A Brain-Wide Neural Network for Glucosensory-Motor Integration During Hypoglycemia

低血糖相关性自主神经功能衰竭（HAAF）是一种严重的并发症， 胰岛素治疗和复发性低血糖的影响，主要发生在1型糖尿病患者中，但在1型糖尿病患者中越来越多 2. HAAF减弱肾上腺素和受损的胰高血糖素反调节反应（CRR），并发展为 “低血糖无意识”。可能会致命。目前提出的HAAF的所有机制都涉及大脑。 这意味着理解控制大脑的大脑网络的组织是一个基本的 目的是了解HAAF的原因。然而，一个主要的障碍是， 这个网络的所有组成部分及其详细的连接体。本提案的目的是 确定来自不同葡萄糖感觉部位的信息在大脑中的分布位置以及潜在的 整合的网站位于。它将使用最先进的亲神经病毒追踪技术，功能性Fos 映射，以及USC开发的一种新的神经信息学工具（Axiome），旨在提取网络 复杂神经解剖数据集的相互作用。三个具体目标将探讨结构和功能 从肾上腺髓质和胰腺驱动内分泌CRR的运动系统之间的相互作用，以及 位于血脑屏障内外的关键葡萄糖敏感区域：腹内侧 下丘脑（VMH）、最后区和肝门静脉壁。尤其要重视 HAAF的一个重要原因是，这些区域中有两个区域很重要，因为它们对内分泌CRRs的贡献， 从快速（VMH）和缓慢发作（肝门静脉）低血糖发展而来。慢发性低血糖是 被认为在糖尿病的医源性胰岛素诱导的低血糖中最普遍。这些新发现将 联合收割机以全新方式结合这些连接和功能结果，从而识别主要网络 成分，并显着提高我们对大脑如何控制血糖反调节的理解 以及它在HAAF中是如何分解的。

Hypoglycemia-associated autonomic failure (HAAF) is a serious complication that develops as a consequence of insulin therapy and recurrent hypoglycemia, primarily in people with type 1 diabetes, but increasingly in type 2. HAAF attenuates epinephrine and compromised glucagon counterregulatory responses (CRRs), and develop 'hypoglycemic unawareness'. It can be fatal. All the mechanisms currently proposed for HAAF involve the brain. This means that understanding the organization of the brain network that controls glycemia is a fundamental objective for understanding the causes of HAAF. However a major impediment is the far from complete picture of all the components of this network together with its detailed connectome. The goal of this proposal is to determine where information from diverse glucosensory sites distributes within the brain and where potential integrative sites are located. It will use state-of-the-art neurotropic viral tracing techniques, functional Fos mapping, and a novel neuroinfomatic tool (Axiome) developed at USC that is designed to extract network interactions from complex neuroanatomical datasets. Three specific aims will explore structural and functional interactions between the motor systems that drive endocrine CRRs from the adrenal medulla and pancreas, and key glucosensing regions that are located inside and outside the blood brain barrier: the ventromedial hypothalamus (VMH), the area postrema, and the wall of the hepatic portal vein. Of particular importance for HAAF is that two of these regions are important because of their contributions to the endocrine CRRs that develop from rapid- (VMH) and slow-onset (hepatic portal vein) hypoglycemia. Slow-onset hypoglycemia is thought to be most prevalent in iatrogenic insulin-induced hypoglycemia in diabetes. These new findings will combine these connectional and functional results in a totally novel way thereby identifying major network components and significantly improving our understanding of how the brain controls glycemic counterregulation and how this breaks down in HAAF.