A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation
Frontiers Cellular Neuroscience
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.
Craddock, T. J.,
Michalovicz, L. T.,
Kelly, K. A.,
Rice, M. A.,
Miller, D. B.,
Klimas, N. G.,
O'Callaghan, J. P.,
(2018). A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation. Frontiers Cellular Neuroscience, 12, 336-352.
Available at: https://nsuworks.nova.edu/cps_facarticles/1637