Intraventricular hemorrhage affects production of cortical interneurons

脑室内出血影响皮质中间神经元的产生

基本信息

批准号：
10355489
负责人：
PRAVEEN BALLABH
金额：
$ 36.53万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355489
关键词：
Affect Animal Model Antioxidants Apoptosis Apoptotic Attentional deficit Autopsy Brain Brain hemorrhage Cell Death Chemicals Complication Data Development Disease Environment Epilepsy Free Radicals Ganglia Generations Genetic Transcription Goals Hemorrhage Human Hyperactivity Impairment Infant Interneuron function Interneurons Major Depressive Disorder Medial Mediating Mental Retardation Mitotic Modeling Nervous System Physiology Neurologic Neurons Nuclear Oryctolagus cuniculus Oxidation-Reduction Oxidative Stress Parvalbumins Pathway interactions Play Population Prefrontal Cortex Pregnancy Premature Infant Production Reverse Transcriptase Polymerase Chain Reaction Role SHH gene SOX6 gene Sampling Seizures Signal Transduction Somatostatin Sulforaphane Survivors Telencephalon Testing United States Up-Regulation adduct calretinin cell injury density high risk inattention intervention effect intraventricular hemorrhage mRNA sequencing neurobehavior neurobehavioral neurobehavioral disorder neurogenesis neuroprotection neuropsychiatry novel novel therapeutics premature prevent progenitor single episode major depressive disorder smoothened signaling pathway transcription factor transcriptomics

项目摘要

Abstract Premature infants with intraventricular hemorrhage (IVH) are at high risk of neurobehavioral disorders, including inattention, hyperactivity, major depressive disorders, and seizures. These disorders can be attributed to the defective development and function of cortical interneurons. However, the effect of IVH on the generation and maturation of cortical interneuron is unknown, even though the window of interneuron neurogenesis overlaps with the period when infants develop IVH (23-28 weeks of gestation). Interneurons are produced in the medial and caudal ganglionic eminence (MGE and CGE). MGE gives rise to parvalbumin+ (PV) and somatostatin+ (SST) interneurons, whereas CGE produces calretinin+ and NRY+ interneurons. The production of interneurons in the MGE is regulated by a number of transcription factors, including Nkx2.1, Dlx1/2, Lhx6/8, and Mash1, which are primarily controlled by Sonic Hedgehog (Shh) signaling pathways. As the post-mitotic interneurons migrate from MGE to the cortical layers, Sox6 plays critical roles in their specification and maturation into PV+ and SST+ interneurons. This production and maturation of interneurons would be affected by IVH, because it initiates in the MGE/CGE and induces oxidative cell injury and death. Our preliminary studies in rabbits with IVH show reduced neurogenesis in the MGE, deficit in PV+ and SST+ interneurons in the upper cortical layers, and a decline in Shh and Sox6 levels relative to controls. To ameliorate neurogenesis in the MGE and restore cortical interneuron deficit, our goal is to a) restore Shh > Nkx2.1 > Sox6 signaling and b) reduce oxidative stress to minimize cell injury and death. Since Nrf2 transcription factor is a master redox switch to turn on several antioxidant pathways, we will activate Nrf2 to minimize oxidative stress in our animal model of IVH. Therefore we hypothesize: i) IVH disrupts interneuron neurogenesis and differentiation in the MGE and CGE resulting in interneuron deficits in the cortical layers of preterm humans & rabbits, and ii) alleviating oxidative stress (Nrf2 stimulation) or activating interneuron production (lenti-mDlx-Shh) and maturation (lenti-mDlx-Sox6) will ameliorate PV and SST deficits and neurological function in rabbits with IVH. In Aim #1, we will determine the effect of IVH on a) apoptosis, proliferation, and density of interneuron progenitors in the MGE (Nkx2.1+, Dlx1/2+) and CGE (Dlx2+ & Coup-TFII+), b) the density of mature interneurons—PV, SST and others--in the upper and lower cortical layers, and c) transcriptional changes in the MGE & CGE. Additionally, we will validate rabbit data in humans by analyzing autopsy materials from preterm infants with and without IVH. In Aim #2 and # 3, we will assess the effect of alleviating oxidative stress (Ad-Nrf2-GFP or sulforaphane) or activating production of Shh (lenti-mDlx-Shh-GFP) and Sox6 (lenti-mDlx-Sox6-GFP) specifically in the interneuron progenitors on a) the density of progenitors in the MGE, b) population of PV+ and SST+ neurons in the cortical layers, c) transcriptional changes in MGE, d) neurobehavioral function in rabbits with IVH. The proposed studies will hasten development of new therapies to prevent neurobehavioral disorders in infants with IVH.

