Brain mast cells link the immune system to anxiety-like behavior

Abstract

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient Kit(W-sh/W-sh) (sash(-/-)) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links.

Fig. 1.

Mast cell effects on open field behavior. (A) Sash^−/− mice (white bars) had a longer latency to enter the center square in the open field test compared to WT mice (black bars). Differences in number of entries into the center square between sash^−/− and WT mice were not significant (P > 0.05). (B) Sash^−/− mice (white bars), compared to the littermate sash^+/− mice (hatched bars), took longer to enter and had fewer entries into the center square. Data are presented as mean ± SEM. **, P < 0.01; *, P < 0.05.

Fig. 2.

Mast cell effects on elevated plus maze behavior. (A) Sash^−/− mice (white bars) had fewer entries and investigations into open arms compared to WT control mice (black bars). The latency to enter an open arm was not significantly different between sash^−/− and WT mice. (B) Sash^−/− mice (white bars) had fewer entries into open arms compared to littermate sash^+/− mice (hatched bars). While there was no difference in the number of investigations into open arms, sash^−/− mice had significantly longer latency to enter an open arm. Data are presented as mean ± SEM. **, P < 0.01; *, P < 0.05.

Fig. 3.

Mast cell deficiency effects on defecation. (A) The excretion rate was higher in sash^−/− mice (white bars) compared to WT mice (black bars) during behavioral testing in the open field arena and elevated plus maze. Baseline home cage defecation in sash^−/− and WT mice was not significantly different. (B) Sash^−/− mice (white bars) had higher defecation rates compared to littermate sash^+/− mice (hatched bars) in all behavioral tests. Baseline home cage defecation was not different between genotypes. Data are presented as mean ± SEM. **, P < 0.01; *, P < 0.05.

Fig. 4.

Cromolyn effects on open field behavior. Cromolyn injected i.p. into WT animals had no significant effects on open field behavior. There were no differences between saline and cromolyn injected animals in number of entries into the center square or the latency to enter the center square. Cromolyn injected into the lateral ventricle resulted in decreased exploratory behavior. Compared to saline injected controls, WT animals injected with cromolyn i.c.v. had fewer entries into the center square. Data are presented as mean ± SEM. *, P < 0.05.

Fig. 5.

Cromolyn effects on elevated plus maze behavior. Cromolyn injected i.p. into WT animals had no significant effects on behavior in the elevated plus maze. There were no differences between saline and cromolyn injected animals in number of entries or investigations into the open arms or the latency to enter an open arm. Cromolyn injected i.c.v. decreased the number of entries into and investigations into open arms. The latency to enter an open arm was increased compared to saline-injected controls. Data are presented as mean ± SEM. **, P < 0.01; *, P < 0.05.