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

Aki Takahashi, Hossein Aleyasin, Mihaela A. Stavarache, Long Li, Flurin Cathomas, Lyonna F. Parise, Hsiao yun Lin, C. Joseph Burnett, Antonio Aubry, Meghan E. Flanigan, Anna Brancato, Caroline Menard, Madeline L. Pfau, Veronika Kana, Jun Wang, Georgia E. Hodes, Tetsuya Sasaki, Michael G. Kaplitt, Sonoko Ogawa, Bruce S. McEwenScott J. Russo

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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 1β (IL-1β) in mediating individual differences in aggression using a resident-intruder mouse model. We found that nonaggressive mice exhibit higher levels of IL-1β 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-1β signaling in the DRN controls expression of aggressive behavior.

Original languageEnglish
Pages (from-to)2563-2579
Number of pages17
JournalMolecular Psychiatry
Volume27
Issue number5
DOIs
StatePublished - May 2022

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