Multiple Sclerosis (MS) is a neuro-inflammatory and degenerative disease with demyelination and axonal damage as pathological hallmarks. The disease is typically treated with immunomodulatory or immunosuppressive therapies with moderate efficacy in the long term. They are associated with high costs and dangerous side-effects caused by immunosuppression. Vagus Nerve Stimulation (VNS) is a well-known technique, with proven safety and cost-efficiency in refractory epilepsy. Recent research in VNS and the vagal nerve (VN) demonstrated an immunomodulatory role for the VN and VNS in inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis. Furthermore, VNS might have the potential to tackle neurodegenerative processes in MS. We will test VNS in Experimental Autoimmune Encephalomyelitis and a demyelinating model in rats, validated preclinical models for MS pathogenesis. We will also investigate chemogenetic locus coeruleus activation as an alternative approach to treat MS inflammation. Our research pioneers as it investigates VNS in a preclinical MS model, aiming to justify clinical trials. As strategic endpoint we postulate cost-efficiency and safety of VNS, and the possible neuroprotective effect of VNS, which is innovative with regards to the existing therapy.