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: 10569094
• 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/10569094
• 关键词: Acceleration; Affect; Animal Model; Antioxidants; Apoptosis; Apoptotic; Attentional deficit; Autopsy; Brain; Brain hemorrhage; Cell Death; Chemicals; Complication; Data; Development; Disease; Environment; Epilepsy; Free Radicals; Generations; Genetic Transcription; Goals; Hemorrhage; Human; Hyperactivity; Impairment; Infant; Interneuron function; Interneurons; Major Depressive Disorder; Medial; Mediating; Mental Retardation; Modeling; Nervous System Physiology; Neurologic; Neurons; Nuclear; Oryctolagus cuniculus; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Parvalbumins; Pathway interactions; Play; Population; Prefrontal Cortex; Pregnancy; Premature Infant; Production; Proliferating; Reverse Transcriptase Polymerase Chain Reaction; Role; SHH gene; SOX6 gene; Sampling; Seizures; Signal Pathway; Signal Transduction; Somatostatin; Specific qualifier value; Sulforaphane; Survivors; Telencephalon; Testing; United States; Up-Regulation; adduct; calretinin; cell injury; density; high risk; inattention; intervention effect; intraventricular hemorrhage; mRNA sequencing; migration; neurobehavior; neurobehavioral; neurobehavioral disorder; neurogenesis; neuroprotection; neuropsychiatry; novel; novel therapeutics; postmitotic; premature; prevent; progenitor; single episode major depressive disorder; 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.

抽象的 脑室室出血（IVH）的早产婴儿有神经行为疾病的高风险，包括 注意力不集中，多动症，主要抑郁症和癫痫发作。这些疾病可以归因于 皮质中间神经元的有缺陷的发育和功能。但是，IVH对一代和 皮质间神经元的成熟是未知的，即使间神经元神经发生的窗口重叠 在婴儿出现IVH的时期（妊娠23-28周）。中间神经元是在媒体上产生的 和尾神经节杰出（MGE和CGE）。 MGE产生白细胞蛋白+（PV）和生长抑素+ （SST）中间神经元，而CGE会产生呼叫蛋白+和NRY+中间神经元。中间神经元的产生 在MGE中，包括许多转录因子，包括NKX2.1，DLX1/2，LHX6/8和MASH1， 主要由声音刺猬（SHH）信号通路控制。作为有丝分裂的中间神经元 Sox6从MGE迁移到皮质层，在其规范中起着关键作用，并成熟到PV+ 和SST+中间神经元。中间神经元的这种产生和成熟将受到IVH的影响，因为它 在MGE/CGE启动并诱导氧化细胞损伤和死亡。我们在兔子的初步研究 IVH显示MGE中的神经发生降低，PV+的防御和上层皮质层中的SST+中间神经元， 相对于对照组，SHH和SOX6水平的下降。改善MGE的神经发生并恢复 皮质间神经元防御，我们的目标是a）恢复shh> nkx2.1> sox6信号传导和b）减少氧化 压力以最大程度地减少细胞损伤和死亡。由于NRF2转录因子是主氧化还原开关 几种抗氧化剂途径，我们将激活NRF2，以最大程度地减少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 在早产和兔子的皮质层中导致中间神经元缺乏，ii）减轻氧化的氧化 应力（NRF2刺激）或激活中间神经元的产生（Lenti-MDLX-SHH）和成熟（Lenti-MDLX-SOX6） 将改善PV，而SST定义了IVH兔子中的神经功能。在AIM＃1中，我们将确定 IVH对MGE中神经元祖细胞中凋亡，增殖和密度的凋亡，NKX2.1+， DLX1/2+）和CGE（DLX2+＆COUP-TFII+），b）成熟中间神经元的密度 - PV，SST等 上层和下皮层，c）MGE＆CGE中的转录变化。此外，我们将验证 人类中的兔子数据通过分析有或没有IVH的早产儿的尸检材料。在AIM＃2和 ＃3，我们将评估减轻氧化应激（AD-NRF2-GFP或Sulforaphane）或激活的效果 在中间神经元中专门生产SHH（Lenti-MDLX-SHH-GFP）和Sox6（Lenti-MDLX-SOX6-GFP） a）MGE中祖细胞的密度，b）皮质中PV+和SST+神经元的种群 层，c）MGE的转录变化，d）IVH兔子的神经行为功能。提出的研究 将开发新疗法，以防止IVH婴儿的神经性疾病。