Role of Paraventricular NK1 Receptor Expressing Spinally-Projecting Neurons in Cardiovascular Control

表达脊髓投射神经元的室旁 NK1 受体在心血管控制中的作用

• 批准号: BB/N003020/1
• 负责人: Richard Barrett-Jolley
• 金额: $ 44.35万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN003020%2F1
• 关键词: Role; Paraventricular; NK1; Receptor; Expressing

Lay SummaryHow The Head Rules the HeartAlthough the heart beats in the absence of any conscious effort, the entire cardiovascular system is controlled by the brain. Sit and relax; your heart rate will come down. Worry, or even just think seriously about exercise and your heart rate will increase in advance of you actually moving. This is the same for other species too. We have recorded the heart rates of horses as they move into the stalls and their heart rate rises to somewhere near maximum before they actually run the first metre. This is often called the "fight or flight" reaction; a term first coined by Walter Cannon about 100yrs ago. In healthy animals, such "higher control" allows for anticipation of cardiovascular demand and is a good thing, since an animal that can anticipate an increased oxygen demand is at an evolutionary advantage. For example, it allows animals to escape predators more efficiently than if they only increase cardiac output just *after* they started running or fighting. An athlete that could not increase heart rate prior to a race would almost certainly loose to one who could. However inappropriate or excessive excitation of the cardiovascular system by emotional stress, shock or other stimulus can have disastrous consequences. In the case of people sudden emergency situations can cause people to die from a cardiovascular incident; a phenomenon using the same neurological pathways as the healthy fight or flight reaction. The same occurs with animals, for example there is an increase in dogs dying from "fright" over the firework period. Similar brain circuitry to that controlling these stress responses is also involved with blood pressure control in a variety of other situations to. Eg, in humans with malfunctioning cardiovascular control neurons, drinking half a litre of water can push up blood pressure by 100mmHg, most elderly people suffer from this phenomenon, to some degree. Whilst experiments over the past century have shown that this level of cardiovascular control involves the hypothalamus the exact neurons responsible are not known. Our laboratory and others have identified a particular group of neurons that may be responsible. Another famous American physiologist, Loewy, once referred to these as the "central command neurons" of the stress response. The full picture turns out to be much more complex and even the idea that these neurons are involved with the stress response has become controversial. The neurons unarguably modulate the cardiovascular system and kidney, but we do not know whether they contribute to cardiovascular stress responses in only some situations, but not others or whether they exclusively play a roll in more subtle, but equally important aspects of cardiovascular control, such as regulation of the volume or electrolyte content of blood. This is particularly interesting, because these aspects of cardiovascular control are known to fail in many older people and contribute to cardiovascular disease. Data also suggests that these neurons also contribute to the daily "circadian" cycle of blood pressure that is seen in humans and other species, where blood pressure increases as we wake and drops (sometimes dangerously) when we sleep. Perhaps these neurons are "polymodal", ie, mediating subtle regulation of the cardiovascular system in response to a wide range of environmental and emotional stimuli. This project will therefore use a range of experimental approaches to investigate the role of a particular subset of these control neurons. Our group has an almost unique combination of skills and experience to enable us to answer these specific questions about the function of these fascinating neurons in animals. Understanding this is not just biologically fascinating, but may pave the way for future development of drugs that can prevent sudden excessive elevations of blood pressure in elderly people and ageing domestic animals.

虽然心脏在没有任何有意识的努力下跳动，但整个心血管系统都是由大脑控制的。坐下来，放松;你的心率会下降。担心，甚至只是认真考虑锻炼，你的心率就会在你真正移动之前增加。其他物种也是如此。我们记录了马匹进入马厩时的心率，在它们真正跑完第一米之前，它们的心率上升到接近最大值。这通常被称为“战斗或逃跑”反应;这个术语最早是由沃尔特·坎农在大约100年前提出的。在健康的动物中，这种“更高的控制”允许预期心血管需求，这是一件好事，因为能够预期增加氧气需求的动物处于进化优势。例如，它使动物能够更有效地逃离捕食者，而不是仅仅在开始奔跑或战斗后才增加心输出量。一个不能在比赛前提高心率的运动员几乎肯定会输给一个能提高心率的运动员。然而，情绪压力、休克或其他刺激对心血管系统的不适当或过度兴奋可能会产生灾难性的后果。在人们的情况下，突发紧急情况可能导致人们死于心血管事件;这种现象使用与健康的战斗或逃跑反应相同的神经通路。同样的情况也发生在动物身上，例如，在燃放烟花期间，死于“惊吓”的狗的数量有所增加。与控制这些压力反应的大脑回路类似，在各种其他情况下也涉及血压控制。例如，在心血管控制神经元功能障碍的人中，喝半升水可以使血压升高100 mmHg，大多数老年人在某种程度上都会受到这种现象的影响。虽然过去世纪的实验表明，这种水平的心血管控制涉及下丘脑，但确切的神经元负责尚不清楚。我们的实验室和其他实验室已经确定了一组可能负责的特定神经元。另一位著名的美国生理学家洛伊（Loewy）曾将这些神经元称为应激反应的“中央指挥神经元”。事实证明，整个情况要复杂得多，甚至这些神经元与压力反应有关的想法也变得有争议。毫无疑问，神经元调节心血管系统和肾脏，但我们不知道它们是否只在某些情况下有助于心血管应激反应，而不是其他情况，或者它们是否只在更微妙但同样重要的心血管控制方面发挥作用，例如调节血液的体积或电解质含量。这是特别有趣的，因为已知心血管控制的这些方面在许多老年人中失败并导致心血管疾病。数据还表明，这些神经元也有助于人类和其他物种的血压的日常“昼夜”周期，当我们醒来时血压会升高，当我们睡觉时血压会下降（有时很危险）。也许这些神经元是“多模态”的，即介导心血管系统对广泛的环境和情感刺激的微妙调节。因此，该项目将使用一系列实验方法来研究这些控制神经元的特定子集的作用。我们的团队拥有几乎独一无二的技能和经验，使我们能够回答这些关于动物中这些迷人的神经元功能的具体问题。了解这一点不仅在生物学上令人着迷，而且可能为未来开发药物铺平道路，这些药物可以防止老年人和衰老的家畜血压突然过度升高。

项目成果

Ion Channels in the Paraventricular Hypothalamic Nucleus (PVN); Emerging Diversity and Functional Roles.

• DOI: 10.3389/fphys.2018.00760
• 发表时间: 2018
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Feetham CH;O'Brien F;Barrett-Jolley R
• 通讯作者: Barrett-Jolley R

Discriminant Analysis of Principle Component analyses of Physiological Data

生理数据主成分分析的判别分析

• DOI: 10.1101/2020.01.09.899898
• 发表时间: 2020
• 作者: Haidar O

Understanding the role of HACD enzymes and very long chain fatty acids in zebrafish muscle development and disease.

了解 HACD 酶和超长链脂肪酸在斑马鱼肌肉发育和疾病中的作用。

• 发表时间: 2019
• 作者: Morgan, R.S.I.

Deep-Channel uses deep neural networks to detect single-molecule events from patch-clamp data

Deep-Channel 使用深度神经网络从膜片钳数据中检测单分子事件

• DOI: 10.1101/767418
• 发表时间: 2019
• 作者: Celik N

Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts

• DOI: 10.3389/fphys.2020.00226
• 发表时间: 2020-03-24
• 期刊: FRONTIERS IN PHYSIOLOGY
• 影响因子: 4
• 作者: Haidar, Omar;O'Neill, Nathanael;Barrett-Jolley, Richard
• 通讯作者: Barrett-Jolley, Richard