Developmental programming of brown adipose tissue sympathetic tone

拟议的研究将使用棕色脂肪组织（BAT）作为平台，以阐明出生后发育影响如何控制交感神经系统（SNS）输入的神经解剖结构，以及这些变化如何对全身生理学和疾病风险易感性产生持久和特定的影响。广泛的发育暴露影响SNS张力到代谢相关器官，包括胰腺，肾脏，脂肪组织和心脏。到目前为止，证据的SNS语气和器官功能的发展影响之间的关系是纯粹的相关性。SNS编程对成人生理学贡献的直接调查的障碍是，在发育期间对其活动的实验操作可能会对影响动物整体健康的器官功能产生影响，这将混淆对结果的解释。我们确定了两种出生后早期暴露，它们专门减少了星状神经节中投射到BAT（SGBAT）的交感神经元的数量，但对健康成年人的生理挑战做出了不同的反应。在30°C下饲养导致对冷而不是高脂肪饮食的反应性的持久影响，而在一窝小奶（SL）中哺乳会导致对饮食诱导的肥胖而不是冷的易感性。本文概述的研究将建立新的系统来测试SGBAT数量的变化是否影响BAT的神经支配和SNS张力（目标1），以及它们是否是必要的和足够的程序对器官功能和生理反应的持久影响冷和饮食挑战（目标2）。我们将利用我们在30°C与22°C下饲养的小鼠中发现的SGBAT神经元的分子上不同的亚群和BAT中差异表达的基因，以揭示SNS回路中编程的分子介导物（Aim 3）。我们将在BAT和SG中进行平行转录组学分析，以确定在发育的关键时期对窝仔数或温度操作的功能反应的特异性来源。由于SGBAT亚类的转录特征由所有SG神经元共享，因此这些研究的经验教训可以应用于其他出生后暴露和器官系统，这些暴露和器官系统与疾病风险的发育编程有关。

The proposed studies will use brown adipose tissue (BAT) as a platform to elucidate how postnatal developmental influences control the neuroanatomical structure of sympathetic nervous system (SNS) inputs and how these changes impart lasting and specific effects on whole body physiology and susceptibility to disease risk. A wide range of developmental exposures influence SNS tone onto metabolically-relevant organs, including pancreas, kidney, adipose tissue and heart. To date, evidence for a relationship between developmental influences on SNS tone and organ function is purely correlational. An obstacle to direct investigations of the contributions of SNS programming to adult physiology is that experimental manipulations of their activity during development would likely have impacts on organ function that affect the overall health of the animal, which would confound interpretation of the results. We identified two early postnatal exposures that specifically reduce the number of sympathetic neurons in the stellate ganglion that project to BAT (SGBAT), but program disparate responses to physiological challenges in healthy adults. Housing at 30°C leads to lasting effects on responsiveness to cold but not high fat diet, while lactation in a small litter (SL) programs susceptibility to diet-induced obesity but not cold. Studies outlined here will establish novel systems to test whether changes in SGBAT number impact innervation and SNS tone onto BAT (Aim 1), and whether they are necessary and sufficient to program lasting effects on organ function and physiological responses to cold and diet challenges (Aim 2). We will leverage our discovery of molecularly distinct subpopulations of SGBAT neurons and differentially expressed genes in BAT from mice raised at 30°C vs. 22°C to uncover molecular mediators of programming in SNS circuits (Aim 3). We will perform parallel transcriptomic analyses in BAT and SG to identify sources of specificity in the functional responses to manipulations of litter size or temperature during a critical period of development. Because transcriptional signatures of SGBAT subclasses are shared by all SG neurons, lessons from these studies can be applied to other postnatal exposures and organ systems that have been implicated in developmental programming of disease risk.