Regulation of hippocampal function by central and peripheral IRS signaling

通过中枢和外周 IRS 信号调节海马功能

• 批准号: 10548150
• 负责人: Morris F. White
• 金额: $ 62.02万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548150
• 关键词: Ablation; Acute; Address; Affect; Age-associated memory impairment; Alzheimer' s disease related dementia; Animals; Attenuated; Beta Cell; Biological Assay; Biological Models; Blood Glucose; Brain; Cells; Clinical; Clinical Research; Cognitive; Development; Diabetes Mellitus; Etiology; Experimental Models; FOXO1A gene; Feedback; Female; Follistatin; Genetic Transcription; Glucose; Health; Hepatic; Hippocampus; Human; Hyperglycemia; IRS1 gene; Impaired cognition; Impairment; Insulin; Insulin Receptor; Insulin Resistance; Insulin deficiency; Investigation; Knock-out; Knockout Mice; Learning; Liver; Longevity; Measurement; Measures; Mediating; Medical; Metabolic; Metabolic Diseases; Methods; Modeling; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nose; Pancreas; Parahippocampal Gyrus; Pattern; Peripheral; Phosphorylation; Proteins; Publishing; Regulation; Research; Role; Serine/Threonine Phosphorylation; Signal Transduction; Site; Structure of beta Cell of islet; System; Testing; Tissues; Transgenes; Up-Regulation; Viral; Water; Weight Gain; Work; aged; attenuation; cognitive function; dentate gyrus; diabetic; experimental study; human disease; impaired glucose tolerance; improved; innovation; insight; insulin secretion; insulin sensitivity; insulin signaling; knock-down; knockout gene; male; morris water maze; mouse model; nerve stem cell; nestin protein; neurogenesis; neuroprotection; non-diabetic; novel strategies; novel therapeutic intervention; prevent; promoter; reconstitution

Abstract The insulin receptor substrate proteins Irs1 and Irs2 mediate insulin/IGF signaling (IIS) throughout the body— including the brain—and mice that lack Irs1 and Irs2 develop insulin resistance and metabolic disease. While substantial evidence exists that peripheral insulin resistance and type 2 diabetes (T2D) exacerbate age-related cognitive decline and ADRD (Alzheimer’s Disease and Related Dementia), ascertaining causation by either impaired central IIS or ‘metabolic sequelae’ of peripheral metabolic disease requires model systems that can yield mechanistic insights. Above all, experimental systems are required that allow measurement of parameters relevant to human cognitive impairment across a range of well-controlled conditions. Our approach satisfies this imperative through routinized analyses of hippocampal function—including partially hippocampus- dependent spatial learning in the Morris water maze (MWM) and neurogenesis in the dentate gyrus of the hippocampus (DG). These assays are validated by our preliminary studies on mice lacking Irs2 in neurons (nIrs2-/- mice), and extended in our approach to mice with unique central (neuronal) and peripheral (e.g. pancreas or liver) expression of Irs1 and Irs2, plus down-stream Foxo1. We moreover analyze directly central IIS mediated by Irs1 and Irs2 in the hippocampus, together with its possible feedback regulation by multi-site serine/threonine phosphorylation of Irs1 and Irs2 (pS/TIrs). AIM1 tests the possibly unique roles of neuronal Irs1 and Irs2 to mediate central IIS—answering whether the benefits to hippocampal function of attenuated neuronal IIS via Irs2 seen in nIrs2-/- mice owe to compensatory upregulation of neuronal IIS via Irs1. AIMs 2-3 focus on the mechanistic significance of metabolic sequela. Since high blood glucose and compensatory insulin hypersecretion are prominent metabolic sequelae of T2D, AIM2 takes a novel approach to restore Irs2 expression in beta cells (reducing glucose) or liver (reducing glucose and insulin) in diabetic Irs2 knockout mice. AIM3 exploits our established LDKO and LTKO mouse models—which lack hepatic Irs1 and Irs2 (diabetic) or Irs1 and Irs2, plus Foxo1 (non-diabetic). First, AIM 3 compares hippocampal function in LDKO vs LTKO mice created acutely using viral Cre. Second, since our published work supports a role of hepatic FoxO1 and increased liver-secreted hepatokine follistatin (Fst) in propagating hepatic insulin resistance to other tissues, AIM 3 employs viral methods to restore FoxO1 expression in LTKO mice, or to knock down expression of Fst in LDKO mice, investigating in detail the effects on hippocampal function. How insulin resistance and diabetes promote cognitive decline is an important clinical and research question. Together, the proposed experiments can elucidate connections between metabolic disease and cognitive dysfunction by dissecting roles of neuronal Irs1 and Irs2, and determining the specific influences of impaired peripheral insulin sensitivity and associated metabolic sequelae upon hippocampal function.

