Vagus Nerve Stimulation as a Treatment Strategy for Gulf War Illness
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Background: Gulf War Illness (GWI) afflicts 25%-33% of the approximately 700,000 military personnel who served in the Persian Gulf War that included Southwest Asia. As GWI is a chronic multi-symptom illness, a variety of symptomology is observed in afflicted personnel. These symptoms include cognitive impairments, headaches, widespread pain, fatigue, gastrointestinal and respiratory issues, as well as other unexplained abnormalities that do not fit into classical medical diagnostic criteria. Treatment options are lacking and are sorely needed to address these chronic, ongoing issues suffered by the brave men and woman who served in the Persian Gulf War.This proposal will focus on particular topics of interest that pertain to the pathobiology of GWI symptomology. Such symptomology has been linked to alterations in central nervous system structure and function, in particular, the role of glial cells, astrocytes and microglia. As glial activation is one hallmark of neuroinflammation, central neuroinflammatory processes are also observed in many exposure models of GWI. As with most inflammatory responses, including a neuroinflammatory response, the response will include peripheral inflammation. Consistent with this notion, studies have cited systemic immune abnormalities in association with GWI. Considering that pain is associated with chronic inflammation and neuroinflammation, including activation of glial cells, it is not surprising that many GWI Veterans report widespread pain. Finally, because of the observation of altered gastrointestinal, cardiovascular, and respiratory issues, research has also focused on the autonomic nervous system and hypothesized that the dysfunction could be related to a lack of parasympathetic tone.The vagus nerve is the thread that links all of these symptom domains together. The vagus nerve is the tenth cranial nerve and regulates the autonomic nervous system through its cholinergic parasympathetic innervation. By way of its efferent and afferent connections, the vagus nerve also mediates the cholinergic anti-inflammatory pathway. This pathway is an immune/neuroimmune reflex pathway that functions to modulate the inflammatory response and ultimately to restore homeostatic functioning. Interestingly, stimulation of the vagus nerve decreases inflammation and neuroinflammation, including glial activation. Vagus nerve stimulation (VNS) also decreases various types of pain, as well as migraines and chronic debilitating headaches. All of these are often seen in GWI. Therefore, the hypothesis of this proposal is that VNS will reverse GWI symptomology. We will test our hypothesis using an established mouse model of GWI symptpmology. Specific Aims: We will test two specific aims for this proposal:Specific Aim 1: Short-term VNS will reverse chronic cognitive, behavioral, pain sensitivity, and pathobiological deficits in a GWI model.Specific Aim 2: Long-term VNS will reverse chronic cognitive, behavioral, pain sensitivity, and pathobiological deficits in a GWI model.Study Design: Our study design is to induce GWI in mice, wait the equivalent of 23 human years, initiate VNS therapy for either 2 or 4 weeks, and then perform behavioral testing followed by pathobiological analysis. Impact: The potential impact of our studies is that if the outcomes support our hypothesis, VNS has the potential to be easily and swiftly adapted in the clinic to offer a therapeutic option to improve the quality of life for GWI Veterans.