Interleukin-1 receptor null mutant mice show decreased anxiety-like behavior and enhanced fear memory

Abstract

IL-1beta is a proinflammatory cytokine that contributes to psychological stress responses and has been implicated in various psychiatric disorders most notably depression. Preclinical studies also demonstrate that IL-1beta modulates anxiety- and fear-related behaviors, although these findings are difficult to assess because IL-1beta infusions influence locomotor activity and nociception. Here we demonstrate that IL-1RI null mice exhibit a behavioral phenotype consistent with a decrease in anxiety-related behaviors. This includes significant effects in the elevated plus maze, light-dark, and novelty-induced hypophagia tests compared to wild-type mice, with no differences in locomotor activity. With regard to fear conditioning, IL-1RI null mice showed more freezing in auditory and contextual fear conditioning tests, and there was no effect on pain sensitivity. Taken together, the results indicate that the IL-1beta/IL-1RI signaling pathway induces anxiety-related behaviors and impairs fear memory.

Fig. 1

Influence of IL-1β or vehicle (VEH) on elevated plus maze and locomotor activity. (A) IL-1β infused rats showed a reduction in number of entries to open arms (t₉ = 2.563, P < 0.05; n = 5–6 per group) and (B) to total arms (t₉ = 2.892, P < 0.05). (C) There was a tendency for a decrease in total time spent in open arms (t₉ = 1.523, P < 0.1). (D) IL-1β infusion decreased general locomotor activity over 60 min time period. *P < 0.05 compared to VEH rats in the t-test, mean ± S.E.M.

Fig. 2

Anxiety-like behaviors in IL-1RI KO mice. (A) IL-1RI KO mice showed a reduced latency to drink in the novelty-induced hypophagia test (t₂₈ = 2.252, P < 0.05; n = 14–16 per group), (B) spent less time in open arms in the elevated plus maze (t₁₄ = 2.172, P < 0.05; n = 8 per group), and (C) took less time to first enter into dark chamber in the light/dark box test (t₁₄ = 2.567, P < 0.05; n = 8 per group) than WT mice. (D and E) However, there is no difference in the homecage locomotor activity (D) (t₁₃ = 0.341, P = n.s.; n = 7–8 per group) or immobility in the forced swim test (E) (t₁₁ = 0.226, P = n.s.; n = 6–7 per group) between IL-1RI KO and WT mice. *P < 0.05 compared to WT mice in the t-test, mean ± S.E.M.

Fig. 3

Fear conditioning in IL-1RI KO mice. (A) There was no difference in mean percentage of freezing during the intervening three tone-shock pairings of the 2 min ITI (F_1,14 = 0.137, P = n.s.; n = 8 per group). (B and C) IL-1RI KO mice showed more freezing during 5 min contextual testing (B, t₁₄ = 2.298, P < 0.05) and during 3 min tone-cued testing (C, t₁₄ = 3.691, P < 0.01) than WT mice. (D) There was no difference in shock sensitivity for each response of flinch, jump, run, and sonic vocalization between WT and IL-1RI KO mice (flinch, t₁₂ = 0.318; jump, t₁₂ = 1.355; run, t₁₂ = 1.167; and vocalization t₁₂ = 1.433, all Ps = n.s.). *P < 0.05, **P < 0.01 compared to WT mice in the t-test, mean ± S.E.M.