Abstract
BackgroundPrevious studies have shown that vagus nerve stimulation (VNS) can attenuate inflammatory responses in peripheral tissues and also improve some neurological disorders and cognitive function in the brain. However, it is not clear how VNS is involved in neuropathological processes in brain tissues. Here, we investigated the regulatory effects of VNS on the production of proinflammatory cytokines in the hippocampus of an animal model of continuous stress (CS).MethodsCS was induced by placing rats in cages immersed with water, and acute or chronic electrical stimulation was applied to the cervical vagus nerve of CS animals. Protein levels in the gastric and hippocampal tissues were measured by western blotting and protein signals analyzed by immunofluorescence staining. von Frey test and forced swimming test were performed to assess pain sensitivity and depressive-like behavior in rats, respectively.ResultsLevels of TNF-α, IL-1β, and IL-6 in the gastric and hippocampal tissues were significantly increased in CS animals compared to the untreated control and downregulated by acute VNS (aVNS). Iba-1-labeled microglial cells in the hippocampus of CS animals revealed morphological features of activated inflammatory cells and then changed to a normal shape by VNS. VNS elevated hippocampal expression of α7 nicotinic acetylcholine receptors (α7 nAChR) in CS animals, and pharmacological blockade of α7 nAChR increased the production of TNF-α, IL-1β, and IL-6, thus suppressing cholinergic anti-inflammatory activity that was mediated by VNS. Chronic VNS (cVNS) down-regulated the hippocampal production of active form of caspase 3 and 5-HT1A receptors and also decreased levels of TNF-α, IL-1β, and IL-6 in the gastric and hippocampal tissues of CS animals. Pain sensitivity and depressive-like behavior, which were increased by CS, were improved by cVNS.ConclusionsOur data suggest that VNS may be involved in modulating pathophysiological processes caused by CS in the brain.
Highlights
Previous studies have shown that vagus nerve stimulation (VNS) can attenuate inflammatory responses in peripheral tissues and improve some neurological disorders and cognitive function in the brain
We have recently reported that the afferent component of VNS increased cholinergic nerve activity in the dorsal vagal complex and resulted in the upregulation of α7 nAChR levels in the liver [12]. α7 nAChR activity in the brain was shown to participate in the regulation of NMDA and GABA receptor activation and correlate with the occurrence of Schizophrenia [17,18,19]
Gastric inflammation in continuous stress (CS) animals is ameliorated by acute VNS (aVNS) It was previously reported that CS in experimental animals causes severe inflammation in the stomach [24]
Summary
Previous studies have shown that vagus nerve stimulation (VNS) can attenuate inflammatory responses in peripheral tissues and improve some neurological disorders and cognitive function in the brain. It is not clear how VNS is involved in neuropathological processes in brain tissues. Since VNS is given to the exposed nerve in experimental animals, anti-inflammatory effects can be influenced by afferent nerve activity through feedback loop in the dorsal vagal complex [10,11,12]. Ascending vagus nerve activity may be involved in activating brainstem nuclei for neuromodulation and affect the limbic system and cerebral cortex, modulating emotional and cognitive function in the brain [7]. Direct evidence verifying VNS-modulated neuroinflammation in the brain via α7 nAChR has not been reported so far
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