Brain region identified as key controller of aggression

Scientists have discovered that a specific area within the brain, known as the cortical amygdala, plays a pivotal role in determining whether male mice behave aggressively or in a friendly manner. This region becomes active when male mice detect scents from other males and when they engage in aggressive actions. Researchers found that reducing the activity of this brain area lessened aggressive behaviors and encouraged more sociable interactions. This work, published in Nature, is the first to pinpoint a single brain area capable of halting aggressive social behavior and encouraging pro-social actions.

Researchers at Mount Sinai were interested in this topic because aggression is a fundamental behavior across species, and studying it in detail could reveal general principles about how the brain controls behavior.

“Aggression is a highly conserved behavior of great importance throughout the animal kingdom, explained study author Antonio Aubry, an instructor at the Icahn School of Medicine. “Thus, by studying the neurobiology of aggression, it has the potential to uncover general principles regarding the relationship between the brain and behavior across a diverse number of species. In humans, aggression is a symptom in numerous psychiatric disorders and can induce psychiatric conditions in victims of aggression. Therefore, a deeper understanding of the neurobiology of aggression has potential to inform therapeutic interventions across many neuropsychiatric disorders.”

To investigate this, the research team conducted a detailed analysis of brain activity in male mice. They used a method to make the brains transparent, allowing them to visualize activity across the entire brain at a cellular level. They looked specifically for cells that were active after male mice had interacted with another male mouse in a standard test of aggression, called the resident-intruder test. Using advanced computer analysis, they mapped the activity patterns across the entire brain. This analysis revealed a network of interconnected brain regions that were particularly active in aggressive male mice, but not in non-aggressive male mice or in female mice.

Within this network, one region stood out: the posterolateral cortical amygdala. This area is part of the olfactory cortex, which is involved in processing smells. The researchers discovered that this cortical amygdala region acts as a central hub within the aggression network, having strong connections to other regions within the network. They observed that specific cells in this area, which respond to the hormone estrogen, were highly active both when mice were exposed to smells from other male mice and when they were exhibiting aggressive behavior.

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“We performed a brain-wide screen of neural activity and discovered that the posterolateral cortical amygdala (COApl) is a key region in shaping the outcome of social interactions in mice,” Aubry told PsyPost.

To further investigate the role of the cortical amygdala, the scientists used several techniques to manipulate its activity. They used tools to temporarily reduce or increase the activity of these specific cells in the cortical amygdala of male mice. When they reduced the activity of these cells, they observed a significant decrease in aggressive behavior. Mice spent less time attacking other males and more time simply investigating them in a friendly manner.

“When mice transition from investigating an animal to attacking, activity in a population of cells which express estrogen receptor 1 (ESR1) is heightened,” Aubry explained. “When we inhibit activity of ESR1 expressing in the COApl, mice engage in more pro-social interaction and less aggression.”

Remarkably, reducing the activity in this brain region didn’t seem to affect the mice’s general sense of smell or their ability to tell the difference between male and female mice based on scent. This suggested that the cortical amygdala is specifically involved in controlling the aggressive aspect of social behavior, rather than just processing smells in general.

“We were surprised that the COApl increased pro-social interaction,” Aubry said. “It was thought that inhibiting the COApl would decrease both aggression and social interaction because this region is part of the olfactory system, which mice use to detect odor cues from other mice. However, we found that mice had no problem detecting the presence of other mice.”

To understand how this brain region exerts its influence, they examined its connections to other brain areas. They found that the cortical amygdala communicates with regions like the ventromedial hypothalamus and the central amygdala, which are known to be involved in aggression. By specifically inhibiting the connections from the cortical amygdala to these downstream regions, they were able to replicate the effect of directly inhibiting the cortical amygdala itself, reducing aggressive behavior.

These findings indicate that the cortical amygdala acts as a key control center for aggression in male mice. It appears to be sensitive to olfactory cues, particularly those from other male mice, and plays a critical role in the transition from social investigation to aggressive actions. By manipulating this single brain region, researchers were able to shift mice between aggressive and pro-social behaviors.

The researchers acknowledge that the whole-brain activity mapping technique they used provides a broad overview but lacks fine-grained detail. It does not capture the precise timing of nerve cell activity or differentiate between specific types of nerve cells. “We view the information gained from this technique as a rough map of the territory to use a guide for more in-depth studies,” Aubry said.

Looking ahead, the research team plans to further investigate how the cortical amygdala fits into the larger brain network that governs aggressive behavior. “Future research will be aimed at understanding how the COApl fits in a broad network of brain regions which enable aggressive behavior,” Aubry explained. “For example, which regions that receive inputs from the COApl are active during aggressive behavior? How are the regions affected when we manipulate the COApl?”

The study, “A crucial role for the cortical amygdala in shaping social encounters,” was authored by Antonio V. Aubry, Romain Durand-de Cuttoli, Elizabeth Karpman, Rachel L. Fisher-Foye, Lyonna F. Parise, Flurin Cathomas, C. Joseph Burnett, Yewon Yang, Chongzhen Yuan, Alexa R. LaBanca, Kenny L. Chan, Kion T. Winston, Hsiao-yun Lin, Farah Dackour, Arman A. Tavallaei, Johana Alvarez, Tadaaki Nishioka, Hirofumi Morishita, Robert C. Froemke, Long Li, and Scott J. Russo.