A new study has revealed how a specific part of the brain drives aggressive behaviour in male mice, shedding light on the neural mechanisms behind social encounters. Researchers from the Icahn School of Medicine at Mount Sinai in New York have pinpointed the posterolateral cortical amygdala, or COApl, as a key player in turning curiosity into confrontation. Published in the journal Nature, the findings could deepen our understanding of aggression across species, including humans, though the scientists caution that direct parallels remain speculative.
“We are interested in aggression because it is a highly conserved behaviour of great importance throughout the animal kingdom and is a symptom of numerous psychiatric conditions,” said Tony Aubry, PhD, a researcher at the Icahn School of Medicine. “By studying the neurobiology of aggression, we have the potential to uncover general principles regarding the relationship between the brain and behaviour and inform therapeutic interventions across many neuropsychiatric disorders.”
The study delves into how male mice transition from sniffing and investigating an intruder to launching an attack, behaviours that mirror the appetitive and consummatory phases of aggression. Using advanced techniques like whole-brain mapping and targeted cell manipulation, the team discovered a network of brain regions, including the hypothalamus and olfactory cortex, that lights up in aggressive males but not in females or non-aggressive counterparts. At the heart of this network sits the COApl, an extended olfactory structure that acts as a hub, coordinating responses to social stimuli.
“In particular, we wanted to discover novel regions involved in the generation of aggressive social behaviour,” Aubry explained. “To this end, we performed a brain-wide screen of neural activity. Following a whole-brain network analysis of this activity, we discovered that the COApl was a potential novel region regulating aggression based on its functional connectivity profile.”
What sets this research apart is its focus on oestrogen receptor 1 expressing cells within the COApl, dubbed COApl Esr1 cells. These cells flare into action during both the investigative sniffing bouts that precede an attack and the attack itself, but only in males. When the researchers inhibited these cells using chemogenetic or optogenetic methods, aggression plummeted. Instead of biting or wrestling, the mice shifted towards pro-social investigation, suggesting that these cells are critical for tipping the balance from curiosity to combat. Intriguingly, this effect was absent in females, highlighting a stark sex difference in how aggression is wired.
“When recording from these cells, we found that they displayed heightened activity when animals transitioned from social investigation to attack behaviours,” Aubry noted. “When we inhibited this cell population throughout the duration of the interaction, we found that mice replaced their drive to engage in aggression with the drive to engage in pro-social interactions. When we inhibited this population as the aggressor was approaching the animal, the aggressor did not transition to attack behaviour as frequently.”
The COApl does not work alone. Its connections to the ventromedial hypothalamus and central amygdala proved essential for driving attack behaviour. By recording brain activity in real time, the team observed heightened coherence between these regions during aggressive episodes, a synchrony absent during mere investigation. This suggests that the COApl acts as a gatekeeper, amplifying the salience of social cues and pushing males towards violence when triggered.
“We also found that inhibiting the outputs of the COApl to the ventromedial hypothalamus and central amygdala shaped the outcome of social interactions in mice,” Aubry added. “These results suggest that the COApl is a key region in determining whether interactions escalate into aggression.”
Beyond aggression itself, the study hints at broader implications. While the COApl drives the act of attacking, other brain areas like the basal forebrain and ventral premammary nucleus enhance the rewarding feelings tied to aggression, whereas the lateral habenula and dorsal raphe nucleus dampen them. This interplay could explain why some individuals find aggression gratifying, a question that resonates beyond the lab.
Looking ahead, the researchers aim to explore the COApl’s role in a wider network of brain regions linked to aggression. “We are currently interested in understanding how the COApl fits into a broader network of brain regions that enable aggressive behaviour,” Aubry said. “For example, which regions receiving inputs from the COApl are active during aggressive behaviour? How are these regions affected when we manipulate the COApl?” The team is also investigating whether the COApl influences other forms of social behaviour, such as pro-social interactions in non-aggressive mice and parenting behaviour.
For now, the findings are confined to mice, but they open doors to exploring how sensory processing and brain circuitry shape social behaviour in other animals. The researchers used outbred mice to capture natural variations in aggression, mirroring the diversity seen in wild populations. As science unravels these neural threads, it edges closer to decoding the roots of conflict, a puzzle with echoes in human society.
