Chronic stress contributes to the development of psychiatric disorders including anxiety and depression. Several inflammatory-related effects of stress are associated with increased interleukin-1 (IL-1) signaling within the central nervous system and are mediated by IL-1 receptor 1 (IL-1R1) on several distinct cell types. Neuronal IL-1R1 is prominently expressed on the neurons of the dentate gyrus, but its role in mediating behavioral responses to stress is unknown. We hypothesize that IL-1 acts on this subset of hippocampal neurons to influence cognitive and mood alterations with stress. Here, mice subjected to psychosocial stress showed reduced social interaction and impaired working memory, and these deficits were prevented by global IL-1R1 knockout. Stress-induced monocyte trafficking to the brain was also blocked by IL-1R1 knockout. Selective deletion of IL-1R1 in glutamatergic neurons (nIL-1R1−/−) abrogated the stress-induced deficits in social interaction and working memory. In addition, viral-mediated selective IL-1R1 deletion in hippocampal neurons confirmed that IL-1 receptor in the hippocampus was critical for stress-induced behavioral deficits. Furthermore, selective restoration of IL-1R1 on glutamatergic neurons was sufficient to reestablish the impairments of social interaction and working memory after stress. RNA-sequencing of the hippocampus revealed that stress increased several canonical pathways (TREM1, NF-κB, complement, IL-6 signaling) and upstream regulators (INFγ, IL-1β, NF-κB, MYD88) associated with inflammation. The inductions of TREM1 signaling, complement, and leukocyte extravasation with stress were reversed by nIL-1R1−/−. Collectively, stress-dependent IL-1R1 signaling in hippocampal neurons represents a novel mechanism by which inflammation is perpetuated and social interactivity and working memory are modulated.
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The RNA-sequencing data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus (DiSabato et al., 2020) and are accessible through GEO Series accession number GSE149195 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149195).
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This research was supported by NIMH R01-MH-109165 and R21-MH-099482 (to NQ), NIMH R01-MH-119670 and NIMH R01-MH-116670 (to JPG and JFS), and NIA R01-AG-051902 (to JPG). DJD, DPN, and SO were supported by a National Institute of Dental and Craniofacial Research Training Grant T32-DE-014320 (to JFS). XL and KGW were supported by the OSU Presidential Fellowship. Our RNA-sequencing was made possible by an allotment of resources from the Ohio Supercomputing Center.
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DiSabato, D.J., Nemeth, D.P., Liu, X. et al. Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0788-3