Is PTSD an Evolutionary Survival Adaptation Initiated by Unrestrained Cytokine Signaling and Maintained by Epigenetic Change?

Stephan Rudzki
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Abstract

Introduction: Treatment outcomes for PTSD with current psychological therapies are poor, with very few patients achieving sustained symptom remission. A number of authors have identified physiological and immune disturbances in Post Traumatic Stress Disorder (PTSD) patients, but there is no unifying hypothesis that explains the myriad features of the disorder.

Materials and methods: The medical literature was reviewed over a 6-year period primarily using the medical database PUBMED.

Results: The literature contains numerous papers that have identified a range of physiological and immune dysfunction in association with PTSD. This paper proposes that unrestrained cytokine signaling induces epigenetic changes that promote an evolutionary survival adaptation, which maintains a defensive PTSD phenotype. The brain can associate immune signaling with past threat and initiate a defensive behavioral response. The sympathetic nervous system is pro-inflammatory, while the parasympathetic nervous system is anti-inflammatory. Prolonged cholinergic withdrawal will promote a chronic inflammatory state. The innate immune cytokine IL-1β has pleiotropic properties and can regulate autonomic, glucocorticoid, and glutamate receptor functions, sleep, memory, and epigenetic enzymes. Changes in epigenetic enzyme activity can potentially alter phenotype and induce an adaptation. Levels of IL-1β correlate with severity and duration of PTSD and PTSD can be prevented by bolus administration of hydrocortisone in acute sepsis, consistent with unrestrained inflammation being a risk factor for PTSD. The nervous and immune systems engage in crosstalk, governed by common receptors. The benefits of currently used psychiatric medication may arise from immune, as well as synaptic, modulation. The psychedelic drugs (3,4-Methylenedioxymethamphetamine (MDMA), psilocybin, and ketamine) have potent immunosuppressive and anti-inflammatory effects on the adaptive immune system, which may contribute to their reported benefit in PTSD. There may be distinct PTSD phenotypes induced by innate and adaptive cytokine signaling.

Conclusion: In order for an organism to survive, it must adapt to its environment. Cytokines signal danger to the brain and can induce epigenetic changes that result in a persistent defensive phenotype. PTSD may be the price individuals pay for the genomic flexibility that promotes adaptation and survival.

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创伤后应激障碍是由未经训练的细胞因子信号引发并由表观遗传学变化维持的进化生存适应吗?
目前的心理疗法治疗PTSD的效果很差,很少有患者能持续缓解症状。许多作者已经确定了创伤后应激障碍(PTSD)患者的生理和免疫紊乱,但没有统一的假设来解释这种疾病的无数特征。材料和方法主要使用PUBMED医学数据库对6年的医学文献进行综述。结果:文献中有许多论文已经确定了一系列与PTSD相关的生理和免疫功能障碍。本文提出,不受限制的细胞因子信号传导诱导表观遗传变化,促进进化生存适应,从而维持防御性PTSD表型。大脑可以将免疫信号与过去的威胁联系起来,并启动防御行为反应。交感神经系统具有促炎作用,副交感神经系统具有抗炎作用。长时间的胆碱能戒断会促进慢性炎症状态。先天免疫细胞因子IL-1β具有多效性,可调节自主神经、糖皮质激素和谷氨酸受体功能、睡眠、记忆和表观遗传酶。表观遗传酶活性的变化可以潜在地改变表型并诱导适应。IL-1β水平与创伤后应激障碍的严重程度和持续时间相关,急性脓毒症患者可通过口服氢化可的松预防创伤后应激障碍,这与无约束炎症是创伤后应激障碍的危险因素相一致。神经系统和免疫系统在共同的感受器的控制下相互作用。目前使用的精神科药物的好处可能来自免疫调节,以及突触调节。迷幻药物(3,4-亚甲基二氧基甲基苯丙胺(MDMA)、裸盖菇素和氯胺酮)对适应性免疫系统具有有效的免疫抑制和抗炎作用,这可能有助于它们对创伤后应激障碍的益处。先天和适应性细胞因子信号可能诱发不同的PTSD表型。结论:生物为了生存,必须适应环境。细胞因子向大脑发出危险信号,并可诱导表观遗传变化,导致持续的防御表型。创伤后应激障碍可能是个体为促进适应和生存的基因组灵活性付出的代价。
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