CRCNS:Comput./Exp.Study:Hypothal.-Pituitary Interaction

描述(申请人提供)：本项目的总体目标是将实验研究与数学建模相结合，以了解下丘脑和脑下垂体之间的相互作用，从而导致催乳素激素的节律性分泌。这项工作将在实验实验室和数学建模实验室之间密切合作完成；这两个实验室位于同一所大学，促进日常互动。这项研究的主要目标是了解怀孕期间大鼠下丘脑内的神经分泌细胞如何与脑下垂体相互作用，以产生催乳素的每日分泌节律。催乳素是哺乳动物体内用途最广泛的激素之一，具有300多种不同的生物活性。交配刺激后分泌的催乳素有许多靶点，包括其他内分泌腺，对维持大鼠的正常妊娠非常重要。催乳素是由垂体促乳素细胞分泌的。这些细胞的分泌受到下丘脑的严格控制，下丘脑是大脑的一个区域，负责将一天中的时间信息传递到身体的其他部位。下丘脑神经元与哺乳细胞之间的相互作用是复杂的，神经元之间以及哺乳细胞之间相互影响，而来自哺乳细胞的催乳素反馈到下丘脑神经元并影响下丘脑神经元。这样的复杂系统是数学建模的理想之选，可以深入了解各种网络交互的影响，并可用作集成信息的工具。在本项目中，数学建模与实验研究相结合。该模型将通过实验数据进行校准，并将做出预测，并在实验室进行测试。这种联合实验-计算方法非常适合于理解复杂的下丘脑-垂体网络。学生培训是该项目的一个重要组成部分。预计研究生和博士后研究员将在本文描述的研究中发挥非常积极的作用。这种参与将提供多学科培训，对于一个日益多学科的工作场所来说，这将是无价的。这项提议有四个具体目标。首先，将开发一个关于脑下乳汁滋养细胞的数学模型。这个模型主要基于我们实验室培养的乳汁滋养细胞的实验数据，将提供对这些细胞活动模式的机械理解。它还将被用来理解荷尔蒙是如何被多巴胺和催产素等激素改变的。其次，使用我们实验室的下丘脑切片数据，将建立下丘脑多巴胺和催产素分泌神经元的数学模型。这些神经分泌细胞调节哺乳细胞的催乳素分泌，自身受视交叉上核(SCN)内神经元的影响。第三个具体目标是建立下丘脑神经元和垂体促乳素细胞之间网络相互作用的数学模型。这个模型将是最小的，专注于细胞之间的网络相互作用，而不是细胞内发生的详细的生物物理过程(前两个目标的目标)。第四，将研究节律性时钟基因在多巴胺和催产素分泌神经元中的作用。如果表达模式是有节律性的，那么这表明这些细胞为垂体提供了昼夜节律的输入，该输入独立于SCN内的神经元，但可能受其携带。这些研究将通过建立正常大脑在没有滥用药物支持脑下垂体的情况下的运作方式来支持NIDA的使命。然后，它将导致对滥用药物对脑垂体功能影响的研究。

DESCRIPTION (provided by applicant): The overall aim of this project is to combine experimental studies with mathematical modeling to understand the interactions between the hypothalamus and the pituitary gland that lead to rhythmic secretion of the hormone prolactin. This work will be done in close collaboration between an experimental lab and a mathematical modeling lab; both labs reside at the same university, facilitating daily interactions. The primary goal of this research is to understand how neurosecretory cells within the hypothalamus interact with the pituitary gland to produce daily rhythms of prolactin secretion in the rat during pregnancy. Prolactin is one of the most versatile hormones of mammalian organisms, with over 300 separate biological activities. The prolactin secreted following the mating stimulus has many targets, including other endocrine glands, and is important for maintaining a normal pregnancy in the rat. Prolactin is secreted by pituitary lactotrophs. Secretion from these cells is tightly regulated by the hypothalamus, a region of the brain that transmits time-of-day information to the rest of the body. The interaction between hypothalamic neurons and lactotrophs is complex; the neurons influence each other as well as the lactotrophs, and prolactin from lactotrophs feeds back onto and influences the hypothalamic neurons. Such a complex system is ideal for mathematical modeling, which can provide insight into the influence of the various network interactions, and can be used as a tool for integrating information. In this project, mathematical modeling is combined with experimental studies. The model will be calibrated by experimental data, and will make predictions that will be tested in the laboratory. This joint experimental-computational approach is well suited for understanding the complex hypothalamus-pituitary network. Student training is an important element of this project. It is anticipated that graduate students and postdoctoral fellows will play very active roles in the research described herein. This participation will provide multi-disciplinary training that will be invaluable for an increasingly multi-disciplinary workplace. There are four specific aims in this proposal. First, a mathematical model will be developed for pituitary lactotrophs. This model, based largely on experimental data on cultured lactotrophs from our lab, will provide a mechanistic understanding of the activity patterns of these cells. It will also be used to understand how the activity is modified by hormones such as dopamine and oxytocin. Second, mathematical models will be developed of hypothalamic dopamine- and oxytocin-secreting neurons, using hypothalamus slice data from our lab. These neurosecretory cells regulate prolactin secretion from lactotrophs, and are themselves under the influence of neurons within the suprachiasmatic nucleus (SCN). The third specific aim is to develop a mathematical model of the network interactions among the various hypothalamic neurons and pituitary lactotrophs. This model will be minimal, focusing on the network interactions between cells rather than the detailed biophysical processes that take place within cells (the goal of the first two aims). Fourth, the role of rhythmic clock gene expression in dopamine- and oxytocin-secreting neurons will be investigated. If the expression patterns are shown to be rhythmic, then this suggests that these cells provide circadian input to the pituitary that is separate from, but may be entrained by, neurons within the SCN. These studies will support the mission of NIDA by establishing the way the normal brain functions in the absence of drugs of abuse to support the pituitary gland. It will then lead to studies of effects of drugs of abuse on brain-pituitary function.