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

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.

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Fig. 1: Individual difference of aggressive behavior and IL-1β response in the periphery and central nervous system.
Fig. 2: Expression of IL-1β and IL-1 receptor type 1 (IL-1R1) mRNA in the DRN of AGG and NON animals.
Fig. 3: Inhibition of IL-1β receptors in the brain increased aggressive behavior of male mice.
Fig. 4: Knockdown of IL-1 receptor type I (IL-1R1) expression in the DRN facilitated aggressive behavior of male mice.
Fig. 5: Individual difference and the effect of IL-1R1 KD in the aggressive encounter-induced activation of serotonin (5-HT) neurons in the DRN.

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Acknowledgements

This research was supported by US National Institutes of Health Grants R01 MH090264-06 and R01 MH104559-02 to SJR. The study was also supported by JSPS KAKENHI Grant Number JP17H04766, JP15K12773, and JP19H05202 to AT. We would like to thank Dr Tsuyoshi Koide and Dr Yosuke Takei for sharing experimental equipment (realtime PCR).

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Takahashi, A., Aleyasin, H., Stavarache, M.A. et al. Neuromodulatory effect of interleukin 1β in the dorsal raphe nucleus on individual differences in aggression. Mol Psychiatry 27, 2563–2579 (2022). https://doi.org/10.1038/s41380-021-01110-4

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