Vagus nerve stimulation modulates hippocampal inflammation caused by continuous stress in rats

J Neuroinflammation. 2022 Feb 2;19(1):33. doi: 10.1186/s12974-022-02396-z.


Background: Previous 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).

Methods: CS 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.

Results: Levels 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.

Conclusions: Our data suggest that VNS may be involved in modulating pathophysiological processes caused by CS in the brain.

Keywords: Cholinergic anti-inflammation; Continuous stress; Hippocampus; Inflammatory cytokines; Neuroinflammation; Vagus nerve stimulation.

MeSH terms

  • Animals
  • Hippocampus / metabolism
  • Inflammation / metabolism
  • Inflammation / therapy
  • Rats
  • Vagus Nerve
  • Vagus Nerve Stimulation*
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism


  • alpha7 Nicotinic Acetylcholine Receptor