Impact Factor 4.300

The world's most-cited Neurosciences journals

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00336

A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation

 Travis Craddock1, 2, 3, 4*,  Lindsay Michalovicz5,  Kimberly A. Kelly5, Mark Rice2, 4, 6, Diane Miller5, Nancy Klimas2, 4, 7, Mariana Morris2, 4,  James O'Callaghan5 and  Gordon Broderick1, 2, 4, 6
  • 1Department of Psychology and Neuroscience, Nova Southeastern University, United States
  • 2Institute for Neuro-Immune Medicine, Nova Southeastern University, United States
  • 3Department of Computer Science, Nova Southeastern University, United States
  • 4Department of Immunology, Nova Southeastern University, United States
  • 5National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention (CDC), United States
  • 6Center for Clinical Systems Biology, Rochester Regional Health, United States
  • 7Miami VA Healthcare System, United States

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.

Keywords: Neuroinflammation, Logical modeling, Systems neuroscience, Regulatory biology, homeostatic regulation, Treatment Course Prediction, Neural glial interaction, mouse models

Received: 27 Apr 2018; Accepted: 12 Sep 2018.

Edited by:

Bernhard T. Baune, Department of Psychiatry, Melbourne Medical School, University of Melbourne, Australia

Reviewed by:

Eberhard Weihe, Philipps-Universität Marburg, Germany
Gourav Roy Choudhury, Texas Biomedical Research Institute, United States
Catherine Toben, University of Adelaide, Australia  

Copyright: © 2018 Craddock, Michalovicz, Kelly, Rice, Miller, Klimas, Morris, O'Callaghan and Broderick. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Travis Craddock, Nova Southeastern University, Department of Psychology and Neuroscience, Fort Lauderdale, Florida, United States, tcraddock@nova.edu