Developmental programming of brown adipose tissue sympathetic tone

拟议的研究将以棕色脂肪组织（BAT）为平台，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和疾病风险易感性产生持久和特异性的影响。广泛的发育暴露会影响SNS张力到代谢相关器官，包括胰腺、肾脏、脂肪组织和心脏。迄今为止，发育影响SNS音调和器官功能之间的关系的证据纯粹是相关的。直接研究SNS编程对成人生理学的贡献的一个障碍是，在发育过程中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，这可能会混淆对结果的解释。我们确定了两种早期产后暴露，它们特异性地减少了星状神经节中投射到BAT （SGBAT）的交感神经元的数量，但在健康成人中，它们对生理挑战的反应是不同的。在30°C的环境中饲养对寒冷的反应性有持久的影响，但对高脂肪饮食没有影响，而小窝产仔（SL）的哺乳对饮食引起的肥胖有易感性，但对寒冷没有影响。本文概述的研究将建立新的系统，以测试SGBAT数量的变化是否影响神经支配和SNS张力对BAT的影响（目的1），以及它们是否必要和充分地对器官功能和对寒冷和饮食挑战的生理反应产生持久影响（目的2）。我们将利用我们在30°C和22°C培养的小鼠中发现的SGBAT神经元分子不同亚群和BAT中差异表达的基因来揭示SNS电路编程的分子介质（目的3）。我们将对BAT和SG进行平行转录组学分析，以确定在发育的关键时期对窝产仔数或温度操纵的功能反应的特异性来源。由于SGBAT亚类的转录特征是所有SG神经元共有的，因此这些研究的经验教训可以应用于与疾病风险发育规划有关的其他出生后暴露和器官系统。

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.