抽象的患有脑室内出血 (IVH) 的早产儿患神经行为障碍的风险很高，包括注意力不集中、多动、重度抑郁症和癫痫发作可归因于这些疾病。然而，IVH 对皮质中间神经元的发育和功能的影响。皮质中间神经元的成熟是未知的，尽管中间神经元神经发生的窗口重叠婴儿发生 IVH 的时期（妊娠 23-28 周）中间神经元产生。尾神经节隆起（MGE 和 CGE）产生小清蛋白+ (PV) 和生长抑素+。 (SST) 中间神经元，而 CGE 产生钙结合蛋白+和 NRY+ 中间神经元。 MGE 中的转录因子受多种转录因子调控，包括 Nkx2.1、Dlx1/2、Lhx6/8 和 Mash1，主要由 Sonic Hedgehog (Shh) 信号通路控制，作为有丝分裂后中间神经元。从 MGE 迁移到皮质层，Sox6 在其规范和成熟为 PV+ 方面发挥着关键作用中间神经元的产生和成熟会受到 IVH 的影响，因为它我们在兔子身上进行的初步研究表明，MGE/CGE 会引发氧化细胞损伤和死亡。 IVH 显示 MGE 神经发生减少，上皮质层 PV+ 和 SST+ 中间神经元缺乏，与对照组相比，Shh 和 Sox6 水平下降改善 MGE 的神经发生并恢复。皮质中间神经元缺陷，我们的目标是 a) 恢复 Shh > Nkx2.1 > Sox6 信号传导，b) 减少氧化由于 Nrf2 转录因子是打开的主要氧化还原开关，因此可以最大程度地减少细胞损伤和死亡。一些抗氧化途径，我们将激活 Nrf2 以最大限度地减少 IVH 动物模型中的氧化应激。因此我们见证了： i) IVH 破坏了 MGE 和 CGE 中的中间神经元神经发生和分化导致早产人类和兔子皮质层的中间神经元缺陷，ii) 减轻氧化应激（Nrf2 刺激）或激活中间神经元生成 (lenti-mDlx-Shh) 和成熟 (lenti-mDlx-Sox6) 将改善 IVH 兔子的 PV 和 SST 缺陷以及神经功能在目标 1 中，我们将确定。 IVH 对 a) MGE 中神经元祖细胞凋亡、增殖和密度的影响 (Nkx2.1+, Dlx1/2+）和 CGE（Dlx2+ 和 Coup-TFII+），b) 成熟中间神经元（PV、SST 等）的密度上皮层和下皮层，以及 c) MGE 和 CGE 中的转录变化此外，我们将验证。通过分析来自患有和不患有 IVH 的早产儿的尸检材料来获得兔子数据。 # 3，我们将评估缓解氧化应激（Ad-Nrf2-GFP或萝卜硫素）或激活特别是在中间神经元中产生 Shh (lenti-mDlx-Shh-GFP) 和 Sox6 (lenti-mDlx-Sox6-GFP) a) MGE 中的祖细胞密度，b) 皮质中的 PV+ 和 SST+ 神经元群层数，c) MGE 的转录变化，d) 患有 IVH 的兔子的神经行为功能。将加速新疗法的开发，以预防患有 IVH 的婴儿的神经行为障碍。