Pharmacologic activation of cholinergic alpha7 nicotinic receptors mitigates depressive-like behavior in a mouse model of chronic stress

作者：Dan Zhao, Xulin Xu, Lin-na Pan, Wei Zhu, Xiaopei Fu, Lianjun Guo, Qing Lü, Jian Wang · 发表于：Journal of Neuroinflammation · 年份：2017 · DOI：10.1186/s12974-017-1007-2 · 被引用次数：84 · 研究领域：Vagus Nerve Stimulation Research、Nicotinic Acetylcholine Receptors Study、Tryptophan and brain disorders

BACKGROUND: It has been shown that chronic stress-induced depression is associated with exaggerated inflammatory response in the brain. Alpha7 nicotinic acetylcholine receptors (α7nAChRs) regulate the cholinergic anti-inflammatory pathway, but the role of cholinergic signaling and α7nAChR in chronic stress has not yet been examined. METHODS: In this study, we used a well-documented model of depression in which mice were exposed to 6 h of restraint stress for 21 consecutive days. Components of cholinergic signaling and TLR4 signaling were analyzed in the hippocampus. The main targets of neuroinflammation and neuronal damage were also evaluated after a series of tests for depression-like behavior. RESULTS: Chronic restraint stress (CRS) induced alterations in components of central cholinergic signaling in hippocampus, including increases in choline acetyltransferase protein expression and decreases in nuclear STAT3 signaling. CRS also increased TLR4 signaling activity, interleukin-1β, and tumor necrosis factor-α expression, microglial activation, and neuronal morphologic changes. Cholinergic stimulation with the α7nAChR agonist DMXBA significantly alleviated CRS-induced depressive-like behavior, neuroinflammation, and neuronal damage, but these effects were abolished by the selective α7nAChR antagonist α-bungarotoxin. Furthermore, activation of α7nAChRs restored the central cholinergic signaling function, inhibited TLR4-mediated inflammatory signaling and microglial activity, a...