The hypothalamic paraventricular nucleus mediates vagus nerve stimulation-enhanced gastric emptying
Background: Vagus nerve stimulation (VNS) improves gastrointestinal (GI) motility, but its central regulatory mechanisms remain unclear. The hypothalamic paraventricular nucleus (PVN) regulates autonomic and neuroendocrine functions. We investigated whether PVN centrally regulates the prokinetic effects of VNS. Methods: Cervical VNS was applied to rats with intestinal manipulation (IM)-induced gastroparesis. GI motility was assessed by gastric emptying (GE) and geometric center (GC) of fluorescein isothiocyanate-dextran. PVN activation during VNS was evaluated by extracellular neuronal firing recording and c-Fos immunostaining. PVN electrical stimulation and muscimol inhibition assessed its causal role. Serum levels of GI motility-related hormones ghrelin and motilin, inflammatory markers TNF-, interleukin (IL)-6, and corticosterone, and gut expression of motilin receptor (MTLR) and myeloperoxidase (MPO), a neutrophil marker, were assessed as potential downstream mediators. Results: IM impaired GE and GC and increased TNF- and IL-6. Cervical VNS enhanced GE and GC, reduced TNF-, IL-6, and MPO, and activated the dorsal motor nucleus of the vagus, nucleus of tractus solitarius, and PVN. PVN neuronal firing increased during VNS in a stimulation-strength dependent manner. Direct PVN stimulation at VNS-evoked firing frequencies enhanced GE, MTLR expression, and serum motilin, which positively correlated with GE. PVN stimulation also reduced IL-6 and MPO. Conversely, PVN inhibition attenuated VNS-enhanced GI motility, and MTLR expression and reduced its anti-inflammatory effects on IL-6 and MPO, although IL-6 was not correlated with GE. Conclusion: PVN acts as a central regulator within the vagal circuit, activated by VNS and gating VNS-enhanced vagal efferent output for gastric emptying and anti-inflammatory effects.