootings that occur in society today, researchers believe that there might be significant overlap in the circuitry that drives aggression in both species.

While the brakes of the car work fine, the society of laboratory mice may intermittently drive through their moments of innocuous rodent combat. But, given the epidemic of violence that exists today, it is of colossal importance for us to understand what happens in the brain when this control breaks down and the mouse is driven from being a good citizen of the cage to rearing its head as a violent beast. 


[1] Wong. L.C., Wang, L.,…Lin, D. (2016). Effective Modulation of Male Aggression through Lateral Septum to Medial Hypothalamus Projection. Current Biology. 26(5):593-604.

[2] Lin, D., Boyle, M. P.,…Anderson, D. (2011). Functional identification of an aggression locus in the mouse hypothalamus. Nature. 26(5):593-604.