摘要 胰岛素受体底物蛋白Irs 1和Irs 2介导全身的胰岛素/IGF信号传导（IIS）。 包括大脑，缺乏Irs 1和Irs 2的小鼠会产生胰岛素抵抗和代谢疾病。而 有大量证据表明，外周胰岛素抵抗和2型糖尿病（T2 D）加重了年龄相关的 认知能力下降和ADRD（阿尔茨海默病和相关痴呆症），通过以下任一项确定因果关系 受损的中枢IIS或外周代谢疾病的“代谢后遗症”需要模型系统， 产生机械的见解。最重要的是，需要实验系统来测量 在一系列良好控制的条件下，与人类认知障碍相关的参数。我们的方法 通过对海马体功能（包括部分海马体功能）的简化分析来满足这一要求， 在Morris水迷宫中的依赖性空间学习（MWM）和齿状回的神经发生 海马（DG）。我们对神经元中缺乏Irs 2的小鼠的初步研究验证了这些测定 （nIrs 2-/-小鼠），并在我们的方法中扩展到具有独特的中枢（神经元）和外周（例如， 胰腺或肝脏）Irs 1和Irs 2的表达，加上下游Foxo 1。我们还直接分析了中央 海马Irs 1和Irs 2介导的IIS及其可能的多位点反馈调节 Irs 1和Irs 2的丝氨酸/苏氨酸磷酸化（pS/TIrs）。AIM 1测试神经元Irs 1可能的独特作用 和Irs 2介导的中枢IIS应答是否有利于海马功能的减弱 在nIrs 2-/-小鼠中观察到的经由Irs 2的神经元IIS归因于经由Irs 1的神经元IIS的补偿性上调。目标2-3 重点探讨代谢后遗症的机制意义。由于高血糖和代偿性 胰岛素分泌过多是2型糖尿病的主要代谢后遗症，AIM 2是一种新的恢复Irs 2的方法 在糖尿病Irs 2敲除的β细胞（减少葡萄糖）或肝脏（减少葡萄糖和胰岛素）中的表达 小鼠AIM 3利用我们建立的LDKO和LTKO小鼠模型-缺乏肝脏Irs 1和Irs 2 （糖尿病）或Irs 1和Irs 2加上Foxo 1（非糖尿病）。首先，AIM 3比较了LDKO与 使用病毒Cre急性产生LTKO小鼠。其次，由于我们发表的工作支持肝脏FoxO 1的作用， 并增加肝脏分泌的肝细胞因子卵泡抑素（Fst）， 组织，AIM 3采用病毒方法恢复LTKO小鼠中FoxO 1的表达，或敲低表达 的Fst在LDKO小鼠，详细调查海马功能的影响。胰岛素抵抗和 糖尿病促进认知功能下降是一个重要的临床和研究问题。在一起，拟议的 实验可以阐明代谢疾病和认知功能障碍之间的联系， 神经元Irs 1和Irs 2的作用，并确定外周胰岛素敏感性受损的具体影响 以及相关的代谢后遗症。