A mathematical model for histamine synthesis, release, and control in varicosities.
A mathematical model for histamine synthesis, release, and control in varicosities.
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DOI：
10.1186/s12976-017-0070-9
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发表时间：
2017-12-12
影响因子：
--
通讯作者：
Reed M
中科院分区：
文献类型：
--
作者：
Best J;Nijhout HF;Samaranayake S;Hashemi P;Reed M
组胺（HA）是一种由组氨酸合成的小分子，在免疫系统中起着重要作用，与过敏、炎症和T细胞调节有关。在大脑中，组胺储存在肥大细胞和其他非神经元细胞中，也作为神经递质。组胺神经元细胞体位于下丘脑的结节乳头（TM）核中，这些神经元将投射发送到整个中枢神经系统（CNS），特别是大脑皮层、杏仁核、基底神经节、海马、丘脑、视网膜和脊髓。HA神经元产生很少的突触，但是当神经元放电时，从细胞体和静脉曲张中释放HA。因此，HA神经系统似乎调节和控制投射区的HA浓度。已知细胞外间隙中的高HA水平抑制5-羟色胺释放，因此HA可能在抑郁症的病因学中起作用。我们比较模型预测HA半衰期，组氨酸加载后的脑HA的浓度，和脑HA后，组氨酸显着增加或减少饮食中的经典生理实验。该模型的预测也是一致的，在体内实验中，细胞外HA测量，使用快速扫描循环伏安法，在前乳头核（PM）后2秒的逆行刺激的TM，无论是没有和存在的H 3自身受体拮抗剂硫代哌丁胺。我们表明，该模型预测以及在细胞外空间超过30秒，在这两个实验中的HA的时间行为。我们能够测量刺激后细胞外间隙中的体内组胺动力学，这为了解大脑功能和控制提供了真实的机会。所观察到的细胞外动力学取决于合成、储存、神经元放电、释放、再摄取、神经胶质细胞和自身受体的控制，以及动物的行为状态（例如，抑郁）或神经炎症的存在。在这种复杂的情况下，数学模型将有助于解释数据和进行计算机实验，以了解因果机制。而且，更好的理解可以提出新的治疗药物靶点。
Histamine (HA), a small molecule that is synthesized from the amino acid histidine, plays an important role in the immune system where it is associated with allergies, inflammation, and T-cell regulation. In the brain, histamine is stored in mast cells and other non-neuronal cells and also acts as a neurotransmitter. The histamine neuron cell bodies are in the tuberomammillary (TM) nucleus of the hypothalamus and these neurons send projections throughout the central nervous system (CNS), in particular to the cerebral cortex, amygdala, basal ganglia, hippocampus, thalamus, retina, and spinal cord. HA neurons make few synapses, but release HA from the cell bodies and from varicosities when the neurons fire. Thus the HA neural system seems to modulate and control the HA concentration in projection regions. It is known that high HA levels in the extracellular space inhibit serotonin release, so HA may play a role in the etiology of depression. We compare model predictions to classical physiological experiments on HA half-life, the concentration of brain HA after histidine loading, and brain HA after histidine is dramatically increased or decreased in the diet. The model predictions are also consistent with in vivo experiments in which extracellular HA is measured, using Fast Scan Cyclic Voltammetry, in the premammillary nucleus (PM) after a 2 s antidromic stimulation of the TM, both without and in the presence of the H 3 autoreceptor antagonist thioperamide. We show that the model predicts well the temporal behavior of HA in the extracellular space over 30 s in both experiments. Our ability to measure in vivo histamine dynamics in the extracellular space after stimulation presents a real opportunity to understand brain function and control. The observed extracellular dynamics depends on synthesis, storage, neuronal firing, release, reuptake, glial cells, and control by autoreceptors, as well as the behavioral state of the animal (for example, depression) or the presence of neuroinflammation. In this complicated situation, the mathematical model will be useful for interpreting data and conducting in silico experiments to understand causal mechanisms. And, better understanding can suggest new therapeutic drug targets.
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