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，例如阻塞性睡眠呼吸暂停 (OSA)，表现为阵发性或不稳定的呼吸和高血压。 OSA 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）是一个模型这些疾病。人类外周动脉化学反射和心肺参数增强 OSA 和 CIH 后的动物模型。血清素 (5-HT) 在 OSA 和 CIH 中发挥作用，但其机制和作用部位仍不清楚。该提案将确定角色和 5-HT 在 CIH 诱导的颈动脉体化学反射增强中的机制。我们已成立于孤束核 (NTS)，颈动脉体感觉传入的中央终止位点，10 CIH 的天数增加了基础突触前自发神经递质的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。总自发性的增加释放增强突触后动作电位放电并在 NTS 细胞中产生短期促进作用。此外，CIH 后 NTS 细胞的基线动作电位放电增加。可能是为了平衡这个预和突触后增强，刺激诱发的神经递质释放减弱。协助性的 CIH 中，行动占主导地位，并将信息传输扩展到心肺核。我们的初步 CIH 的电生理学、分子学和影像学研究表明 5-HT 在 CIH 中发挥重要作用化学传入功能、NTS 神经元活动和初级突触的突触传递。的效果 5-HT 通过激活不同的 5-HT 受体（抑制性和兴奋性）而发生。 NTS 突触的突触后细胞。主要假设是 5-HT 调节 CIH 依赖性通过化学感应传入、突触后 NTS 细胞的作用，动脉化学反射的可塑性两者之间通过其对离子电流和神经元活动的影响进行信息传递。此外，不同 5-HT 受体的功能及其在突触前和突触后的兴奋性和抑制性平衡站点调节这种可塑性。最终效果是化学感应 NTS 信息传递的增加突触。拟议的研究将确定 5-HT1/2 受体在化学感应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，具体如下目标将在控制下并遵循 CIH 条件来实现。目标 1 将确定 5-HT 在化学感受器感觉神经元中的离子电流和动作电位放电。目标 2 将确定 5-HT 对化学感受器感觉传入和 NTS 二阶细胞之间突触传递的影响。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，这些研究将增强我们对 CIH 引起的可塑性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措施的见解。 7. 项目叙述慢性间歇性缺氧是心肺疾病的一个模型，表现为周期性缺氧。呼吸和高血压。临床和实验数据表明神经递质的作用血清素。这些研究的结果将确定血清素在这方面的作用的相关性和机制。疾病模型，期望了解潜在的治疗干预措施。