Table_4_A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation.XLSX

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.

神经元与神经胶质细胞之间的异常炎症信号传导可发展为持续性疾病行为相关障碍，对学习、记忆与神经发生产生负面影响。尽管已有大量文献描述了二者间的相互作用，但目前仍缺乏能够阐释神经胶质相互作用复杂前馈与反馈机制的综合数学模型。本研究从文献中的各类研究与综述中整合分子与细胞信号传导信息，构建了大脑内神经元-胶质细胞相互作用的逻辑自洽理论模型，以探究神经元-胶质细胞稳态调控在神经炎症持续进程中的作用。我们将逻辑规则应用于该连接图谱，以预测系统的稳态行为。针对应激预致敏神经炎症小鼠模型中的RNA测序（RNAseq）基因表达谱，我们验证了模型预测的稳态特征。采用元分析计算二异丙基氟磷酸酯（diisopropyl fluorophostphate, DFP）暴露小鼠（预先接受或未接受糖皮质激素应激激素皮质酮（CORT）预致敏）的炎症谱与模型预测的平衡态之间的相似性显著性，并对神经炎症反应程度进行评估。除正常稳态调控外，我们的模型还预测了一种与慢性神经炎症一致的交替自我持续状态。来自暴露于DFP与CORT+DFP小鼠皮层的RNA测序基因表达谱与该神经炎症预测状态相符，而仅暴露于CORT的样本匹配度可忽略不计。暴露后假定治疗策略的模拟结果在理论上显示可将系统恢复至正常健康调控状态，其中广谱抗炎药物展现出最高的成功概率。本研究结果支持大脑自身的稳态驱动在暴露于有机磷酸酯DFP（伴或不伴CORT预致敏）相关慢性神经炎症持续进程中的作用。疾病谱与模型精确预测值之间的偏差表明，存在额外因素或针对每种暴露的大脑调控环路的永久性改变。