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.

根据对SIDS脑干组织的观察，我们推测SIDS的发病机制涉及我们现在所说的“延髓神经元能系统”的异常。在这个项目中，我们定义了新生仔猪的神经化学和受体解剖的神经元在延髓多巴胺能系统中，我们专门破坏他们局灶性或广泛的，我们观察到所产生的影响军队的稳态过程。这些包括对CO2增加和O2减少的呼吸反应，上气道反射， 血压影响呼吸。我们使用一个未麻醉的新生小猪模型，在这个模型中，我们可以很容易地测试清醒和睡眠中的这种自我平衡过程。首先，我们用5-HT（1A）受体激动剂微透析抑制神经元，或用5，7-二氢睾酮或5-羟色胺转运蛋白（SERT）抗体与细胞毒素皂草素（SAP）的结合物杀死神经元。我们还将抑制和杀死表达NK 1或毒蕈碱M1亚型受体的髓质多巴胺能系统内的神经元。对于具有NK 1受体的神经元，我们使用NK 1拮抗剂或物质P-SAP。对于具有M1受体的神经元，我们使用telenzepine或m1-toxin 1（一种高度特异性的长效M1受体拮抗剂）。这些实验将涉及在三个头端至尾侧柱内的各个部位的局部应用，这些柱定义了髓质多巴胺能系统或同时在“所有”部位广泛应用。与重点应用，我们问，如果每一个稳态过程可以定位到一个特定的网站内的髓质肾上腺素能系统。随着广泛的应用，我们问这些稳态过程是否利用分布在许多位置的神经元。神经元内的5-羟色胺能神经元可以通过共定位于其中的肽来进一步分类。促甲状腺激素释放激素（TRH）和P物质（SP）是两种特别感兴趣的激素，因为它们对呼吸和血压具有已知的强烈作用。我们将在骨髓中缝中微透析T3，它将与核β 2甲状腺受体结合，抑制TRH的产生和释放，使我们能够检查T3在甲状腺疾病中的作用。 内源性TRH在我们体内平衡过程中的作用。总的来说，本项目的目标是观察在延髓运动能系统中诱导的局灶性或广泛分布的异常是否会影响我们体内稳态过程的功能，例如导致猝死。