Gustatory and interoceptive regulation of hypertension

项目摘要 钠（Na+）的过度消费是美国和世界各地的一个主要健康问题， 它与许多健康状况有关，包括高血压--一个主要的危险因素， 心血管疾病钠摄入量与高血压的关系广泛存在 虽然认识到了这一点，但对这种关系背后的机制还没有很好地理解。拟议 实验的目的是通过调查来描述这种关系的机制 调节Na+-味觉/摄入和血压（BP）的感觉系统。我的初步研究 在小鼠中进行的研究发现，在结状神经节和岩神经节中表达 血管紧张素1a型受体（NPGAT 1aR）向孤束核（NTS）发送传入。的 NPG含有神经元，其功能是感知血压的压力感受器或味觉感受器 有Na+味的传入神经。有趣的是，NTS中传入神经的光遗传学激发 NPGAT 1aR可显著降低血压和Na+摄入量。此外，老鼠过度食用 氯化钠溶液，并通过给予醋酸脱氧皮质酮（DOCA盐） 相对于血压正常的小鼠，需要更高频率的刺激来降低血压。 总的来说，我的初步结果表明，NPGAT 1aR向NTS发送传入， 血压的内感受和Na+味觉的感受以及这些神经元的兴奋性 可用于研究Na+过量摄入后高血压的病因。因此我 我提出了一个总体假设，即NPGAT 1aR向NTS发送调节血液的传入神经 压力和Na+摄入，以及这些神经元上的AT 1aR（s）有助于DOCA的发展。 盐性高血压为了证实或反驳这一假设，我将讨论以下目标。目标1将使用 NPGAT 1aR传入的神经解剖学特征和光遗传学激活在吻侧和 尾侧NTS，以确定这些传入神经的连接和兴奋是否足以 在基础条件下和血容量耗尽后改变Na+摄入量和血压。 目的二是利用Cre-LoxP系统和病毒介导的基因转移技术，选择性地缺失AT 1aR， NPG以确定这些AT 1aR是否是增加Na+摄入和减少 DOCA-盐高血压模型的压力反射敏感性。总的来说，这些 实验将揭示脑干中味觉和内感受性的整合， 了解Na+摄入与血压调节之间的关系，从而提供新的 可以用来开发高血压治疗方法的洞察力。

PROJECT SUMMARY The overconsumption of sodium (Na+) is a major health problem in the U.S. and around the world, having been linked to many health conditions, including hypertension—a major risk factor for cardiovascular disease. While the relationship between Na+-intake and hypertension is widely recognized, the mechanism(s) behind this relationship are not well understood. The proposed experiments aim to delineate the mechanism(s) underlying this relationship by investigating sensory systems that regulate Na+-taste/intake and blood pressure (BP). My preliminary studies conducted in mice discovered that neurons within the nodose and petrosal ganglion that express the angiotensin type 1a receptor (NPGAT1aR) send afferents to the nucleus of the solitary tract (NTS). The NPG contains neurons that function as baroreceptors that sense blood pressure or as gustatory afferents that transduce Na+-taste. Intriguingly, optogenetic excitation of afferents in the NTS arising from NPGAT1aR significantly reduces blood pressure and Na+-intake. Moreover, mice overconsuming NaCl solutions and rendered hypertensive via deliver of deoxycorticosterone acetate (DOCA-salt) required greater frequencies of stimulation to lower blood pressure relative to normotensive mice. Collectively, my preliminary results suggest that the NPGAT1aR send afferents to the NTS that mediate the interoception of blood pressure and the perception of Na+-taste and the excitability of these neurons can be used to study the etiology of hypertension that follows Na+ overconsumption. Accordingly, I have developed the overall hypothesis that NPGAT1aR send afferents to the NTS that regulate blood pressure and Na+-intake, and that AT1aR(s) on these neurons contribute to the development of DOCA- salt hypertension. To confirm or refute this hypothesis, I will address the following aims. Aim 1 will use neuroanatomical characterizations and optogenetic activation of NPGAT1aR afferents in the rostral and caudal NTS to determine whether the connectivity and excitation of these afferents are sufficient to alter Na+-intake and blood pressure under basal conditions and following depletion of blood volume. Aim 2 will use Cre-LoxP system and virally-mediated gene transfer to selectively delete AT1aR(s) from the NPG to determine whether these AT1aR are necessary for increased Na+-intake and decreased baroreflex sensitivity that accompany the DOCA-salt model of hypertension. Collectively, these experiments will shed light on gustatory and interoceptive integration in the brainstem to better understand the relationship between Na+-intake and blood pressure regulation, thereby providing novel insight that can be leveraged to develop treatments for hypertension.