Department of Mathematics, The Ohio State University, 231 W 18th Ave., Columbus, OH, 43210, USA.
Department of Mathematics, Duke University, Durham, NC, 27708, USA.
BMC Neurosci. 2020 Sep 23;21(1):40. doi: 10.1186/s12868-020-00587-z.
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.
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、攻击和自杀倾向、强迫症、酗酒、焦虑和情感障碍。全面理解需要基因组学、神经化学、电生理学和行为学。这些科学问题令人望而生畏，但对于人类健康却很重要，因为选择性血清素再摄取抑制剂和其他药理学药物被用于治疗各种疾病。本文提出了一种新的血清素代谢确定性模型和一种新的系统群体模型，该模型考虑了酶和转运体表达水平、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不同自受体假设下细胞外血清素的稳态分布，并展示了色氨酸输入对稳态和膳食的影响。我们使用确定性模型来解释雄性和雌性小鼠海马体的实验数据，并说明自身受体的短期动力学。我们表明，血清素可能有两种再摄取机制，而且自身受体具有持久的影响，并将我们的结果与黑质网状部的血清素动力学测量结果进行了比较。我们还展示了组氨酸如何影响血清素动力学。我们研究了表明在小鼠群体中存在非常可变的反应曲线的实验数据，并询问模型中的参数变化有多少可以产生数据中观察到的变化。最后，我们展示了系统群体模型如何用于研究特定的生物学和临床问题。
我们已经表明，我们的新模型可以用于研究色氨酸输入和膳食的影响，以及不同脑核中实验反应曲线的行为。系统群体模型包含个体差异，可以用于研究临床问题和药物疗效的变化。确定性模型和系统群体模型的代码都可以从作者处获得，并可供其他研究人员用于研究血清素系统。
