Abstract
Aberrant inflammatory signaling between neuronal and glial cells can develop into a persistent sickness behavior-related disorders, negatively impacting learning, memory, and neurogenesis. While there is an abundance of literature describing these interactions, there still lacks a comprehensive mathematical model describing the complex feed-forward and feedback mechanisms of neural-glial interaction. Here we compile molecular and cellular signaling information from various studies and reviews in the literature to create a logically-consistent, theoretical model of neural-glial interaction in the brain to explore the role of neuron-glia homeostatic regulation in the perpetuation of neuroinflammation. Logic rules are applied to this connectivity diagram to predict the system's homeostatic behavior. We validate our model predicted homeostatic profiles against RNAseq gene expression profiles in a mouse model of stress primed neuroinflammation. A meta-analysis was used to calculate the significance of similarity between the inflammatory profiles of mice exposed to diisopropyl fluorophostphate (DFP) [with and without prior priming by the glucocorticoid stress hormone corticosterone (CORT)], with the equilibrium states predicted by the model, and to provide estimates of the degree of the neuroinflammatory response. Beyond normal homeostatic regulation, our model predicts an alternate self-perpetuating condition consistent with chronic neuroinflammation. RNAseq gene expression profiles from the cortex of mice exposed to DFP and CORT+DFP align with this predicted state of neuroinflammation, whereas the alignment to CORT alone was negligible. Simulations of putative treatment strategies post-exposure were shown to be theoretically capable of returning the system to a state of typically healthy regulation with broad-acting anti-inflammatory agents showing the highest probability of success. The results support a role for the brain's own homeostatic drive in perpetuating the chronic neuroinflammation associated with exposure to the organophosphate DFP, with and without CORT priming. The deviation of illness profiles from exact model predictions suggests the presence of additional factors or of lasting changes to the brain's regulatory circuitry specific to each exposure.
Highlights
Neuroinflammation, the enhanced expression of inflammatory mediators in the brain, has been associated with a variety of central nervous system (CNS) disorders, including cognitive dysfunction, mental illness, and neurodegeneration
While our understanding of neuronal-glial interactions continues to grow, we present here a minimal model of the principal regulatory mechanisms linking 5 cell types, through 10 signaling molecules
Communication between neuronal and glial cells is mediated by neurotransmitter, hormone and cytokines levels in the brain, which are further regulated by the blood-brain barrier (BBB) and T Cells within the CNS (Tian et al, 2012)
Summary
Neuroinflammation, the enhanced expression of inflammatory mediators in the brain, has been associated with a variety of central nervous system (CNS) disorders, including cognitive dysfunction, mental illness, and neurodegeneration. Numerous studies have shown the body’s ability to communicate inflammatory information to the brain via both humoral and neuronal mechanisms (Hermans et al, 2011; Jurgens and Johnson, 2012), resulting in behavioral changes deemed “sickness behavior” (Dantzer et al, 2008; Koo and Duman, 2008). Processing of this inflammatory information by the brain can result in cellular activation and the production of inflammatory cytokines within the CNS. Immune responses in the context of an ongoing exposure to repeated stressors or a stressor subsequent to an underlying immune reaction can potentiate such cytokine responses further perpetuating neuroinflammation (Frank et al, 2016)
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