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: 10162475
• 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/10162475
• 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 (Brain); Human; 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; Proteins; Publishing; Regulation; 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; 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IRS1和IRS2介导体内的胰岛素/胰岛素样生长因子信号(IIS)。 包括大脑--以及缺乏IRS1和IRS2的小鼠会出现胰岛素抵抗和代谢性疾病。而当 大量证据表明，外周胰岛素抵抗和2型糖尿病(T2D)会加剧与年龄相关的疾病 认知衰退和ADRD(阿尔茨海默病和相关痴呆症)，通过以下任一项确定原因 中枢IIS受损或外周代谢性疾病的“代谢后遗症”需要模型系统能够 产生机械论的见解。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，与人类认知损害相关的参数。我们的方法 通过对海马体功能的常规分析--包括部分海马体--来满足这一需求 大鼠Morris水迷宫依赖空间学习与海马齿状回神经发生 海马区(DG)。我们对神经元中缺少irs2的小鼠的初步研究证实了这些方法的有效性。 (nIrs2-/-小鼠)，并将我们的方法扩展到具有独特的中枢(神经元)和外周(例如 胰腺或肝脏)表达IRS1和Irs2，以及下游的Foxo1。此外，我们还直接分析了中心 IRS1和Irs2介导的海马区IIS及其可能的多部位反馈调节 IRS1和IRS2的丝氨酸/苏氨酸磷酸化(PS/TIR)。AIM1测试神经元IRS1可能的独特作用 和Irs2介导的中枢IIS-回答是否对海马区功能有利减弱 在nIrs2-/-小鼠中看到的通过irs2的神经元IIS是通过IRS1代偿性上调的。AIMS 2-3 关注代谢后遗症的机制意义。由于高血糖和代偿性 胰岛素高分泌是T2D的显著代谢后遗症，AIM2采取了一种新的方法恢复IRS2 糖尿病irs2基因敲除后β细胞(降糖)或肝脏(降糖和胰岛素)的表达 老鼠。AIM3利用了我们已建立的LDKO和LTKO小鼠模型--缺乏肝脏IRS1和IRS2 (糖尿病)或IRS1和Irs2，加上Foxo1(非糖尿病)。首先，AIM 3比较了LDKO和LDKO患者的海马区功能 LTKO小鼠使用病毒CRE产生了剧烈的反应。第二，由于我们发表的工作支持肝脏FoxO1的作用 和增加肝脏分泌的肝细胞因子卵泡抑素(Fst)在传播肝脏胰岛素抵抗 组织中，AIM 3使用病毒方法恢复LTKO小鼠中FoxO1的表达或下调其表达 FST对LDKO小鼠的作用，详细研究其对海马区功能的影响。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。总而言之，建议的 实验可以通过解剖阐明代谢性疾病和认知功能障碍之间的联系 神经元IRS1和IRS2的作用及外周胰岛素敏感性受损的特异性影响 以及相关的代谢后遗症对海马体功能的影响。