MEDULLARY SEROTONERGIC SYSTEM AND RESPIRATORY CONTROL IN THE UNANESTHETIZED PIG

未麻醉猪的髓质血清素系统和呼吸控制

• 批准号: 7410020
• 负责人: EUGENE Edward NATTIE
• 金额: $ 26.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7410020
• 关键词: Affect; Agonist; All Sites; Anatomy; Antibodies; Apnea; Asphyxia; Autoreceptors; Binding; Blood Pressure; Brain Stem; Breathing; Carbon Dioxide; Carrier Proteins; Cells; Chemicals; Development; Dialysis procedure; Disruption; Event; Family suidae; Goals; Hypoxia; Immunohistochemistry; Infant; Injection of therapeutic agent; Lateral; Life; Localized; Location; Microdialysis; Modeling; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Muscarinics; Neurons; Newborn Infant; Nuclear; Pathogenesis; Peptides; Phenotype; Physical Dialysis; Process; Production; Reflex action; Reflex control; Role; Serotonin; Serotonin Agonists; Side; Site; Sleep; Stanolone; Substance P; Substance P Receptor; Sudden Death; Sudden infant death syndrome; Sus scrofa; System; Testing; Thyroid Gland; Thyrotropin-Releasing Hormone; Tissues; Toxin; Triiodothyronine; Wakefulness; base; inhibitor/antagonist; interest; killings; m1-toxin1; medullary serotonergic system; noradrenergic; receptor; research study; respiratory; response; serotonin receptor; serotonin transporter; substance P-saporin; telenzepine; thermal stress

Based on observations made in brainstem tissue of SIDS cases we hypothesize that the pathogenesis of SIDS involves abnormalities in what we now call the 'medullary serotonergic system'. In this project we define in newborn piglets the neuroehemical and receptor anatomy of the neurons in the medullary serotonergic system, we specifically disrupt them focally or widely, and we observe the resultant effects on an army of homeostatic processes. These include the ventilatory responses to increased CO2 and decreased O2, upper airway reflexes, and blood pressure effects on breathing. We use an unanesthetized newborn piglet model in which we can easily test this array of homeostatic processes in both wakefulness and sleep. Initially we inhibit serotoncrgic neurons by microdialysis of an agonist for the 5-HT(1A) autorceeptor or kill them by injection of 5, 7 DHT or a conjugate of anantibody for the serotonin transport protein (SERT) and the cell toxin saporin (SAP). We will also inhibit and kill neurons within the medullary serotonergic system that express the NK1 or muscarinic M1 subtype receptors. For neurons with NK1 receptors we use an NK1 antagonist or substance P-SAP. For neurons with M1 receptors we use telenzepine or the m1-toxin1 (a highly specific long acting M1 receptor antagonist). These experiments will involve focal application at various sites within three rostral-to-caudal colulumns that define the medullary serotonergic system or widely at 'all' sites simultaneously. With focal application we ask if each homeostatic process can be localized to a specific site within the medullary serotonergic system. With wide application we ask if these homeostatic processes utilize neurons distributed at many locations. Serotonergic neurons within the meduliary serotonergic system can be further classified by peptides that are co-localized within them. Thyrotropin releasing hormone (TRH) and substance P (SP) are two such that are of particular interest in that they have known strong effects on breathing and blood pressure. We will microdialyze T3 in the medullary raphe, which will bind to nuclear beta2 thyroid receptors and inhibit TRH production and release allowing us to examine the role of endogenous TRH in the function of our array of homeostatic processes. Overall, the goal of this project is to see if a induced focal or widely distributed abnormality in the medullary semtonergic system couid affect function in our array of homeostatic processes such as to contribute to sudden death.

基于在SIDS病例的脑干组织中进行的观察结果，我们假设SIDS的发病机理涉及我们现在称为“髓质血清素能系统”的异常。在这个项目中，我们在新生小​​猪中定义了髓质血清素能系统中神经元的神经心理和受体解剖结构，我们特别在局部或广泛地破坏它们，并观察到对稳态过程的影响。这些包括对增加二氧化碳和减少O2的通气反应，上呼吸道反射以及 血压对呼吸的影响。我们使用一个未经麻醉的新生小猪模型，在该模型中，我们可以在清醒和睡眠中轻松测试这一数组的稳态过程。最初，我们通过对5-HT（1A）自耐受的激动剂的微量透析抑制血清骨质神经元，或通过注射5、7 DHT或血清素蛋白转运蛋白（Sert）和细胞毒素糖蛋白（SAP）的呼吸蛋白（SERT）的抗体来杀死它们。我们还将抑制和杀死表达NK1或毒蕈碱M1亚型受体的髓质血清素能系统中的神经元。对于具有NK1受体的神经元，我们使用NK1拮抗剂或物质P-SAP。对于带有M1受体的神经元，我们使用端旋或M1-Toxin1（一种高度特异性的长作用M1受体拮抗剂）。这些实验将涉及三个位置上的位置上的焦点应用，以同时定义髓质血清素能系统或同时在“所有”位点广泛定义髓质血清素能系统。通过焦点应用，我们询问是否可以将每个稳态过程定位到髓质血清素能系统中的特定位点。通过广泛的应用，我们询问这些稳态过程是否利用在许多位置分布的神经元。髓质血清素能系统中的血清素能神经元可以通过在其中共定位的肽进一步分类。甲状腺激素释放激素（TRH）和P（SP）是两个，因此特别感兴趣的是它们对呼吸和血压有很强的影响。我们将在髓质raphe中的微甲基酶T3，它将与核β2甲状腺受体结合并抑制TRH的产生和释放，从而使我们能够检查 内源性TRH在我们一系列稳态过程的功能中。总体而言，该项目的目的是查看在我们在我们的一系列稳态过程中，诸如促进猝死的近代semontonergic系统中诱导的局灶性或广泛分布的异常。