CAREER: Hypothalamic Tanycytes and Neuronal Plasticity in the Regulation of Energy Balance

能量平衡的调节需要与下丘脑的沟通和协调，下丘脑可以说是维持能量平衡最重要的大脑区域，营养信号和食欲通路在能量消耗回路中汇聚。下丘脑中有一种特殊的细胞类型在机制层面上还没有得到很好的理解，那就是伸长细胞，这是一种假定的干细胞群，分布在下丘脑和大脑内部脑室之间的界面上。伸长细胞能够感知脑脊液（CSF）中循环的因子，对葡萄糖感知很重要，并表现出改变和再生的能力，但调节这些特性的信号通路尚不清楚。利用标记和谱系追踪成人大脑中发育中的细胞的方法，本项目旨在了解伸长细胞及其在不同能量平衡条件下更新成人下丘脑神经元的能力。该项目包括阐明伸长细胞中特定生长因子信号通路在促进成人大脑下丘脑神经元再生能力中的作用的研究。这个项目更广泛的影响包括为在这个项目下进行毕业论文研究的学生提供一个正式的高级顶点课程，并且，为了增加一般的科学职业机会，在当地社区大学系统进行为期一周的课程，该课程涵盖并可以连接到这个项目的主要研究者的实验室的暑期奖学金。许多代谢干预，如运动或热量限制，被认为会影响下丘脑的神经可塑性，或大脑调节能量平衡的指挥中心。特别是，排列在下丘脑第三脑室的伸长细胞被认为不仅介导下丘脑核与脑脊液循环因子之间的交流，而且还作为成体神经干细胞，在各种能量信号的响应中取代下丘脑核。该项目使用由首席研究员开发的成体神经干细胞报告小鼠，研究伸长细胞如何影响成体大脑的神经可塑性和能量平衡调节。为了确定骨形态发生蛋白信号通过1型受体（BMPR1A）是否影响α或β伸长细胞的神经发生，研究人员使用Rax-Cre或Glast-Cre小鼠消融BMPR1A，随后评估能量状态和伸长细胞向下丘脑神经元的分化。总的来说，这些研究将促进对下丘脑可塑性响应能量状态变化的关键机制的理解。该项目由综合活动办公室的既定计划刺激竞争研究（EPSCoR）共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The regulation of energy balance requires communication and coordination with the hypothalamus, arguably the most important brain region for maintaining energy balance and where nutritional signals and appetite pathways converge on energy expenditure circuitry. One specialized cell type in the hypothalamus that is not well understood at the mechanistic level is the tanycytes, a putative stem cell population that lines the interface between the hypothalamus and one of the brain's internal ventricles. Tantycytes are able to sense factors circulating in the cerebrospinal fluid (CSF) and are important for glucose sensing and exhibit the ability to change and regenerate, but the signaling pathways that regulate these characteristics are not well understood. Using approaches to mark and lineage-trace developing cells in the adult brain, this project aims to understand tanycytes and their ability to renew adult hypothalamic neurons in response to varying conditions of energy balance. The project includes studies to elucidate the role of particular growth factor signaling pathways in tanycytes in enabling this regenerative ability of hypothalamic neurons in the adult brain. The broader impacts of this project include a formal senior Capstone course for students working conducting their senior thesis research under this project, and, to increase access to scientific careers in general, a week-long course on in the local community college system that covers and that can bridge to a summer fellowship in the laboratory of the principal investigator of this project.Numerous metabolic interventions, such as exercise or caloric restriction, are thought to impact neural plasticity in the hypothalamus, or the brain's command center for regulating energy balance. In particular, the tanycytes that line the hypothalamic third ventricle are thought not only to mediate communication between hypothalamic nuclei and circulating factors in the cerebrospinal fluid, but also to act as adult neural stem cells, replacing hypothalamic nuclei in response to various energetic cues. Using adult neural stem cell reporter mice developed by the principal investigator, this project examines how tanycytes impact neural plasticity and energy balance regulation in the adult brain. To determine whether or not bone morphogenetic protein signaling through the type 1 receptor (BMPR1A) impacts neurogenesis in alpha or beta tanycytes, the investigators use Rax-Cre or Glast-Cre mice to ablate BMPR1A, followed by assessment of energy status and tanycyte differentiation into hypothalamic neurons. Collectively, the studies will advance understanding of key mechanisms involved in hypothalamic plasticity in response to changing energy status. This project is co-funded by the Established Program to Stimulate Competitive Research (EPSCoR) of the Office of Integrative Activities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.