Foundational tools to study the impacts of sympathetic activity on the neuroanatomy and function of brown adipose tissue

项目摘要 越来越多的证据支持棕色/米色脂肪组织（BAT）有助于基底动脉粥样硬化的观点。 研究人员发现，在成年人中，BAT的活性降低会导致肥胖。交感神经刺激 增加啮齿动物体内BAT的活性。报告说，信号从星状神经节（SG）调节 在人类的产热，提出了一种可能性，微创方法，以刺激交感神经 从SG到锁骨上BAT（scBAT）的投射具有作为抗肥胖疗法的潜力。的 SG的神经解剖学是复杂的，因为交感神经元和感觉神经元轴突离开神经节 通过6-8个不同的出口点到达外围的各种目标。用于SG的神经调节 预测到BAT具有临床应用，刺激方案必须避免预测到BAT。 心脏和上肢的SG从理论上讲，这可以通过物理聚焦电 当SG神经元离开SG或进入scBAT储库时，刺激SG神经元。或者，遗传学方法可以 使用限制药理学操作神经支配BAT的SG神经元的亚群。这些 在小鼠模型和人体组织样本中的补充研究将作为决定 这些策略是可行的治疗选择。 拟议的研究旨在填补关键的信息空白，并开发全面 映射调节BAT的神经回路，并探索BAT神经调节作为抗- 肥胖治疗目标1中的研究将使用转基因小鼠模型和荧光神经元模型的组合。 示踪剂，以确定在BAT和前肢投射索马之间是否存在任何物理重叠， SG或其离开SG的出口点。与此同时，我们将进行第一次映射研究的投影， 在人类尸检标本中SG与scBAT的关系。研究调节或记录神经活动的主要障碍 在SG中，这个神经节包含许多不同类型的传入和传出神经元，它们调节广泛的神经元。 一系列生理功能。目标2中的研究将定义SG不同亚群的分子标记 投射到BAT和心脏的神经元。然后，我们将确定这些标记中是否有任何一个是保守的， 人体手术样本最后，目标3的研究将建立系统，以评估 神经调节对交感神经纤维组织的影响， 测量BAT氧化能力和活性。为了帮助这些努力，我们将开发成像技术 交感神经投射在完好的BAT仓库中。此外，我们还将验证关键的体内试验，以评估 神经调节对BAT功能的影响可以很容易地转化为人类。除了影响 在最佳可得技术领域，这些研究还将为今后的努力提供坚实的基础，以了解现有的 SG神经调节疗法对其他治疗方法难治的广泛病症具有有益效果。 治疗，包括室性心动过速，慢性局部疼痛综合征和创伤后应激障碍。

PROJECT SUMMARY A growing body of evidence supports the idea that brown/beige adipose tissue (BAT) contributes to basal metabolism in adult humans, and that diminished BAT activity can lead to obesity. Sympathetic nerve stimulation increases BAT activity in rodents. Reports that signaling from the stellate ganglion (SG) modulates thermogenesis in humans, raises the possibility that minimally-invasive approaches to stimulate sympathetic projections from the SG to supraclavicular BAT (scBAT) have potential as an anti-obesity therapy. The neuroanatomy of the SG is complex, because sympathetic and sensory neuronal axons leave the ganglion through 6-8 different exit points to reach a wide variety of targets in the periphery. For neuromodulation of SG projections to BAT to have clinical applications, it is essential that stimulation protocols avoid projections from the SG to the heart and upper extremities. In theory, this can be achieved by physically focusing the electrical stimulus to SG neurons as they exit the SG or enter the scBAT depot. Alternatively, genetic approaches could be used restrict pharmacological manipulations to the subpopulation of SG neurons that innervates BAT. These complementary studies in mouse models and human tissue samples will serve as the basis for deciding which of these strategies are viable therapeutic options. The proposed studies are designed to fill critical information gaps and to develop tools needed for comprehensive mapping of neural circuits regulating BAT and to explore the potential use of BAT neuromodulation as an anti- obesity therapy. Studies in Aim 1 will use combinations of transgenic mouse models and fluorescent neuronal tracers to determine whether there is any physical overlap between BAT and forelimb-projecting soma within the SG or their exit points out of the SG. In parallel, we will perform the first mapping studies of the projections from the SG to scBAT in human autopsy specimens. A major obstacle to studies to modulate or record neural activity in the SG is that this ganglion contains many different types of afferent and efferent neurons that regulate a wide range of physiological functions. Studies in Aim 2 will define molecular markers for distinct subpopulations of SG neurons that project to BAT and heart. Then we will determine whether any of these markers are conserved in human surgical samples. Finally, studies in Aim 3 will establish systems to evaluate the impact of neuromodulation on the organization of sympathetic fibers in conjunction with well-established assays to measure BAT oxidative capacity and activity. To aid these efforts, we will develop techniques to image sympathetic projections in an intact BAT depot. In addition, we will validate key in vivo assays needed to assess the impacts of neuromodulation on BAT function that can be readily translated to humans. In addition to impacts on the BAT field, these studies will also provide a strong foundation for future efforts to understand how existing SG neuromodulation therapies have beneficial effects on a wide range of conditions that are refractory to other treatments, including ventricular tachycardia, chronic regional pain syndrome and post-traumatic stress disorder.