Exposing the latent phenotype of Gulf War Illness: examination of the mechanistic mediators of cognitive dysfunction

Abstract

Though it has been over 30 years since the 1990-1991 Gulf War (GW), the pathophysiology of Gulf War Illness (GWI), the complex, progressive illness affecting approximately 30% of GW Veterans, has not been fully characterized. While the symptomology of GWI is broad, many symptoms can be attributed to immune and endocrine dysfunction as these critical responses appear to be dysregulated in many GWI patients. Since such dysregulation emerges in response to immune threats or stressful situations, it is unsurprising that clinical studies suggest that GWI may present with a latent phenotype. This is most often observed in studies that include an exercise challenge during which many GWI patients experience an exacerbation of symptoms. Unfortunately, very few preclinical studies include such physiological stressors when assessing their experimental models of GWI, which creates variable results that hinder the elucidation of the mechanisms mediating GWI. Thus, the purpose of this review is to highlight the clinical and preclinical findings that investigate the inflammatory component of GWI and support the concept that GWI may be characterized as having a latent phenotype. We will mainly focus on studies assessing the progressive cognitive impairments associated with GWI and emphasize the need for physiological stressors in future work to create a more unified hypothesis that can identify potential therapeutics for this patient population.

Keywords: acetylcholine; acetylcholinesterase; hippocampus; lipopolysaccharide; pyridostigmine bromide; stress.

Figure 1

Immune and stress challenges reveal the deleterious effects of GWI on hippocampal function. (A) Three months after treatment cessation, our rat model of GWI exhibits sensitized hippocampal responses to both immune and stress challenges, effects that would be missed if our endpoint measures were assessed at resting conditions. (B) When challenged with i.p. LPS, rats with a history of PB treatment exhibit exaggerated hippocampal levels of IL-1β (represented in figure), IL-12, and GM-CSF relative to LPS-treated controls, while no differences were observed among saline-treated groups. (C) A history of PB treatment also potentiated hippocampal acetylcholine efflux after i.p LPS and a 1-hour immobilization challenge (represented in figure) but did not alter basal levels of acetylcholine in this region. These findings, along with the data shown in Panel A, suggest that PB sensitizes cholinergic responses in the hippocampus but also dysregulates the anti-inflammatory actions of acetylcholine. (D) As elevations in pro-inflammatory cytokines and acetylcholine efflux in the hippocampus are known to impair memory consolidation, this dysregulation of the cholinergic anti-inflammatory network are likely driving the 24-hour memory deficits observed in NOR under LPS challenge and MWM performance. Thus, the latent phenotype of GWI and its progressive cognitive impairments will not be fully elucidated until more GWI studies include physiological stressors and unmask these aberrant responses. [Data adapted from and 76].