Medullary Serotonergic Involvement In Sleep, Thermoregulation & cardiorespiration

髓质血清素参与睡眠、体温调节

• 批准号: 7410021
• 负责人: ROBERT A DARNALL
• 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/7410021
• 关键词: Affect; Age; Anatomy; Antibodies; Apnea; Area; Arousal; Asphyxia; Attention; Autoreceptors; Blood Pressure; Blood flow; Cardiovascular system; Carrier Proteins; Cells; Data; Dendroaspis; Disruption; Electroencephalography; Event; Fractals; Habitats; Heart Rate; Heat Stress Disorders; Homeostasis; Hypercapnia; Hyperpnea; Hypoxia; Infant; Laboratories; Lateral; Lesion; Life; Location; Metabolic; Methods; Muscarinic M1 Receptor; Muscarinics; Nature; Neurons; Neurotoxins; Phenotype; Physiologic Thermoregulation; Play; Reflex action; Regulation; Role; Serotonin; Serotonin Receptor Binding; Shivering; Siblings; Site; Skin; Sleep; Sleep Architecture; Sudden Death; Sudden infant death syndrome; System; Techniques; Telemetry; Testing; Thermogenesis; Toxin; Venoms; Wakefulness; base; behavior observation; concept; indexing; instrument; lateral column; m1-toxin1; medullary serotonergic system; neurochemistry; novel; programs; receptor; research study; respiratory; response; serotonin transporter; substance P-saporin; thermal stress

The important findings that a substantial subset of SIDS infants have decreases in serotonin receptor binding the ventral medulla form the basis for the hypothesis that abnormalities in the 'medullary 5-HT system' play an important rote in SIDS. Neurons in this region participate in widespread autonomic functions including cardiorespiratory control, thermoregutation, and based on recent new information from our laboratory, sleep. The overall aim of this proposal is to investigate the roles of phenotypically specific neurons in the medullary 5-HT system on sleep homeostasis, responses to a thermal stress, and on cardiorespiratory variability. Our strategy will be to use novel neurochemicals to locally inhibit or destroy serotonergic neurons and/or neurons expressing the 5-HT(1A), NK1, or m1 muscarinic receptor in chronically instrumented piglets. 8-OH DPAT will be used to selectively activate 5-HT(1A) autoreceptors on 5-HT neurons, and 5,7-DHT or the neurotoxin saporin conjugated to an antibody to the serotonin transporter protein (SERT-SAP) will be used to selectively destroy serotonergic neurons. Analogous methods will be usedto inhibit or destroy neurons expressing the NK1 or m1 muscarinic receptor with SP-SAP or a powerful toxin obtained from the venom of the green mamba highly selective for m1 muscarinic receptors (m1-toxin1). We will evaluate the effects of these specific 'lesions' on sleep architecture in piglets using EEG wavelet analysis and behavioral observations during short (6 hr) plethysmograph recordings, and long (12-24 hr) recordings in their natural habitat (with the sow and siblings) using telemetry. We will also evaluate responses to thermal stresses focusing on shivering and non-shivering thermogenesis, skin blood flow, and hyperpnea. Finally, we will use the sensitive techniques of fractal analysis to evaluate the complexity of cardiorespiratory variability, the decrease in which is associated with decreased ability of a control system to respond to a perturbation. Indeed, infants who subsequently die of SIDS have decreases in heart rate variability. Lesions will be made in the midline and lateral columns and all areas simultaneously to test the hypothesis that neurons are organized in a functionally specific manner. We hypothesize that the medullary 5-HT system is a major site for the integration of cardiorespiratory, thermoregulatory, and sleep and arousal mechanisms, and that abnormalities in this region could produce local or widespread effects that might contribute to sudden death.

重要的发现，一个实质性的子集的SIDS婴儿有减少5-羟色胺受体结合腹侧髓质形成的基础上的假设，即异常的“髓质5-羟色胺系统”在SIDS中发挥重要作用。该区域的神经元参与广泛的自主功能，包括心肺控制，体温调节，以及根据我们实验室最近的新信息，睡眠。这个建议的总体目标是调查表型特异性神经元在延髓5-HT系统中对睡眠稳态，热应激反应和心肺变异性的作用。我们 策略将是使用新的神经化学物质局部抑制或破坏慢性器械仔猪中的多巴胺能神经元和/或表达5-HT（1A）、NK 1或M1毒蕈碱受体的神经元。8-OH DPAT将用于选择性激活5-HT神经元上的5-HT（1A）自身受体，而5，7-DHT或与5-羟色胺转运蛋白抗体缀合的神经毒素皂草素（SERT-SAP）将用于选择性破坏多巴胺能神经元。类似的方法将被用来抑制或破坏表达NK 1或M1的神经元 毒蕈碱受体与SP-SAP或从绿色曼巴蛇毒液中获得的对m1毒蕈碱受体具有高度选择性的强效毒素（m1-toxin 1）。我们将使用EEG小波分析和行为观察，在短（6小时）体积描记器记录和长（12-24小时）记录在其自然栖息地（与母猪和兄弟姐妹）使用遥测这些特定的“病变”对睡眠结构的影响进行评估。我们还将评估对热应力的反应，重点是寒战和非寒战产热，皮肤血流量和呼吸过度。最后，我们将使用分形分析的敏感技术 为了评估心肺变异性的复杂性，其降低与控制系统响应扰动的能力降低相关联。事实上，随后死于SIDS的婴儿心率变异性降低。将在中线和侧柱以及所有区域同时进行损伤，以检验神经元以功能特异性方式组织的假设。我们假设，髓5-HT系统是一个主要网站的心肺，体温调节，睡眠和觉醒机制的整合，并在这一地区的异常可能会产生局部或广泛的影响，可能会导致猝死。