What are the bases of aggressive behavior?

In her PhD, Sabrina van Heukelum studies the biological differences behind pathological and healthy aggression.

Being a scientist hasn‘t always been the goal of Sabrina van Heukelum. When she started her Bachelor’s in Psychology in the Netherlands, she was interested in working at the clinic. But one lecture was decisive in changing her mind. “I had my first lecture about the brain (about [brain] plasticity) and I was hooked! I got so curious about how the brain works and [about] brain pathologies that I knew that I had to change my plans and become a researcher.” After that, she opted for a research-oriented Master’s instead of a clinical one. And since 2016, she has been a Ph.D. candidate in Neuroscience at the Donders Institute for Brain, Cognition, and Behaviour, in the Netherlands.

The initial idea for her Ph.D. project also came from a lecture. While the professor was explaining pathological cases of aggression in children, she started wondering what exactly happened in their brains that influence them to be like that. This motivated her to write her project to investigate the biological basis of aggression. After applying this project’s idea to one competition at her institute, she won the funding to finance her Ph.D. studies. She could finally start her research about possible neurobiological causes of aggression.

Aggression is characterized as hostile or violent behavior, in which one individual attacks another. Such behavior, present in different animal species, it’s important for survival. It can help to guarantee territories, resources, status, and/or mating partners. But for any species, there is a healthy limit. “During our lifespan, most of us will have faced, witnessed, or even committed at least one violent aggressive act. (…) While in certain situations aggression fulfills an adaptive function, it can quickly escalate into pathological behavior, and control mechanisms are needed to prevent that. Especially for us humans in our modern world, there are only a few instances where aggression is an adaptive behavior. As such, aggression is the fourth leading cause of death among people aged 15–29 in Europe alone.”

As a consequence of pathological aggression, individuals and societies pay, literally, a high cost. A study estimated violence-related expenses to be $14.76 trillion in 2017 (or 12.4% of global gross domestic product (GDP)). These included military and security expenditures, as well as costs related to physical injuries, mental health issues, property damage, and incarceration. “Victims of aggression do not only suffer from the immediate and acute physical and/or emotional harm. They also often deal with long-term physical and/or mental health problems. (…) As such, studies that show the underlying mechanisms of failed aggression control are necessary to create treatments for affected individuals.”

As mentioned before, aggression is present in many other species, not only in humans. Furthermore, different species of mammals have common brain regions shown to be involved in regulating aggressive acts. One of these species is the mouse. Usually, their aggressive behavior consists of tail rattles or bites to robust body parts, like the back. But there is one strain of mice that is naturally more aggressive. This group is called BALB/cJ, and these animals often bite other mice in more vulnerable places, like the neck, face, and belly. “Mice of the BALB/cJ strain show pathological aggression. They break all the fighting rules in the animal kingdom: they attack younger and weaker animals, they do not stop when the other animal shows submissive behavior, and they attack sensitive body parts like the belly and neck, body parts where a bite can be potentially lethal”, explains Sabrina.

Curiously, a “sibling” group of this strain, the BALB/CByJ, isn’t considered to be pathologically aggressive. They are more likely to only show the natural aggressive behavior of tail rattling and biting robust body parts. And exactly the differences between the non-aggressive and the aggressive mice strains that intrigued Sabrina and her colleagues.

To study this, they focused on one brain region previously related to controlling aggression, the anterior cingulate cortex (ACC). This area is present at the frontal cortex and is part of a network involved in emotional regulation. Their first question concerned the ACC structure. Comparing the ACC of aggressive and non-aggressive mice, are there changes in the numbers of neurons? The answer was intriguing. Despite observing a bigger volume in the ACC of aggressive mice, they saw a decreased number of neurons. Then, is there other(s) cell type(s) contributing to the increased volume? Based on their results, the answer is likely coming from another brain cell group: the glial cells. “The total number of neurons in the cingulate cortex was dramatically reduced in the aggressive mice. In contrast to the decrease in neuron number, we saw an increase in glia number”, tells Sabrina.

Scheme showing in light red the location of the anterior cingulate cortex (ACC) in the brain of different species.  Abbreviations: ACC, anterior cingulate cortex; Cg1, cingulate area 1; Cg2, cingulate area 2; IL, infralimbic cortex; MCC, midcingulate cortex; PL, prelimibic cortex. Source: van Heukelum et al, 2020.

But does the decrease or increase in the number of cells interfere with the function of the ACC? To answer this, Sabrina and her colleagues performed a behavioral assay called resident-intruder. In this assay, a mouse is put into the cage of another mouse and the researchers measure how the two animals interact. After this test, the team measured the activity of neurons by tracking a gene that is expressed whenever a neuron is active. As a result, the scientists saw that ACC neurons of aggressive mice were less active than non-aggressive ones. “We then checked the activity of cingulate cortex and we saw that the aggressive mice failed to engage their cingulate cortex during fights. Their activity level was much lower than in the non-aggressive mice.”

Then, the changes in cell numbers come together with lower activation of ACC neurons in aggressive mice. What then happens if ACC neurons are activated? Do the animals become less aggressive? This was the group’s next step. “At that point, we wondered whether we could stop the aggressive behavior if we artificially increased cingulate cortex activity. We did that with an approach called chemogenetics (also known as DREADDs), where you inject a viral construct into your brain region of interest. That construct contains a receptor that will be expressed in the excitatory neurons and activated upon injecting a certain drug. The receptor we used enabled us to increase the activity of the cingulate cortex and when we did that the mice greatly reduced their aggression. Especially the dangerous bites directed towards the belly and neck were nearly absent. So simply activating cingulate cortex helped these mice to regain control over their aggressive drive and to better assess the situation.”

The study published this year has made a great contribution in further clarifying the role of the ACC in controlling aggression. But it is important to highlight that these experiments were conducted only in male mice. Studies in females, as well as in other species, including humans, are needed to strengthen the relationship between ACC and aggression control. Furthermore, ACC isn’t the only brain area related to regulating aggression. “We have only looked at a specific part of the cingulate cortex, the anterior cingulate cortex. It is unknown how its neighboring part, the midcingulate cortex, affects aggressive behavior. Similarly, it is unclear whether all types of neurons are affected by neuron death or whether only a certain population is dying”, explains Sabrina. Finally, it is still open when exactly all the changes observed by Sabrina and her group start to happen in the brain. “When does this happen? When the mice are still very young? If so, could we prevent the neuron death, and would that prevent aggressive behavior?” All many interesting questions to be answered in the future.

When asked about her references, Sabrina highlights the importance of having supportive Ph.D. supervisors in her career. “My main references are two of my Ph.D. supervisors, Dr. Martha N. Havenith and Dr. Arthur S. C. Franca. They have taught me so much about science but also about believing in myself. I can always go to them with questions, both scientific and personal. They’ve paved the way for me to develop myself as a scientist.” Besides, she mentioned that brainstorming with her colleagues, searching the literature, and listening to scientific talks help to boost her creativity. “I also found out that new ideas flow better when having a pen and paper close and a nice piece of homemade cake!”

When not at the bench, Sabrina likes spending time with her dog and her family, especially during pandemics times. She also likes reading, watching series, and playing games. “During more normal times I like organizing game nights with friends; be it board or card games, I have a bit of a competitive streak.”

Thank you very much, Sabrina, for sharing your work and a bit of your story. A lot of success in your career! 🙂

You can follow more updates about her career here.

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