Hypothalamic Modulation of Parasympathetic Cardiac Neurons

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）是发生在美国人口中多达24%的男性和9%的女性中的一种主要的心血管健康风险，但人们对其知之甚少。OSA可参与多种心血管疾病的发生和发展，包括猝死、高血压、心律失常、心肌缺血和中风。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动脉压升高（~2 mmHg）方面效果甚微，但CPAP是侵入性的，耐受性差，尽管存在OSA风险，但经常停止。最近的研究表明，下丘脑室旁核（PVN）内神经元的活动对心血管对压力和脱水等挑战的反应至关重要，但在OSA模型中，这些神经元的活动并未受损，而是具有增强的活性，并参与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PVN中的抗利尿激素（AVP）神经元是交感兴奋性的，而抗利尿激素受体的激活会抑制心脏保护的副交感心脏迷走神经（cvn），但最近的研究提供了令人兴奋的新证据，证明从不同PVN神经元群释放的神经肽催产素具有心脏保护作用。催产素减少了焦虑和压力对心血管的不良影响，正如本研究将测试的那样，可能也减少了慢性夜间间歇性缺氧/高碳酸血症的有害后果。该项目挑战了PVN仅是交感神经兴奋性的范式，并将测试PVN有两种截然不同的途径，一种是共同释放催产素，激活CVNs并具有心脏保护作用，另一种途径是加压素抑制CVNs并增加不利的心血管变化。此外，这项工作将测试这些通路是否被改变，以及这两个PVN神经元群是否可以被不同地控制，以减轻或增强OSA模型中发生的不利心血管变化。该项目将解决我们在知识方面的主要空白，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.