Hypothalamic Modulation of Parasympathetic Cardiac Neurons

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）是一种主要的心血管健康风险，但人们对其了解甚少，美国人群中约24%的男性和9%的女性会发生这种风险。OSA可参与猝死、高血压、心律失常、心肌缺血和脑卒中等多种心血管疾病的发生和发展。OSA的治疗主要是持续气道正压通气（CPAP），虽然这种治疗在降低升高的动脉压（~2 mmHg）方面效果甚微，但CPAP具有侵入性，耐受性差，尽管存在OSA的风险，但通常会中断。最近的研究表明，下丘脑室旁核（PVN）内的神经元中的活性对于对诸如应激和脱水的挑战的心血管反应是关键的，其未受损，而是在OSA模型中具有增强的活性，并且参与OSA诱导的高血压的维持和/或产生。然而，PVN是一个异质核。尽管室旁核中的加压素（AVP）神经元是交感神经兴奋性的，并且加压素受体的激活抑制心脏保护性副交感神经心脏迷走神经元（CVNs），但最近的工作提供了令人兴奋的新证据，即从不同的室旁核神经元群体释放的神经肽催产素具有心脏保护性。催产素可以减少焦虑和压力对心血管的不良影响，正如这项研究将要测试的那样，它可能还可以减少慢性夜间间歇性缺氧/高碳酸血症的有害影响。该项目挑战PVN仅是交感神经兴奋的范式，并将测试PVN有两种相反的途径，一种是共同释放催产素，激活CVN并具有心脏保护作用，另一种途径是加压素抑制CVN并增加不良心血管变化。此外，这项工作将测试这些通路是否被改变，以及这两个PVN神经元群体是否可以被差异化控制以减轻或增强OSA模型中发生的不良心血管变化。该项目将解决我们知识中的主要空白，并有望为评估包括OSA在内的心血管疾病患者的新的潜在治疗方法和靶点奠定基础。

DESCRIPTION (provided by applicant): One major, yet poorly understood cardiovascular health risk that occurs in as many as ~24% of males and 9% of females within the United States population is obstructive sleep apnea (OSA). OSA can participate in both the initiation and progression of several cardiovascular diseases including sudden death, hypertension, arrhythmias, myocardial ischemia and stroke. Treatment of OSA is primarily continuous positive airway pressure (CPAP), and while this treatment is marginally effective in reducing elevated arterial pressure (~2 mmHg) CPAP is intrusive, poorly tolerated and often discontinued despite the risks of OSA. Recent work has suggested activity in neurons within the paraventricular nucleus of the hypothalamus (PVN) that are critical for the cardiovascular responses to challenges such as stress and dehydration are not impaired, but rather possess augmented activity in models of OSA and are involved in the maintenance and/or generation of OSA induced hypertension. However the PVN is a heterogeneous nucleus. Whereas vasopressin (AVP) neurons in the PVN are sympathoexcitatory, and activation of vasopressin receptors inhibits cardioprotective parasympathetic cardiac vagal neurons (CVNs), recent work has provided exciting new evidence that the neuropeptide oxytocin, released from a different population of PVN neurons, is cardioprotective. Oxytocin reduces the adverse cardiovascular consequences of anxiety and stress and, as this study will test, perhaps the deleterious consequences of chronic nocturnal intermittent hypoxia/hypercapnia. This project challenges the paradigm that the PVN is solely sympathoexcitatory, and will test that there are two contrasting pathways from the PVN, one that co-releases oxytocin, activates CVNs and is cardioprotective, and another pathway in which vasopressin inhibits CVNs and increases adverse cardiovascular changes. Furthermore this work will test if these pathways are altered and if these two populations of PVN neurons can be differentially controlled to mitigate or enhance the adverse cardiovascular changes that occur in a model of OSA. This project will address major gaps in our knowledge and hopefully constitute a foundation for appraising new potential treatments and targets for patients with cardiovascular diseases including OSA.