Stress-induced microglial activation occurs through β-adrenergic receptor: noradrenaline as a key neurotransmitter in microglial activation

Background: The involvement of microglia in neuroinflammatory responses has been extensively demonstrated. Recent animal studies have shown that exposure to either acute or chronic stress induces robust microglial activation in the brain. In the present study, we investigated the underlying mechanism of brain microglial activation by acute stress. Methods: We first looked at the spatial distribution of the noradrenaline (NA)-synthesizing enzyme, DBH (dopamine beta-hydroxylase), in comparison with NA receptors-beta 1, beta 2, and beta 3 adrenergic receptors (beta 1-AR, beta 2-AR, and beta 3-AR)after which we examined the effects of the beta-blocker propranolol and alpha-blockers prazosin and yohimbine on stress-induced microglial activation. Finally, we compared stress-induced microglial activation between wild-type (WT) mice and double-knockout (DKO) mice lacking beta 1-AR and beta 2-AR. Results: The results demonstrated that (1) microglial activation occurred in most studied brain regions, including the hippocampus (HC), thalamus (TM), and hypothalamus (HT); (2) within these three brain regions, the NA-synthesizing enzyme DBH was densely stained in the neuronal fibers; (3) beta 1-AR and beta 2-AR, but not beta 3-AR, are detected in the whole brain, and beta 1-AR and beta 2-AR are co-localized with microglial cells, as observed by laser scanning microscopy; (4) beta-blocker treatment inhibited microglial activation in terms of morphology and count through the whole brain; alpha-blockers did not show such effect; (5) unlike WT mice, DKO mice exhibited substantial inhibition of stress-induced microglial activation in the brain. Conclusions: We demonstrate that neurons/microglia may interact with NA via beta 1-AR and beta 2-AR.