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Adaptation of Brainstem Circuits to Chronic Hypoxia

脑干回路对慢性缺氧的适应

基本信息

批准号：
8238323
负责人：
David Douglas Kline
金额：
$ 36.6万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8238323
关键词：
Action Potentials Acute Address Afferent Neurons Afferent Pathways Animal Model Arrhythmia Attenuated Blood Pressure Brain Stem Breathing Calcium Calcium Channel Cardiovascular Diseases Carotid Body Cell Nucleus Cells Chemoreceptors Chronic Clinical Data Disease Disease model Equilibrium Exposure to Ganglia Health Heart failure Homeostasis Human Hypertension Hypoxia Individual Modeling Neurons Neurotransmitters Nucleus solitarius Obstructive Sleep Apnea Peripheral Play Potassium Channel Presynaptic Terminals Protocols documentation Respiration Disorders Role Sensory Serotonin Site Sleep Fragmentations Stimulus Synapses Synaptic Transmission System Techniques Testing Therapeutic Intervention Training expectation improved innovation insight molecular imaging neurotransmitter release postsynaptic presynaptic receptor receptor expression receptor function respiratory response sensory integration

项目摘要

Certain cardiovascular and respiratory disorders, such as Obstructive Sleep Apnea (OSA), manifest as episodic or unstable breathing and hypertension. OSA is associated with systemic hypertension, heart failure, respiratory alterations and cardiac arrhythmias. Exposure to chronic intermittent hypoxia (CIH) is a model for these disorders. Peripheral arterial chemoreflexes and cardiorespiratory parameters are augmented in humans with OSA and animal models following CIH. A role for serotonin (5-HT) has been suggested in OSA and CIH, but its mechanism(s) and its site of action remain unclear. This proposal will determine the role and mechanisms of 5-HT in the CIH-induced augmentation of carotid body chemoreflex. We have established in the nucleus of the solitary tract (NTS), the central termination site of carotid body sensory afferents, that 10 days of CIH increases basal presynaptic spontaneous neurotransmitter release and asynchronous release that occurs following a stimulus train that mimics chemoafferent discharge. This augmentation in total spontaneous release enhances postsynaptic action potential discharge and generates short-term facilitation in NTS cells. Also, baseline action potential discharge increases in NTS cells following CIH. Possibly to balance this pre- and postsynaptic enhancement, stimulus-evoked neurotransmitter release is attenuated. The facilitatory actions predominate and extend information transfer to cardiorespiratory nuclei in CIH. Our preliminary electrophysiological, molecular and imaging studies on CIH suggest that 5-HT has an important role on chemoafferent function, NTS neuronal activity and synaptic transmission at this primary synapse. The effect of 5-HT occurs through the activation of distinct 5-HT receptors, both inhibitory and excitatory, on the pre- and postsynaptic cell of the NTS synapse. The leading hypothesis is that 5-HT modulates the CIH-dependent plasticity of the arterial chemoreflex by actions at the chemosensory afferent, the postsynaptic NTS cell, and the information transfer between the two through its effect on ionic currents and neuronal activity. Furthermore, the function of distinct 5-HT receptors and their excitatory and inhibitory balance at the pre- and postsynaptic sites regulates such plasticity. The net effect is an increase in information transfer at the chemosensory-NTS synapse. The proposed studies will ascertain the function of 5-HT1/2 receptors in chemosensory neurons from the petrosal ganglia, NTS cells, and their synaptic connection. To test this hypothesis, the following specific aims will be addressed under control and following CIH conditions. Aim 1 will determine the role of 5-HT on ionic currents and action potential discharge in chemoreceptor sensory neurons. Aim 2 will ascertain the role of 5-HT on synaptic transmission between chemoreceptor sensory afferents and NTS second order cells. Aim 3 will resolve the role of 5-HT on ionic currents and action potential discharge in postsynaptic NTS cells. Taken together, these studies will enhance our understanding of the consequences of CIH-induced plasticity in the respiratory control system and provide insights into possible specific therapeutic interventions in OSA. 7. Project Narrative Exposure to chronic intermittent hypoxia is a model for cardiorespiratory diseases that manifest as periodic breathing and hypertension. Clinical and experimental data have suggested a role for the neurotransmitter serotonin. Results from these studies will determine the relevance and mechanism of serotonin's action in this disease model with the expectation of understanding potential therapeutic interventions.

某些心血管和呼吸系统疾病，如阻塞性睡眠呼吸暂停（OSA），表现为间歇性或不稳定的呼吸和高血压。阻塞性睡眠呼吸暂停与全身性高血压、心力衰竭、呼吸改变和心律失常。暴露于慢性间歇性缺氧（CIH）是一种模型，这些紊乱。人类外周动脉化学反射和心肺参数增加 OSA和CIH后动物模型。5-羟色胺（5-HT）在OSA和CIH中的作用已被提出，但其作用机制和作用部位尚不清楚。这一建议将确定其作用， 5-HT在CIH诱导的颈动脉体化学反射增强中的作用机制。我们已经建立在孤束核（NTS），颈动脉体感觉传入的中枢终末部位，10 CIH增加了基础突触前自发神经递质释放和异步释放，发生在模仿化学传入放电的刺激序列之后。这种完全自发的增强释放增强突触后动作电位放电，并在NTS细胞中产生短期易化。此外，CIH后NTS细胞的基线动作电位放电增加。或许是为了平衡这一点，和突触后增强，刺激诱发的神经递质释放减弱。易化在CIH中，动作占主导地位并将信息传递扩展到心肺核。我们的初步对CIH的电生理学、分子生物学和影像学研究表明，5-HT在CIH的发病机制中起重要作用。化学传入功能、NTS神经元活动和该初级突触处的突触传递。的影响 5-HT是通过激活不同的5-HT受体而产生的，既有抑制性的，也有兴奋性的， NTS突触的突触后细胞主要假设是5-HT调节CIH依赖性的通过化学感觉传入、突触后NTS细胞的作用，动脉化学反射的可塑性，以及通过对离子电流和神经元活动的影响，两者之间的信息传递。此外，委员会认为，不同5-HT受体的功能及其在突触前和突触后的兴奋和抑制平衡位点调节这种可塑性。净效应是在化学感觉-NTS的信息传递增加突触这项研究将确定5-HT 1/2受体在化学感受神经元中的功能，岩神经节、NTS细胞及其突触连接。为了验证这一假设，以下具体目标将在控制和CIH条件下得到解决。目的1将确定5-HT在化学感受器感觉神经元的离子电流和动作电位放电。目标2将确定 5-HT对化学感受性感觉传入与孤束核二级细胞间突触传递的影响目标3 将解决5-HT对突触后NTS细胞离子电流和动作电位放电的作用。采取总之，这些研究将加强我们对CIH诱导的可塑性在大脑中的后果的理解。呼吸控制系统，并提供对OSA可能的具体治疗干预的见解。7.项目叙述暴露于慢性间歇性缺氧是表现为周期性的心肺疾病的模型呼吸和高血压。临床和实验数据表明，神经递质血清素这些研究的结果将确定5-羟色胺在这一过程中的作用的相关性和机制。疾病模型，以期了解潜在的治疗干预措施。