Autoreceptor control of serotonin dynamics.
Autoreceptor control of serotonin dynamics.
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DOI：
10.1186/s12868-020-00587-z
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发表时间：
2020-09-23
期刊：
影响因子：
2.4
通讯作者：
Reed M
中科院分区：
文献类型：
--
作者：
Best J;Duncan W;Sadre-Marandi F;Hashemi P;Nijhout HF;Reed M
血清素是一种神经递质，与多种行为有关，包括进食和体重调节、社会等级、攻击和自杀、强迫症、酗酒、焦虑和情感障碍。全面理解涉及基因组学、神经化学、电生理学和行为学。这些科学问题令人生畏，但对人类健康很重要，因为使用选择性血清素再摄取抑制剂和其他药物来治疗疾病。本文提出了一个新的血清素代谢的确定性模型和一个新的系统群体模型，该模型考虑了酶和转运蛋白表达水平、色氨酸输入和自身受体功能的巨大变化。我们讨论了模型的稳态和细胞外血清素在不同假设下对自身受体的稳态分布，并展示了色氨酸输入对稳态的影响和膳食的影响。我们利用确定性模型解释了雄性和雌性小鼠海马反应的实验数据，并说明了自受体的短期动态。我们发现血清素可能有两种再摄取机制，并且自体受体具有持久的影响，并将我们的结果与黑质网状部血清素动力学的测量结果进行了比较。我们还展示了组胺如何影响血清素动力学。我们检查了显示小鼠群体中非常可变的反应曲线的实验数据，并询问模型中参数的多少变化是产生观察到的数据变化所必需的。最后，我们展示了系统种群模型如何潜在地用于研究特定的生物学和临床问题。我们已经证明，我们的新模型可以用于研究色氨酸输入和膳食的影响以及不同脑核的实验反应曲线的行为。该系统的人口模型包含个体差异，可用于研究临床问题和药物疗效的变化。确定性模型和系统种群模型的代码都可以从作者那里获得，并且可以被其他研究人员用于研究血清素能系统。
Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding involves genomics, neurochemistry, electrophysiology, and behavior. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders. This paper presents a new deterministic model of serotonin metabolism and a new systems population model that takes into account the large variation in enzyme and transporter expression levels, tryptophan input, and autoreceptor function. We discuss the steady state of the model and the steady state distribution of extracellular serotonin under different hypotheses on the autoreceptors and we show the effect of tryptophan input on the steady state and the effect of meals. We use the deterministic model to interpret experimental data on the responses in the hippocampus of male and female mice, and to illustrate the short-time dynamics of the autoreceptors. We show there are likely two reuptake mechanisms for serotonin and that the autoreceptors have long-lasting influence and compare our results to measurements of serotonin dynamics in the substantia nigra pars reticulata. We also show how histamine affects serotonin dynamics. We examine experimental data that show very variable response curves in populations of mice and ask how much variation in parameters in the model is necessary to produce the observed variation in the data. Finally, we show how the systems population model can potentially be used to investigate specific biological and clinical questions. We have shown that our new models can be used to investigate the effects of tryptophan input and meals and the behavior of experimental response curves in different brain nuclei. The systems population model incorporates individual variation and can be used to investigate clinical questions and the variation in drug efficacy. The codes for both the deterministic model and the systems population model are available from the authors and can be used by other researchers to investigate the serotonergic system.
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