Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Mar 13;40(5):1289-96.
doi: 10.1038/npp.2014.317.

The role of brain interleukin-1 in stress-enhanced fear learning

Meghan E Jones  1 , Christina L Lebonville  1 , Daniel Barrus  1 , Donald T Lysle  1
Affiliations

The role of brain interleukin-1 in stress-enhanced fear learning

Meghan E Jones et al. Neuropsychopharmacology. .

Abstract

Posttraumatic stress disorder (PTSD) has been shown to be associated with pro-inflammatory markers, including elevated plasma levels of interleukin-1β (IL-1β). However, the precise role of neuroinflammation and central immune signaling on the development of this debilitating psychological disorder is not known. Here, we used stress-enhanced fear learning (SEFL), an animal model of the disorder, to examine the role of central IL-1β in PTSD. The results show that the severe stressor in SEFL induces a time-dependent increase in IL-1β immunoreactivity and mRNA expression within the dentate gyrus of the dorsal hippocampus (DH). There was no increase in IL-1β in the basolateral amygdala or the perirhinal cortex. Moreover, blocking the action of IL-1β following the severe stressor with IL-1 receptor antagonist (10 μg, intracerebroventricular (i.c.v.), 24 and 48 h after the stressor) prevented the development of SEFL. To provide further support for the role of IL-1β in the development of SEFL, we show that systemic morphine, a treatment which is known to reduce both PTSD and SEFL, also reduces IL-1β expression in the DH induced by the severe stressor. These studies provide the first evidence that IL-1 is involved SEFL and suggest that IL-1 signaling in the brain may have a critical role in the development of PTSD.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Severe stress induced IL-1β in the dorsal hippocampus. Representative images ( × 20) of IL-1β (green) in the dorsal hippocampus from animals in each of the six groups are shown on the left. The top right panel shows ImageJ analysis of positive fluorescence stain (top right) in the dentate gyrus, CA1, CA3, basolateral amygdala, and perirhinal cortex. IL-1β immunoreactivity was significantly enhanced at 6 h after (but not immediately after) severe stress only in the dentate gyrus of the dorsal hippocampus. This enhancement persisted through 72 h (*p<0.05 compared with NS control). qPCR analysis of mRNA expression confirmed the IL-1β increase in the dorsal hippocampus that we observed with immunohistochemistry (bottom right). IL-1β mRNA was enhanced at 48 h following severe stress (*p<0.05 compared with NS control). Further, IL-1β-positive cells were also counted in the dentate gyrus of the dorsal hippocampus (bottom right) and the same pattern was confirmed. (*p<0.05 compared with 0 h). Error bars indicate SEM.
Figure 2
Figure 2
IL-1ra prevents the development of SEFL. IL-1ra infusion (i.c.v., 10 μg at 24 and 48 h after removal from Context A) significantly reduced conditioned freezing behavior in Context B across test days. There were no significant differences between groups at baseline. Within the vehicle-treated groups, foot shock in Context A (open squares) significantly enhanced freezing behavior in Context B compared with animals that did not receive foot shock in Context A (open circles), demonstrating an SEFL effect. There was no effect of IL-1ra in the group that did not receive foot shock in Context A (closed circles). Most importantly, animals that received foot shock in Context A followed by IL-1ra infusion (closed squares) did not differ from the groups that did not receive foot shock in Context A. Error bars indicate SEM.
Figure 3
Figure 3
Morphine attenuates stress-induced IL-1β in the dorsal hippocampus. Representative images ( × 20) of IL-1β (green) in the dentate gyrus of the dorsal hippocampus from animals in each of the four groups are shown in (a). ImageJ analysis of positive fluorescence stain (b) revealed that in vehicle treated animals (NS/Veh and Shock/Veh), foot shock significantly enhanced IL-1β; however, morphine administration suppressed the induction of IL-1β in animals that received foot shock followed by morphine treatment (Shock/M). IL-1β- positive cells were also counted in the dentate gyrus of the dorsal hippocampus (c) and the same pattern was confirmed. (*greater than NS/Veh, p<0.05; †greater than Shock/M, p<0.05). Error bars indicate SEM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acheson DT, Gresack JE, Risbrough VB. Hippocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder. Neuropharmacology. 2012;62:674–685. - PMC - PubMed
    1. Anagnostaras SG, Gale GD, Fanselow MS. Hippocampus and contextual fear conditioning: recent controversies and advances. Hippocampus. 2001;11:8–17. - PubMed
    1. Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G, et al. Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus. 2003;13:826–834. - PubMed
    1. Bai YM, Su TP, Tsai SJ, Wen-Fei C, Li CT, Pei-Chi T, et al. Comparison of inflammatory cytokine levels among type I/type II and manic/hypomanic/euthymic/depressive states of bipolar disorder. J Affect Disord. 2014;166:187–192. - PubMed
    1. Brennan FX, Beck KD, Servatius RJ. Proinflammatory cytokines differentially affect leverpress avoidance acquisition in rats. Behav Brain Res. 2004;153:351–355. - PubMed

Publication types

MeSH terms