Adaptation of Brainstem Circuits to Chronic Hypoxia

脑干回路对慢性缺氧的适应

• 批准号: 7612033
• 负责人: David Douglas Kline
• 金额: $ 37万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612033
• 关键词: Action Potentials; Acute; Address; Afferent Neurons; Afferent Pathways; Animal Model; Arrhythmia; Arts; Attenuated; Blood Pressure; Brain Stem; Breathing; Calcium; Calcium Channel; Cardiovascular system; 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; Myxoid cyst; Neurons; Neurotransmitters; Nucleus solitarius; Obstructive Sleep Apnea; Peripheral; Play; Potassium; 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; public health relevance; receptor; receptor expression; respiratory; response; sensory integration; serotonin receptor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：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有关。暴露于慢性间歇性缺氧（CIH）是这些疾病的一个模型。患有 OSA 的人类和 CIH 后的动物模型中，外周动脉化学反射和心肺参数均增强。血清素 (5-HT) 在 OSA 和 CIH 中发挥作用，但其机制和作用位点仍不清楚。该提案将确定 5-HT 在 CIH 诱导的颈动脉体化学反射增强中的作用和机制。我们在孤束核（NTS）（颈动脉体感觉传入的中央终止位点）中确定，10天的CIH增加了基础突触前自发神经递质的释放和模仿化学传入放电的刺激序列后发生的异步释放。总自发释放的增加增强了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。可能是为了平衡这种突触前和突触后的增强，刺激诱发的神经递质释放被减弱。在 CIH 中，促进作用占主导地位并将信息传递扩展到心肺核。我们对 CIH 的初步电生理学、分子和影像学研究表明，5-HT 对化学传入功能、NTS 神经元活动和初级突触的突触传递具有重要作用。 5-HT 的作用是通过激活 NTS 突触的突触前和突触后细胞上不同的 5-HT 受体（抑制性和兴奋性）来实现的。主要假设是，5-HT 通过对化学感觉传入神经、突触后 NTS 细胞的作用以及通过其对离子电流和神经元活动的影响在两者之间进行信息传递来调节动脉化学反射的 CIH 依赖性可塑性。此外，不同 5-HT 受体的功能及其在突触前和突触后位点的兴奋性和抑制性平衡调节着这种可塑性。最终效果是化学感应 NTS 突触的信息传递增加。拟议的研究将确定岩神经节、NTS 细胞的化学感应神经元中 5-HT1/2 受体的功能及其突触连接。为了检验这一假设，将在控制和 CIH 条件下实现以下具体目标。目标 1 将确定 5-HT 对化学感受器感觉神经元的离子电流和动作电位放电的作用。目标 2 将确定 5-HT 对化学感受器感觉传入和 NTS 二级细胞之间突触传递的作用。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。总而言之，这些研究将增强我们对 CIH 诱导的呼吸控制系统可塑性后果的理解，并为 OSA.7 可能的具体治疗干预措施提供见解。 公共卫生相关性：暴露于慢性间歇性缺氧是心肺疾病的一个模型，表现为周期性呼吸和高血压。临床和实验数据表明神经递质血清素的作用。这些研究的结果将确定血清素在该疾病模型中作用的相关性和机制，并期望了解潜在的治疗干预措施。