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Unique brain endothelial profiles activated by social stress promote cell adhesion, prostaglandin E2 signaling, hypothalamic–pituitary–adrenal axis modulation, and anxiety

Abstract

Chronic stress may precipitate psychiatric disorders including anxiety. We reported that Repeated Social Defeat (RSD) in mice increased accumulation of inflammatory monocytes within the brain vasculature, which corresponded with increased interleukin (IL)-1 Receptor 1-mediated activation of endothelia, and augmented anxiety-like behavior. One unknown, however, is the role of immune-activated endothelia in regulating the physiological and behavioral responses to social stress. Thus, we sought to determine the RNA profile of activated endothelia and delineate the pathways by which these endothelia communicate within the brain to influence key responses to social stress. First, endothelial-specific RiboTag mice were exposed to RSD and brain endothelial mRNA profiles from the whole brain and prefrontal cortex were determined using RNAseq. RSD increased expression of cell adhesion molecules (Icam1), inflammatory genes (Lrg1, Lcn2, Ackr1, Il1r1), and cyclooxygenase-2 (Ptgs2/COX-2). In studies with IL-1R1KO mice, there was clear dependence on IL-1R1 on endothelia-associated transcripts including Lrg1, Icam1, Lcn2. Moreover, prostaglandin (PG)E2 was increased in the brain after RSD and Ptgs2 was localized to endothelia, especially within the hypothalamus. Next, a selective COX-2 inhibitor, Celecoxib (CCB), was used with social stress. RSD increased PGE2 in the brain and this was abrogated by CCB. Moreover, CCB reduced RSD-induced Hypothalamic–Pituitary–Adrenal (HPA) axis activation with attenuation of hypothalamic paraventricular neuron activation, hypothalamic Crh expression, and corticosterone in circulation. Production, release, and accumulation of inflammatory monocytes after RSD was COX-2 independent. Nonetheless, CCB blocked anxiety-like behavior in response to RSD. Collectively, social stress stimulated specific endothelia RNA profiles associated with increased cell adhesion, IL-1 and prostaglandin signaling, HPA axis activation, and anxiety.

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Fig. 1: RSD promoted a unique RNA profile in brain endothelia consistent with increased cell adhesion, leukocyte migration, and prostaglandin synthesis.
Fig. 2: Immune-induced endothelial activation after RSD was dependent on IL-1R1.
Fig. 3: PGE2 increased in the brain after RSD and Ptgs2 was increased in the PFC and PVN.
Fig. 4: COX-2 inhibition with Celecoxib attenuated RSD-induced PGE2 signaling and HPA axis activation.
Fig. 5: COX-2 inhibition with Celecoxib attenuated RSD-induced anxiety.

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Acknowledgements

We would like to thank Dr. Ning Quan (Florida Atlantic University) for providing access to his IL-1R1r/r mouse line which was a valuable tool in these studies. Illustrations included in this publication were created with BioRender.com.

Funding

This research was supported by NIMH R01-MH-119670 and NIMH R56-MH-116670 (to JPG and JFS). WY was supported by National Institute of Neurological Disorders and Stroke Training Grant T32-NS-105864 (to JPG) and F30-MH-125524 (to WY). The authors declare no competing financial interests.

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WY, JFS, and JPG contributed to study conception and design. WY, SPS, RGB, EJG, and NRG contributed to data collection. WY, SPS, and EJG contributed to analysis and interpretation of results. WY, NRG, JFS, and JPG contributed to manuscript preparation. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to John F. Sheridan or Jonathan P. Godbout.

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Yin, W., Swanson, S.P., Biltz, R.G. et al. Unique brain endothelial profiles activated by social stress promote cell adhesion, prostaglandin E2 signaling, hypothalamic–pituitary–adrenal axis modulation, and anxiety. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01434-x

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