Vagus Nerve Stimulation Ameliorates Cognitive Impairment and Increased Hippocampal Astrocytes in a Mouse Model of Gulf War Illness

Abstract

Gulf war illness (GWI), is a chronic multi-symptom illness that has impacted approximately one-third of the veterans who served in the 1990 to 1991 Gulf War. GWI symptoms include cognitive impairments (eg, memory and concentration problems), headaches, migraines, fatigue, gastrointestinal and respiratory issues, as well as emotional deficits. The exposure to neurological chemicals such as the anti-nerve gas drug, pyridostigmine bromide (PB), and the insecticide permethrin (PER), may contribute to the etiologically related factors of GWI. Various studies utilizing mouse models of GWI have reported the interplay of these chemical agents in increasing neuroinflammation and cognitive dysfunction. Astrocytes are involved in the secretion of neuroinflammatory cytokines and chemokines in pathological conditions and have been implicated in GWI symptomology. We hypothesized that exposure to PB and PER causes lasting changes to hippocampal astrocytes, concurrent with chronic cognitive deficits that can be reversed by cervical vagus nerve stimulation (VNS). GWI was induced in CD1 mice by injecting the mixture of PER (200 mg/kg) and PB (2 mg/kg), i.p. for 10 consecutive days. VNS stimulators were implanted at 33 weeks after GWI induction. The results show age-related cognitive alterations at approximately 9 months after exposure to PB and PER. The results also showed an increased number of GFAP-labeled astrocytes in the hippocampus and dentate gyrus that was ameliorated by VNS.

Experimental Models of Gulf War Illness, a Chronic Neuropsychiatric Disorder in Veterans

“…When working with mice for GWI modeling, unique challenges and considerations are present. The most common and well‐accepted protocol only uses PB and PM in a single intraperitoneal injection (Abdullah et al., 2011; 2013; Utasv et al., 2020; Venkatasamy et al., 2021). Interestingly, exposure to DEET and chronic restraint stress are unaccounted for in most GWI mouse models.…”

“…Despite the simplified nature, mouse models of GWI have been successful in showing neurobehavioral, immunohistochemical, lipidomic, and proteomic changes (Abdullah et al, 2011(Abdullah et al, , 2012(Abdullah et al, , 2016Bryant et al, 2021;Kozlova et al, 2022). Notably, GWI induction in mice gives investigators a shorter timeline and different methodology to choose from that yields a clear progression of GWI symptoms for various interventional studies (Abdullah et al, 2011(Abdullah et al, , 2012Venkatasamy et al, 2021). In GWI, although brain damage is irreversible, we hope that these GWI-like models can help elucidate approaches to reduce or mitigate neuropsychiatric sequelae that result from GWI, especially in aged veterans.…”

“…Interestingly, exposure to DEET and chronic restraint stress are unaccounted for in most GWI mouse models. Previous models have been established for mice using 40 mg/kg DEET and chronic restraint stress, but this protocol is not commonly adopted, likely due to similar neurocognitive deficits being observed without these additional steps (Abdullah et al., 2012; 2013; Kodali et al., 2018; Kozlova et al., 2022; Venkatasamy et al., 2021). Additionally, GWI chemicals administered via the intraperitoneal route may also cause postinjection gastrointestinal complications resulting in animal removal from studies (Hernandez, Morales‐Soto, Grubišić, Fried, & Gulbransen, 2020; Seth et al., 2018).…”

Sepsis-Induced Brain Dysfunction: Pathogenesis, Diagnosis, and Treatment

“…The vagus nerve is composed of afferent and efferent nerves, and the activated vagus nerve also acts as an anti-inflammatory mechanism: activating the hypothalamic-pituitary-adrenal axis, thereby producing endogenous steroids and suppressing inflammatory responses [ 77 ].The activated vagus nerve also releases acetylcholine, which binds to nicotinoid receptors on the surface of macrophages to suppress inflammatory responses via negative feedback [ 78 ]. Vagus activation has also been shown to suppress neuroinflammatory responses by regulating the activation of microglia [ 74 ] and the number of astrocytes in the hippocampus and dentate gyrus [ 79 ], alleviate the loss of neurons [ 80 ], and at last improve sepsis-induced brain dysfunction. Future studies should focus on drug exploration or clinical transformation [ 74 ].…”

Effects and neuroprotective mechanisms of vagus nerve stimulation on cognitive impairment with traumatic brain injury in animal studies: A systematic review and meta-analysis

“…Recently, vagus nerve stimulation (VNS) has been suggested as a promising tool for improving cognitive impairment ( 10 , 11 ). Over the past few decades, the modulation of vagal nerve function has shown clinical efficacy for the treatment of conditions, such as epilepsy, depression, and migraine ( 12 ).…”