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.

抽象的 胰岛素受体底物蛋白IRS1和IRS2培养基胰岛素/IGF信号传导（IIS） - 包括大脑 - 缺乏IRS1和IRS2的小鼠会产生胰岛素抵抗和代谢疾病。尽管 有大量证据表明外周胰岛素抵抗和2型糖尿病（T2D）加剧与年龄有关 认知能力下降和ADRD（阿尔茨海默氏病和相关痴呆症），通过任何一个确定原因 受损的外周种代谢疾病中央IIS或“代谢后遗症”需要模型系统 产生机械见解。最重要的是，需要实验系统，以测量 在一系列良好控制条件下，与人类认知障碍有关的参数。我们的方法 通过常规的海马功能分析来满足这一势在必行 - 包括部分海马 莫里斯水迷宫（MWM）中的依赖空间学习和神经发生 海马（DG）。这些测定是通过我们对神经元缺乏IRS2的小鼠的初步研究来验证的 （NIRS2 - / - 小鼠），并在我们对具有独特中心（神经元）和周围的小鼠的方法中扩展（例如 IRS1和IRS2的胰腺或肝脏表达，以及下游FOXO1。我们直接分析中央 由IRS1和IRS2在海马中介导的IIS，以及其可能通过多站点的反馈调节 IRS1和IRS2（PS/TIRS）的丝氨酸/苏氨酸磷酸化。 AIM1测试神经元IRS1的独特作用 和IRS2调解中央IIS-撤下衰减的海马功能的好处 在NIRS2 - / - 小鼠中看到的神经元IIS归因于通过IRS1对神经元II的补偿性上调。目标2-3 专注于代谢后遗症的机械意义。由于高血糖和代偿性 胰岛素过度分泌是T2D的突出代谢后遗症，AIM2采用了一种新的方法来恢复IRS2 在糖尿病IRS2敲除中的β细胞（还原葡萄糖）或肝脏（还原葡萄糖和胰岛素）中的表达 老鼠。 AIM3利用了我们已建立的LDKO和LTKO鼠标模型 - 缺乏肝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中的海马功能 LTKO小鼠使用病毒CRE急性产生。第二，自我们发表的工作支持Hepatitic Foxo1的角色以来 并增加了肝脏分泌的肝动物卵脂素（FST）在传播肝胰岛素耐药性方面 组织，目标3个员工的病毒方法来恢复LTKO小鼠中FOXO1的表达，或者降低表达 LDKO小鼠的FST的详细研究，详细研究了对海马功能的影响。胰岛素抵抗和 糖尿病促进认知能力下降是一个重要的临床和研究问题。一起，提议 实验可以通过解剖来阐明代谢疾病与认知功能障碍之间的联系 神经元IRS1和IRS2的作用，并确定周围胰岛素敏感性受损的特定影响 以及海马功能上的相关代谢后遗症。