Bilateral BBSRC-FAPESP: Behavioural and neuroendocrine mechanisms regulating hydromineral homeostasis - a lifelong perspective

哺乳动物有机体的体液处于不断流动的状态。即使在没有脱水、出血或饥饿等挑战的情况下，由于正常的、强制性的肾脏排泄功能以及呼吸和排汗过程，盐和水也不断丢失。人体有两种机制来控制水和盐的消耗和排泄，以保持健康所需的最佳身体内容。第一种机制涉及脑室旁核(PVN)的一部分产生一种名为加压素的荷尔蒙，该荷尔蒙告诉肾脏保存水分。第二种机制是行为机制，涉及口渴和食盐的本能，这些本能在情感上驱使生物体纠正其液体平衡。这些机制可能会出错，导致健康状况不佳。例如，在住院的老年患者中，相当大比例的患者明显存在液体平衡障碍，脱水是老年人发病和死亡的常见原因。据报道，人类对各种脱水挑战的反应随着年龄的增长而下降，这似乎涉及口渴和食盐量的减少，以及加压素生产的失调。体液平衡失调影响健康的另一种方式是饮食中钠的过量摄入，这与几种慢性退行性疾病的发展有关，如心血管疾病，包括高血压。这些疾病由于预期寿命的增加而变得更加普遍，逐渐降低了生活质量，增加了对医疗和社会援助的需求。流行病学和实验研究表明，在子宫和哺乳期间发生的事件可能会在成人生活中造成长期后果。有趣的是，怀孕期间过量的盐分摄入和脱水都会增加成年后代的食盐胃口，这可能会影响长期的健康和福祉。我们最近产生了令人兴奋的新证据，表明下丘脑室旁核不仅参与加压素的产生，而且在产生控制盐消费的本能方面也起着核心作用。因此我们假设：i)室旁核整合了对盐和不平衡的荷尔蒙和行为反应。Ii)这些综合功能在老年时受到干扰，导致口渴感觉减少，钠摄取减少，AVP神经元的活动改变。iii)这些综合功能因胎儿暴露在高盐环境中而受到干扰，导致成人食盐摄入量的设定值重新编程。或者现在的目标是破译PVN控制盐和水的动态平衡的行为(口渴和钠摄取)和激素(AVP合成和分泌)机制的分子机制。此外，我们将找出这些机制是如何在老年和胎儿编程后出错的。

The bodily fluids of the mammalian organism are in a constant state of flux. Even in the absence of challenges such as dehydration, haemorrhage or starvation, salt and water are constantly being lost as a consequence of normal, obligatory renal excretory functions, and by the processes of respiration and perspiration. The body has two mechanisms that function to control the consumption and the excretion of water and salt, in order to maintain the optimal bodily content required for good health. The first mechanism involves the production by a part of the brain paraventricular nucleus (PVN) of a hormone called vasopressin that tells the kidney to conserve water. The second mechanism is behavioural, and involves the instincts of thirst and salt appetite that emotionally drive the organism to correct its fluid balance. These mechanisms can go wrong resulting in ill-health. For example, disorders of fluid balance are evident in a substantial proportion of elderly patients admitted to hospital, and dehydration is a frequent cause of morbidity and mortality in old people. An age-related decline in the response to a variety of dehydrating challenges has been reported in humans, and this seems to involve a reduction in thirst and salt appetite, as well as dysregulation of vasopressin production. Another way that disorders of fluid balance can affect wellbeing is as a consequence of an excessive intake of dietary sodium, which is associated with the development of several chronic degenerative diseases, such as cardiovascular disorders, including hypertension. These medical conditions, which are becoming more prevalent as a result of increased life expectancy, progressively decrease life quality and increase the need for medical and social assistance. Epidemiological and experimental studies have suggested that events occurring in utero and during lactation can result in long-term consequences in adult life. Interestingly, both excessive salt intake and dehydration during pregnancy provoke increased salt appetite in adult offspring, which may then impact on long-term health and wellbeing. We have recently produced exciting new evidence that suggests that the PVN is not only involved in the production of vasopressin, but also has a central role in generating the instincts that control the consumption of salt. We thus hypothesise:i) that the PVN integrates hormonal and behavioural responses to salt and imbalance. ii) that these integrative functions are perturbed in old age, resulting in decreased thirst perception, reduced sodium appetite, and altered activity of AVP neurones.iii) that these integrative functions are perturbed by foetal exposure to high salt, resulting in a reprogramming of the set point for adult salt consumption. Or aims are now to decipher the molecular mechanisms by which the PVN controls behavioural (thirst and sodium appetite) and hormonal (AVP synthesis and secretion) mechanisms of salt and water homeostasis. Further, we will find out how these mechanisms go wrong in old age and following foetal programming.