Intraventricular hemorrhage affects production of cortical interneurons

脑室内出血影响皮质中间神经元的产生

• 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
• 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

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.

摘要 患有脑室内出血（IVH）的早产儿发生神经行为障碍的风险较高，包括 注意力不集中、多动症、重度抑郁症和癫痫发作。这些疾病可归因于 皮质中间神经元的发育和功能缺陷。然而，IVH对生殖的影响和 皮质中间神经元的成熟是未知的，即使中间神经元神经发生的窗口重叠 与婴儿发生IVH的时期（妊娠23-28周）。中间神经元产生于 尾侧神经节隆起（MGE和CGE）。MGE产生小清蛋白+（PV）和生长抑素+ (SST)CGE产生钙视网膜蛋白+和NRY+中间神经元。中间神经元的产生 在MGE中受许多转录因子调节，包括Nkx2.1、Dlx 1/2、Lhx 6/8和Mash 1， 其主要由Sonic Hedgehog（Shh）信号通路控制。有丝分裂后的中间神经元 从MGE迁移到皮质层，Sox 6在其特化和成熟为PV+中起着关键作用 SST+神经元。这种中间神经元的产生和成熟将受到IVH的影响，因为它 在MGE/CGE中起始并诱导氧化性细胞损伤和死亡。我们在兔子身上的初步研究 IVH显示MGE中神经发生减少，上皮层中PV+和SST+中间神经元缺陷， 以及Shh和Sox 6水平相对于对照的下降。改善MGE的神经发生， 我们的目标是a）恢复Shh > Nkx 2.1> Sox 6信号传导和B）减少氧化应激， 以减少细胞损伤和死亡。由于Nrf 2转录因子是一个主氧化还原开关， 几种抗氧化途径，我们将激活Nrf 2，以尽量减少我们的IVH动物模型中的氧化应激。 因此，我们假设：i）IVH破坏了MGE和CGE中的中间神经元神经发生和分化 导致早产的人和兔的皮质层中的中间神经元缺陷，和ii）减轻氧化性 应激（Nrf 2刺激）或激活中间神经元产生（lenti-mDlx-Shh）和成熟（lenti-mDlx-Sox 6） 可改善IVH兔PV和SST缺陷及神经功能。在目标#1中，我们将确定 IVH对a）MGE（Nkx2.1+， Dlx 1/2+）和CGE（Dlx 2 + & Coup-TFII+），B）在所述细胞中的成熟中间神经元-PV、SST和其它-的密度。 上皮层和下皮层，和c）MGE & CGE中的转录变化。此外，我们将验证 通过分析患有和不患有IVH的早产儿的尸检材料获得的兔子人体数据。在目标#2和 #3，我们将评估减轻氧化应激（Ad-Nrf 2-GFP或萝卜硫素）或激活 在中间神经元中特异性产生Shh（lenti-mDlx-Shh-GFP）和Sox 6（lenti-mDlx-Sox 6-GFP） a）MGE中祖细胞的密度，B）皮质中PV+和SST+神经元的群体 层，c）MGE的转录变化，d）患有IVH的兔的神经行为功能。拟议的研究 将加速开发新的治疗方法，以预防IVH婴儿的神经行为障碍。