Adaptation of Brainstem Circuits to Chronic Hypoxia

描述（由申请人提供）：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。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）是这些疾病的模型。在患有OSA的人和CIH后的动物模型中，外周动脉化学反射和心肺参数增加。5-羟色胺（5-HT）在OSA和CIH中的作用已被提出，但其机制和作用部位仍不清楚。本研究旨在探讨5-HT在CIH诱导的颈动脉体化学感受器反射增强中的作用及其机制。我们已经建立了在孤束核（NTS），颈动脉体感觉传入的中央终止部位，即10天的CIH增加基础突触前自发神经递质释放和异步释放，发生在刺激列车，模仿化学传入放电。这种总自发释放的增加增强了突触后动作电位放电，并在NTS细胞中产生短期易化。此外，CIH后NTS细胞的基线动作电位放电增加。可能为了平衡这种突触前和突触后增强，刺激诱发的神经递质释放被减弱。易化作用在CIH中占主导地位，并将信息传递扩展到心肺核团。我们对CIH的初步电生理、分子和影像学研究表明，5-HT在化学传入功能、NTS神经元活动和这一初级突触的突触传递中起重要作用。5-HT的作用通过激活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）而发生。主要的假设是，5-HT调制CIH依赖的可塑性动脉化学感受器反射的化学感觉传入，突触后NTS细胞，和两者之间的信息传递，通过其对离子电流和神经元活动的影响的行动。此外，不同的5-HT受体的功能和它们在突触前和突触后位点的兴奋性和抑制性平衡调节这种可塑性。净效应是在化学感觉-NTS突触处的信息传递增加。这些研究将确定5-HT 1/2受体在岩神经节、NTS细胞化学感觉神经元中的功能及其突触连接。为了检验这一假设，将在控制和CIH条件下解决以下具体目标。目的1研究5-HT对化学感受性神经元离子电流和动作电位放电的影响。目的二：探讨5-HT在化学感受性感觉传入与孤束核二级细胞突触传递中的作用。目的3探讨5-HT对孤束核突触后细胞离子电流和动作电位放电的影响。总之，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的可能的特定治疗干预提供见解。 公共卫生相关性：暴露于慢性间歇性缺氧是表现为周期性呼吸和高血压的心肺疾病的模型。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5-羟色胺在这种疾病模型中的作用的相关性和机制，并期望了解潜在的治疗干预措施。

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.