Anti-seizure effect and neuronal activity change in the genetic-epileptic model rat with acute and chronic vagus nerve stimulation

Abstract Background VNS showed time-dependent anti-seizure effect. However, the precise mechanism of VNS in acute and chronic anti-seizure effect has not been fully elucidated. Noda epileptic rat (NER) is genetic epilepsy model rat which exhibits spontaneous generalized tonic-clonic seizure (GTC) approximately once per 30 h and frequent dialeptic seizure (DS). We performed acute and chronic VNS on NER to focus on the acute and chronic anti-epileptic effect and neuronal activity change by VNS. Methods We performed acute VNS (2 h) on 22 NERs (VNS, n  = 11, control, n  = 11), then subsequently administered chronic (4 weeks) VNS on 10 of 22 NERs (VNS n  = 5, control n  = 5). We evaluated the acute and chronic anti-seizure effects of VNS on GTC and DS by behavioral and electroencephalographical observation (2 h every week). We carried out double immunofluorescence for biomarkers of short-term (c-Fos) and long-term (ΔFosB) neuronal activation to map regions in the brain that were activated by acute (VNS n  = 6, control n  = 6) or chronic VNS (VNS n  = 5, control n  = 5). Furthermore, we performed chronic VNS (4 w) on 12 NERs (VNS n  = 6, control n  = 6) with long-term observation (8 h a day, 5d per week) to obtain an adequate number of GTCs to elucidate the time dependent anti-epileptic effect on GTC. Results Acute VNS treatment reduced GTC seizure frequency and total duration of the DS. Chronic VNS resulted in a time-dependent reduction of DS frequency and duration. However, chronic VNS did not show time-dependent reduction of GTC frequency. There were significant c-Fos expressions in the central medial nucleus (CM), mediodorsal thalamic nucleus (MDM), locus coeruleus (LC), and nucleus of solitary tract (NTS) after acute VNS. And there were significant ΔFosB expressions in the lateral septal nucleus (LSV), medial septal nucleus (MSV), MDM, and pontine reticular nucleus caudal (PnC) after chronic VNS. Any decrease in frequency of GTCs by chronic VNS could not be confirmed even with long-term observation. Conclusion We confirmed acute VNS significantly reduced the frequency of GTC and duration of DS. Chronic VNS decreased the frequency and duration of DS in a time-dependent manner. The brainstem and midline thalamus were activated after acute and chronic VNS. The forebrain was activated only after chronic VNS.