The role of central 5-HT in heart rate and blood pressure regulation during sleep in the neonatal period

中枢5-HT在新生儿期睡眠心率和血压调节中的作用

• 批准号: 9256640
• 负责人: Jennifer Leigh Magnusson
• 金额: $ 2.91万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256640
• 关键词: Address; Affect; Age; Age-Months; Agonist; Anabolism; Antibodies; Atenolol; Atropine; Baroreflex; Blood Pressure; Bradycardia; Brain; Brain Stem; Breathing; Cardiac; Cardiovascular Physiology; Cardiovascular system; Catheters; Cell Nucleus; Cessation of life; Data; Defect; Disodium Salt Nitroprusside; Electromyography; Enzymes; Failure; Future; Heart; Heart Rate; Hour; Hypotension; Hypoxia; Immunohistochemistry; Incidence; Infant; Injection of therapeutic agent; Intravenous; Knowledge; Maintenance; Measures; Mediating; Monitor; Mus; Neonatal; Nerve; Neurons; Pattern; Pharmaceutical Preparations; Pharmacology Study; Phenotype; Phenylephrine; Rattus; Research; Rest; Risk; Rodent; Role; Serotonergic System; Serotonin; Serotonin Receptor 5-HT1A; Signal Transduction; Sleep; Sudden Death; Sudden infant death syndrome; TPH2; Tachycardia; Testing; Vasomotor; Venous; Wakefulness; Work; base; behavior observation; blood pressure regulation; cholinergic; cisterna magna; experience; heart rate monitor; infancy; infant death; insight; pup; respiratory; response; translational study

Project Summary/Abstract The Sudden Infant Death Syndrome (SIDS) occurs during sleep. Most SIDS cases have major defects in the brainstem serotonin (5-hyrdoxytryptamine, 5-HT) system, including reduced 5-HT and tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in central 5-HT synthesis. In addition, rare recordings captured from SIDS cases indicate that death is preceded by bradycardia and hypotension, suggesting failure of autonomic mechanisms governing heart rate (HR) and blood pressure (BP). However, how reduced 5-HT could compromise heart rate and blood pressure regulation during sleep is unresolved. My proposed research directly addresses this knowledge gap. We hypothesize that during the neonatal period, 5-HT is important in the maintenance of BP and HR predominantly during quiet sleep (QS), when 5-HT neurons are active, and not during active sleep (AS), when these neurons are silent. Our over-arching hypothesis is that the bradycardia and hypotension displayed by 5-HT-deficient neonatal rodents occurs primarily in QS, due to enhanced cholinergic drive to the heart and associated defects in the cardiac baroreflex. To test this hypothesis, we will measure HR, BP and sleep state in freely-behaving 2 week-old rats deficient in TPH2 (TPH2-/-) and wild-type controls. A femoral arterial catheter will be used to monitor HR and BP across AS and QS, determined using nuchal electromyogram and behavioral observation. Drugs will be administered intravenously to determine autonomic tone to the heart under resting conditions, and the strength of the cardiac baroreflex in AS and QS. Immunohistochemistry against Fos will be used to assess the extent to which the activity of barosensitive autonomic nuclei is influenced by 5- HT deficiency. These findings will therefore give new insight into how a specific loss of serotonergic signaling could increase the risk of sudden death in a sleeping infant, and provide the knowledge needed for new translational studies in infants.

项目摘要/摘要 婴儿猝死综合症(SID)发生在睡眠中。大多数小岛屿发展中国家的案例都存在重大缺陷 脑干5-羟色胺(5-羟色胺，5-HT)系统，包括还原的5-羟色胺和色氨酸羟化酶2 (TPH2)，中枢5-羟色胺合成的限速酶。此外，从小岛屿发展中国家捕获的罕见录音 病例显示死亡前有心动过缓和低血压，提示自主神经功能衰竭。 心率(HR)和血压(BP)的调节机制。然而，减少5-羟色胺会如何妥协 睡眠期间的心率和血压调节尚未解决。我提出的研究直接解决了 这种知识鸿沟。我们推测，在新生儿期，5-羟色胺在维持脑血管紧张素转换酶中起重要作用。 BP和HR主要发生在5-羟色胺神经元活跃的安静睡眠(QS)期间，而不是在活跃睡眠期间 (AS)，当这些神经元沉默时。我们最重要的假设是心动过缓和低血压 5-羟色胺缺乏的新生啮齿动物主要发生在QS，这是由于胆碱能驱动增强到 心脏及其相关的压力感受器反射缺陷。为了验证这一假设，我们将测量HR、BP和 行为自由的2周龄TPH2缺陷大鼠(TPH2-/-)和野生型对照组的睡眠状态。大腿骨 动脉导管将被用来监测AS和QS的心率和血压，通过颈部肌电确定 和行为观察。药物将通过静脉给药来确定心脏的自主张力 在安静状态下，AS和QS的心脏压力感受性反射的强度。免疫组织化学抗 FOS将被用来评估5-羟色胺对压力敏感自主神经核活性的影响程度。 羟色胺缺乏。因此，这些发现将提供新的见解，以了解5-羟色胺能信号的具体丢失是如何 可能会增加熟睡婴儿猝死的风险，并提供新的 婴儿的翻译研究。