Neuromodulatory effect of interleukin 1β in the dorsal raphe nucleus on individual differences in aggression

Heightened aggressive behavior is considered as one of the central symptoms of many neuropsychiatric disorders including autism, schizophrenia, and dementia. The consequences of aggression pose a heavy burden on patients and their families and clinicians. Unfortunately, we have limited treatment options for aggression and lack mechanistic insight into the causes of aggression needed to inform new efforts in drug discovery and development. Levels of proinflammatory cytokines in the periphery or cerebrospinal fluid were previously reported to correlate with aggressive traits in humans. However, it is still unknown whether cytokines affect brain circuits to modulate aggression. Here, we examined the functional role of interleukin 1 beta (IL-1 beta) in mediating individual differences in aggression using a resident-intruder mouse model. We found that nonaggressive mice exhibit higher levels of IL-1 beta in the dorsal raphe nucleus (DRN), the major source of forebrain serotonin (5-HT), compared to aggressive mice. We then examined the effect of pharmacological antagonism and viral-mediated gene knockdown of the receptors for IL-1 within the DRN and found that both treatments consistently increased aggressive behavior of male mice. Aggressive mice also exhibited higher c-Fos expression in 5-HT neurons in the DRN compared to nonaggressive mice. In line with these findings, deletion of IL-1 receptor in the DRN enhanced c-Fos expression in 5-HT neurons during aggressive encounters, suggesting that modulation of 5-HT neuronal activity by IL-1 beta signaling in the DRN controls expression of aggressive behavior.

Automated summary

The study demonstrated the significant role of IL-1 beta in regulating aggression, showing that non-aggressive mice had higher levels of IL-1 beta in the DRN compared to aggressive mice, and pharmacological antagonism or gene knockdown of IL-1 receptors in the DRN increased aggressive behavior. This suggests that modulation of 5-HT neuronal activity by IL-1 beta signaling in the DRN controls the expression of aggressive behavior.