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

低血糖期间糖感运动整合的全脑神经网络

• 批准号: 10208880
• 负责人: Alan G Watts
• 金额: $ 39.34万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208880
• 关键词: Address; Adrenal Glands; Adrenal Medulla; Animals; Atlases; Attention; Attenuated; Behavior; Blood - brain barrier anatomy; Blood Glucose; Brain; Brain region; Cell Nucleus; Clinical; Closure by clamp; Complex; Complication; Data Set; Deafferentation procedure; Diabetes Mellitus; Distributed Systems; Dorsal; Endocrine; Epinephrine; Failure; Female; Foundations; Functional disorder; Ganglionectomy; Glucagon; Goals; Hepatic; Herpesvirus 1; Human Papillomavirus; Hypoglycemia; Hypothalamic structure; Iatrogenesis; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans; Label; Life; Location; Mediator of activation protein; Mesentery; Motor; Motor output; Neurons; Output; Pancreas; Peripheral; Persons; Portal vein structure; Property; Rattus; Recurrence; Sensory; Sex Differences; Site; Spinal; Structure; Structure of area postrema; Symptoms; System; Techniques; Tracer; Variant; Viral; base; connectome; counterregulation; data space; design; glycemic control; hindbrain; improved; male; mind control; motor control; neural network; neuroinformatics; neurotransmission; neurotropic; novel; novel strategies; open source; response; spatial relationship; superior mesenteric vein; tool; virtual

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.

低血糖相关的自主神经衰竭(Haaf)是一种严重的并发症。 胰岛素治疗和复发性低血糖，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.HAF减弱肾上腺素和受损的胰高血糖素反调节反应(CRR)，并发展 “没有意识到低血糖”。这可能是致命的。目前提出的所有针对HAAF的机制都涉及大脑。 这意味着，了解控制血糖的大脑网络的组织是基本的 目的了解房颤的发生原因。然而，一个主要的障碍是远非完整的图景 这个网络的所有组件以及它的详细连接体。这项提议的目标是 确定来自不同糖感部位的信息在大脑中的分布位置和潜在的位置 综合网站的位置。它将使用最先进的嗜神经性病毒追踪技术，功能性Fos 映射，以及南加州大学开发的用于提取网络的新的神经信息工具(AXIome) 来自复杂神经解剖学数据集的交互作用。三个具体目标将探讨结构和功能 驱动肾上腺髓质和胰腺内分泌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感受区：腹内侧 下丘脑(VMH)、最后区和肝门静脉壁。对……特别重要 其中两个区域是重要的，因为它们对内分泌CRR的贡献 由快速(VMH)和缓慢起病(肝门静脉)低血糖发展而来。迟发性低血糖是 被认为是糖尿病中最常见的医源性胰岛素诱导的低血糖。这些新发现将 以一种全新的方式组合这些连接和功能结果，从而识别主要网络 并显著提高了我们对大脑如何控制血糖反调节的理解 以及这是如何在哈夫崩溃的。