Hungry, stressed chicks? Understanding Hypothalamic Regulation of Appetite in Birds

早期生命是生命中极其重要的时期，作为发育中的胚胎经历的压力可能会产生终生后果。在鸟类中，将孵化中的母亲或发育中的鸡蛋暴露在应激刺激下，可以改变后代的生存、繁殖成功、生产力、健康和福利。食欲和体重受到神经和内分泌系统的密切调控，这些系统特别容易受到压力的影响。在这个项目中，我们将研究早期生活应激编程对大脑馈送回路的神经生物学机制。目的是确定鸟类的食欲是如何发展的，以及它是如何受到出生前压力的影响的。鸟类大脑中的摄食回路是在胚胎发育的后半段建立起来的，它们在孵化前1到2天就达到了它们的特征。虽然在鸟类中，神经回路的形成在很大程度上是未知的，但在鸟类中，大脑的生长在孵化之前基本完成，比如鹌鹑，因为在这些物种中，幼鸟从孵化开始就相对成熟和活动。由于这些神经回路似乎发展迅速，需要在孵化后发挥作用，我们假设大脑喂养回路在发育过程中特别容易受到应激激素的影响。在这里，我们将调查这是否会导致永久性的大脑回路功能失调，从而导致孵化后特征的变化。我们将研究鸟类大脑回路在活跃地发展和形成连接时，早期生命中大脑功能活动和行为的变化。我们还将检查暴露在早期生活压力下的胚胎和雏鸟在它们的喂养回路中是否存在差异，因为我们从以前的工作中知道，它们成年后体重较轻。我们将通过在受精卵中注射皮质酮，将应激激素(皮质酮)水平提高到自然产生的高水平。这模仿了有压力的母亲在卵子中沉积的压力荷尔蒙信号(鹌鹑早期生活应激编程模型)。我们所有的研究都将在雄性和雌性鹌鹑身上进行，因为有证据表明，在食欲调节方面存在性别差异。我们将通过使用神经元激活的标记来绘制正常鸟类大脑中的功能性摄食(饥饿和饱足)的路径，以及随后暴露于产前皮质酮的大脑中的路径。我们将确定这些细胞是增加还是降低食欲。我们还将调查早期生活压力是否会影响雏鸟孵化后的摄食行为和一般运动。我们将通过量化基因表达来检查在经历了早期生活应激编程的胚胎和雏鸡中，调节食欲的关键激素和神经回路是否发生了变化。使用一种名为电生理学的技术来记录大脑中喂养回路的电脉冲，我们将研究早期生活应激是否会改变喂养回路中细胞对葡萄糖的敏感性。检测到葡萄糖变化的脑细胞向大脑通报身体的新陈代谢需求。有趣的是，鸟类脑液中测得的葡萄糖水平比哺乳动物高几倍，这表明葡萄糖调节在鸟类中可能更重要。我们已经开发出一种新的针对鹌鹑胚胎和雏鸟的脑切片制剂，并且(据我们所知)是英国目前唯一能够做到这一点的实验室。我们将提供鸟类大脑对葡萄糖敏感性的新数据，并量化细胞属性和活动是否发生变化。这些研究非常重要，因为它们将为调节新孵化雏鸟食欲的大脑机制提供独特的信息，并阐明早期生活应激可能编程大脑中的摄食回路的机制。

Early life is extremely important time of life and stress experienced as a developing embryo can have lifelong consequences. In birds, exposing an incubating mother or developing egg to stressful stimuli can change survival, breeding success, productivity, health and welfare of the offspring. Appetite and body weight are closely regulated by the nervous and endocrine systems and these systems are particularly vulnerable to stress. In this project we will investigate the neurobiological mechanisms of early life stress programming on brain feeding circuits. The aim is to determine how appetite is developed in birds and how it is affected by pre-natal stress.Feeding circuits in the bird brain are established during the second half of embryonic development and they achieve their characteristics 1 to 2 days before hatch. Although the development of the neural circuit formation is largely undetermined in birds, brain growth is largely complete before hatching in species, such as quail, where the young are relatively mature and mobile from hatch. As these neural circuits appear to develop rapidly and need to become functional after hatch, we hypothesise that brain feeding circuits are especially vulnerable to stress hormones during development. Here we will investigate whether this results in permanent dysregulation of brain circuit function leading to changes in post hatch characteristics. We will investigate the changes in functional brain activity and behaviour across early life when avian brain circuits are actively developing and forming connections. We will also examine whether embryos and chicks exposed to early life stress have differences in their feeding circuits as we know from our previous work that they have lower body weights as adults. We will increase levels of stress hormone (corticosterone) to naturally occurring high levels by injecting corticosterone into fertilised quail eggs. This mimics the stress hormone signal that stressed mothers deposit into the egg (quail early life stress programming model). All our studies will be performed in both male and female quail as there is evidence to suggest there are sex differences in appetite regulation.1. We will map the functional feeding (hunger and satiation), pathways within the normal bird brain and subsequently in brains exposed to prenatal corticosterone by using a marker of neuronal activation. We will identify whether the cells increase or decrease appetite. We will also investigate whether early life stress affects feeding behaviour and the general movement of the chicks once they have hatched.2. We will examine whether the key hormone and neural circuits, that regulate appetite, are changed in embryos and chicks that have been subjected to early life stress programming by quantifying the gene expression.3. Using a technique to record electrical impulses of the feeding circuits in the brain called electrophysiology, we will investigate whether early life stress changes the sensitivity of cells in the feeding circuit to glucose. Brain cells that detect changes in glucose inform the brain of the metabolic needs of the body. Interestingly, the glucose levels measured in brain fluid of birds are several fold higher than in mammals indicating that glucose regulation may be more important in birds. We have developed a novel brain slice preparation for quail embryo and chick and are (to our knowledge) the only lab in the UK currently able to do this. We will provide novel data on the sensitivity of the bird brain to glucose and quantify if there are changes in the cells properties and actions.These studies are important as they will provide unique information into the brain mechanisms that regulate appetite in newly hatched chicks and elucidate the mechanisms by which early life stress may program the feeding circuits in the brain.