TY - JOUR
T1 - Pharmacologic activation of cholinergic alpha7 nicotinic receptors mitigates depressive-like behavior in a mouse model of chronic stress
AU - Zhao, Dan
AU - Xu, Xulin
AU - Pan, Linna
AU - Zhu, Wei
AU - Fu, Xiaopei
AU - Guo, Lianjun
AU - Lu, Qing
AU - Wang, Jian
N1 - Funding Information:
This research was supported by the National Natural Science Foundation of China (Nos. 5351603910, 81001432, 81001425, and 81173038), the Fundamental Research Funds for the Central Universities (HUST: No. 2016YXMS190), the National Institutes of Health (R56 NS096549, R21 NS101614, R01AT007317, R01NS078026), and a “Stimulating and Advancing ACCM Research (StAAR)” grant from the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/2
Y1 - 2017/12/2
N2 - 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, and increased the number of regulatory T cells in the hippocampus. Conclusions: These findings provide evidence that α7nAChR activation mitigates CRS-induced neuroinflammation and cell death, suggesting that α7nAChRs could be a new therapeutic target for the prevention and treatment of depression.
AB - 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, and increased the number of regulatory T cells in the hippocampus. Conclusions: These findings provide evidence that α7nAChR activation mitigates CRS-induced neuroinflammation and cell death, suggesting that α7nAChRs could be a new therapeutic target for the prevention and treatment of depression.
KW - Chronic restraint stress
KW - Depression
KW - Neuroinflammation
KW - Nicotinic acetylcholine receptor
KW - TLR4
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U2 - 10.1186/s12974-017-1007-2
DO - 10.1186/s12974-017-1007-2
M3 - Article
C2 - 29197398
AN - SCOPUS:85036560308
SN - 1742-2094
VL - 14
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
IS - 1
M1 - 234
ER -