Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, 29208, USA.
Department of Pharmacology, Physiology, & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, 29209, USA.
J Neuroinflammation. 2022 Jun 27;19(1):167. doi: 10.1186/s12974-022-02508-9.
Stress-induced mental illnesses (mediated by neuroinflammation) pose one of the world's most urgent public health challenges. A reliable in vivo chemical biomarker of stress would significantly improve the clinical communities' diagnostic and therapeutic approaches to illnesses, such as depression.
Male and female C57BL/6J mice underwent a chronic stress paradigm. We paired innovative in vivo serotonin and histamine voltammetric measurement technologies, behavioral testing, and cutting-edge mathematical methods to correlate chemistry to stress and behavior.
Inflammation-induced increases in hypothalamic histamine were co-measured with decreased in vivo extracellular hippocampal serotonin in mice that underwent a chronic stress paradigm, regardless of behavioral phenotype. In animals with depression phenotypes, correlations were found between serotonin and the extent of behavioral indices of depression. We created a high accuracy algorithm that could predict whether animals had been exposed to stress or not based solely on the serotonin measurement. We next developed a model of serotonin and histamine modulation, which predicted that stress-induced neuroinflammation increases histaminergic activity, serving to inhibit serotonin. Finally, we created a mathematical index of stress, S and predicted that during chronic stress, where S is high, simultaneously increasing serotonin and decreasing histamine is the most effective chemical strategy to restoring serotonin to pre-stress levels. When we pursued this idea pharmacologically, our experiments were nearly identical to the model's predictions.
This work shines the light on two biomarkers of chronic stress, histamine and serotonin, and implies that both may be important in our future investigations of the pathology and treatment of inflammation-induced depression.
由神经炎症介导的应激相关精神疾病是全球最紧迫的公共卫生挑战之一。可靠的应激体内化学生物标志物将极大地改善临床界对抑郁症等疾病的诊断和治疗方法。
雄性和雌性 C57BL/6J 小鼠经历慢性应激范式。我们将创新的体内血清素和组胺伏安测量技术、行为测试以及前沿的数学方法相结合，将化学物质与应激和行为相关联。
在经历慢性应激范式的小鼠中，炎症诱导的下丘脑组胺增加与海马体细胞外液中血清素的减少同时发生，无论其行为表型如何。在具有抑郁表型的动物中，发现了血清素与抑郁行为指标的严重程度之间的相关性。我们创建了一个高精度的算法，可以仅根据血清素测量来预测动物是否经历了应激。我们接下来开发了一个血清素和组胺调节模型，该模型预测应激诱导的神经炎症会增加组胺能活性，从而抑制血清素。最后，我们创建了一个应激的数学指数 S，并预测在慢性应激期间，当 S 较高时，同时增加血清素和减少组胺是恢复血清素至应激前水平的最有效化学策略。当我们从药理学上研究这个想法时，我们的实验几乎与模型的预测结果一致。
这项工作揭示了两种慢性应激生物标志物，组胺和血清素，并暗示它们在我们未来对炎症诱导性抑郁的病理和治疗的研究中可能都很重要。
