Adaptation of Brainstem Circuits to Chronic Hypoxia

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综合征与系统性高血压、心力衰竭、 呼吸改变和心律失常。暴露于慢性间歇性低氧(CIH)是一种 这些障碍。人类外周动脉化学反射和心肺参数增加 阻塞性睡眠呼吸暂停综合征和动物模型遵循CIH。5-羟色胺(5-羟色胺)在OSA和CIH中的作用已被提出， 但其作用机制(S)和作用部位尚不清楚。这项提案将确定其作用和 5-羟色胺在CIH引起的颈动脉体化反射增强中的作用机制我们已经在 孤束核(NTS)，颈动脉体感传入的中枢终末部位，即10 脑出血天数增加基础突触前自发神经递质释放和异步释放 发生在模拟化学传入放电的刺激序列之后。这种增强完全是自发的 释放能增强NTS细胞突触后动作电位的放电，并产生短期易化作用。 此外，脑出血后NTS细胞的基线动作电位放电增加。可能是为了平衡这一前- 突触后增强，刺激诱发的神经递质释放减弱。促进者 在脑出血中，动作主导并将信息传递延伸到心肺核团。我们的预赛 对脑出血的电生理、分子和影像研究表明，5-羟色胺在脑出血中起重要作用。 该初级突触的化学传入功能、NTS神经元活动和突触传递。的影响 5-羟色胺是通过激活不同的5-羟色胺受体而发生的，既有抑制性的，也有兴奋性的。 NTS突触的突触后细胞。主要的假说是5-羟色胺调节CIH依赖 动脉化学反射的可塑性通过作用于化学感觉传入、突触后NTS细胞和 通过对离子电流和神经元活动的影响，在两者之间传递信息。此外， 不同类型5-羟色胺受体的功能及其在突触前后的兴奋和抑制平衡 这些位点调节着这种可塑性。净效应是增加了化学感受器的信息传递 Synapse。拟议的研究将确定5-HT1/2受体在化学感觉神经元中的功能。 岩神经节、NTS细胞及其突触连接。为了检验这一假设，以下是具体的 AIMS将在控制下并遵循CIH条件进行处理。目标1将确定5-羟色胺在 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-羟色胺对化学感受器感觉传入与NTS二级细胞间突触传递的影响目标3 将解决5-羟色胺对突触后NTS细胞离子电流和动作电位放电的作用。已被占用 综上所述，这些研究将加强我们对CIH诱导的可塑性在 并提供对阻塞性睡眠呼吸暂停综合征可能的具体治疗干预措施的见解。7.项目叙事 暴露于慢性间歇性低氧是周期性表现的心肺疾病的一种模型 呼吸和高血压。临床和实验数据表明，神经递质在 血清素。这些研究的结果将确定5-羟色胺在这一过程中的相关性和作用机制 疾病模型，期望了解潜在的治疗干预措施。

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.