Histamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety

Background: Anxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general regulator for whole-brain activity, may result in anxiety, suggesting an involvement of the central histaminergic signaling in the modulation of anxiety. However, the neural mechanisms involved have not been fully identified. Methods: Here, we examined the effect of histaminergic signaling in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors both in normal and acute restraint stressed male rats by using anterograde tracing, immunofluorescence, qPCR, neuropharmacology, molecular manipulation and behavioral tests. Results: We found that histaminergic neurons in the hypothalamus send direct projections to the BNST, which forms a part of the circuitry involved in stress and anxiety. Infusion of histamine into the BNST produced anxiogenic effect. Moreover, histamine H1 and H2 receptors are expressed and distributed in the BNST neurons. Blockade of histamine H1 or H2 receptors in the BNST did not affect anxiety-like behaviors in normal rats, but ameliorated anxiogenic effect induced by acute restraint stress. Furthermore, knockdown of H1 or H2 receptors in the BNST induced anxiolytic effect in acute restraint stressed rats, which confirmed the pharmacological results. Limitations: A single dose of histamine receptor antagonist was used. Conclusions: Together, these findings demonstrate a novel mechanism for the central histaminergic system in the regulation of anxiety, and suggest that inhibition of histamine receptors may be a useful strategy for treating anxiety disorder.

Automated summary

The central histaminergic system plays an important role in regulating anxiety. Histaminergic neurons in the hypothalamus directly project to the bed nucleus of the stria terminalis (BNST), a brain region involved in anxiety and stress. The presence of histamine receptors in the BNST suggests their involvement in anxiety modulation. Blocking histamine receptors in the BNST ameliorated anxiety symptoms, suggesting a potential therapeutic strategy for anxiety disorder.