Adaptation of Brainstem Circuits to Chronic Hypoxia

描述(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)，表现为阵发性或呼吸不稳定和高血压。OSA与全身性高血压、心力衰竭、呼吸改变和心律失常有关。暴露于慢性间歇性低氧(CIH)是这些疾病的一个模型。阻塞性睡眠呼吸暂停患者和脑出血后动物模型的外周动脉化学反射和心肺参数增加。5-羟色胺(5-羟色胺)在阻塞性睡眠呼吸暂停综合征和脑出血中的作用已被提出，但其作用机制(S)和作用部位尚不清楚。本研究将确定5-羟色胺在CIH引起的颈动脉小体化学反射增强中的作用和机制。我们在颈动脉体感传入的中枢终止点孤束核(NTS)证实，10天的CIH增加了基础突触前自发神经递质的释放和模拟化学传入放电的刺激序列后发生的异步释放。这种总自发释放的增加增强了NTS细胞的突触后动作电位放电，并产生了短期的促进作用。此外，脑出血后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。易化作用主导并将信息传递延伸到心肺核团。我们对脑出血的电生理、分子和影像研究表明，5-羟色胺在该初级突触的化学传入功能、NTS神经元活动和突触传递中起重要作用。5-羟色胺的作用是通过激活NTS突触的突触前和突触后细胞上不同的5-羟色胺受体，包括抑制性和兴奋性的。主要的假说是，5-羟色胺通过作用于化学感觉传入和突触后NTS细胞，并通过其对离子电流和神经元活动的影响，调节动脉化学反射的CIH依赖性可塑性，并在两者之间进行信息传递。此外，不同的5-羟色胺受体的功能及其在突触前和突触后位置的兴奋和抑制平衡调节这种可塑性。净效应是增加了化学感觉-NTS突触的信息传递。这些研究将确定5-HT1/2受体在岩神经节、NTS细胞的化学感觉神经元中的功能以及它们之间的突触联系。为了验证这一假设，将在控制和遵循CIH条件下实现以下具体目标。目的1研究5-羟色胺对化学感受器感觉神经元离子电流和动作电位放电的影响。目的2探讨5-羟色胺在化学感受器感觉传入和NTS二级细胞突触传递中的作用。目的3研究5-羟色胺对突触后NTS细胞离子电流和动作电位放电的影响。综上所述，这些研究将加强我们对CIH诱导的呼吸控制系统可塑性后果的理解，并为OSA可能的特定治疗干预提供见解。 公共卫生相关性：暴露在慢性间歇性低氧环境中是心肺疾病的一种模式，这种疾病表现为周期性呼吸和高血压。临床和实验数据表明了神经递质5-羟色胺的作用。这些研究的结果将确定5-羟色胺在这种疾病模型中作用的相关性和机制，以期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.