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

大脑如何控制心脏虽然心脏在无意识的情况下跳动，但整个心血管系统是由大脑控制的。坐下来放松；你的心率会下降。担心，甚至只是认真考虑运动，你的心率会在你真正运动之前增加。这对其他物种也是一样的。我们记录了马进入马厩时的心率，在它们真正跑完第一米之前，它们的心率会上升到接近最大值。这通常被称为“战斗或逃跑”反应；这个词最早是由沃尔特·坎农在大约100年前创造的。在健康的动物中，这种“更高的控制”允许对心血管需求的预测，这是一件好事，因为能够预测到增加的氧气需求的动物在进化上具有优势。例如，它可以让动物更有效地逃离捕食者，而不是仅仅在它们开始奔跑或战斗后才增加心输出量。在比赛前不能提高心率的运动员几乎肯定会输给可以提高心率的运动员。然而，由于情绪紧张、休克或其他刺激而引起的心血管系统的不适当或过度兴奋会造成灾难性的后果。就人而言，突发紧急情况可能导致人死于心血管事件；一种使用与健康的战斗或逃跑反应相同的神经通路的现象。同样的情况也发生在动物身上，例如，在烟花燃放期间，狗死于“惊吓”的人数有所增加。控制这些压力反应的类似大脑回路也涉及到其他各种情况下的血压控制。例如，心血管控制神经元功能失常的人，喝半升水可以使血压升高100毫米汞柱，大多数老年人在某种程度上都有这种现象。虽然过去一个世纪的实验表明，这种程度的心血管控制涉及下丘脑，但具体负责的神经元尚不清楚。我们的实验室和其他实验室已经确定了一组特定的神经元可能负责。另一位著名的美国生理学家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，甚至这些神经元参与应激反应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参与心血管应激反应，而不是在其他情况下，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，因为已知这些方面的心血管控制在许多老年人中失效并导致心血管疾病。数据还表明，这些神经元也参与了人类和其他物种的日常“昼夜节律”血压循环，当我们醒来时血压升高，当我们睡觉时血压下降（有时很危险）。也许这些神经元是“多模态”的，也就是说，在对各种环境和情绪刺激作出反应时，介导心血管系统的微妙调节。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老年家畜的血压突然过度升高。

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.