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 介导全身胰岛素/IGF 信号传导 (IIS) — 包括大脑——缺乏 Irs1 和 Irs2 的小鼠会出现胰岛素抵抗和代谢疾病。 大量证据表明，外周胰岛素抵抗和 2 型糖尿病 (T2D) 恶化与年龄相关 认知能力下降和 ADRD（阿尔茨海默病和相关痴呆），通过以下任一方式确定因果关系 中枢 IIS 受损或外周代谢疾病的“代谢后遗症”需要能够 最重要的是，需要能够测量的实验系统。 我们的方法在一系列良好控制的条件下与人类认知障碍相关的参数。 通过对海马功能（包括部分海马）的常规分析来满足这一要求 莫里斯水迷宫（MWM）中的依赖性空间学习和齿状回的神经发生 这些测定通过我们对神经元缺乏 Irs2 的小鼠的初步研究得到验证。 （nIrs2-/- 小鼠），并将我们的方法扩展到具有独特中枢（神经元）和外周（例如，神经元）的小鼠。 此外，我们还直接分析中枢的 Irs1 和 Irs2 以及下游 Foxo1 的表达。 海马中 Irs1 和 Irs2 介导的 IIS 及其可能的多位点反馈调节 Irs1 和 Irs2 (pS/TIrs) 的丝氨酸/苏氨酸磷酸化测试了神经元 Irs1 可能的独特作用。 和 Irs2 介导中枢 IIS——回答减弱的海马功能是否有好处 在 nIrs2-/- 小鼠中观察到的通过 Irs2 的神经元 IIS 归因于通过 Irs1 2-3 的神经元 IIS 的补偿性上调。 重点关注高血糖以来代谢后遗症的机制意义。 胰岛素分泌过多是 T2D 的显着代谢后遗症，AIM2 采用新方法恢复 Irs2 糖尿病 Irs2 敲除中的 β 细胞（降低葡萄糖）或肝脏（降低葡萄糖和胰岛素）中的表达 AIM3 利用我们建立的 LDKO 和 LTKO 小鼠模型，这些模型缺乏肝脏 Irs1 和 Irs2。 （糖尿病）或 Irs1 和 Irs2，加上 Foxo1（非糖尿病） 首先，AIM 3 比较 LDKO 与 Irs2 中的海马功能。 其次，我们发表的工作支持肝脏 FoxO1 的作用。 肝脏分泌的肝因子卵泡抑素 (Fst) 增加，将肝脏胰岛素抵抗传播到其他部位 在组织中，AIM 3 采用病毒方法恢复 LTKO 小鼠中的 FoxO1 表达，或敲低表达 Fst 对 LDKO 小鼠的影响，详细研究了胰岛素抵抗和海马功能的影响。 糖尿病促进认知能力下降是一个重要的临床和研究问题。 实验可以通过剖析阐明代谢疾病和认知功能障碍之间的联系 神经元 Irs1 和 Irs2 的作用，并确定外周胰岛素敏感性受损的具体影响 以及海马功能相关的代谢后遗症。