Functional mechanisms underlying hippocampal damage and behavioral abnormalities caused by perinatal hyperoxia

围产期高氧引起海马损伤和行为异常的功能机制

基本信息

  • 批准号:
    9125696
  • 负责人:
  • 金额:
    $ 26.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-03-01 至 2018-02-28
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Developmental brain injury is a major risk factor for neurological sequelae, including cognitive impairment, learning disability, Attention Deficit/Hyperactivity Disorder and cerebral palsy. Susceptibility to injury is especially high in prematurely born neonates. The cellular and physiological mechanisms underlying long-term consequences of premature birth on brain development are poorly understood, in particular damage to specific neural circuits. Diverse insults to the preterm brain contribute to injury, but little is known about the neurological effects of high tissue oxygen tension or hyperoxia (HO), which is associated with poor neurological outcome. Premature infants express lower levels of antioxidant enzymes than term infants, and lack adequate defenses against oxidative stress arising from the transition to increased oxygen tension at delivery. Our mouse model of perinatal HO-induced brain injury, using short-term exposure to high oxygen tension (80%) at P6-P8, shows delayed white matter development, disrupted integrity of axonal myelin, motor hyperactivity and impaired motor coordination. Learning disability and hyperactivity in survivors of preterm birth suggest damage to brain structures critical for memory formation. The hippocampus is a brain structure central to cognitive processing. As this brain region remains active in postnatal and adult neurogenesis, and in remodeling/synaptic plasticity, it is particulary vulnerable to insults. Our preliminary findings in the hippocampus indicate that perinatal HO generates reactive oxygen species, reduces parvalbumin- and GAD65-expressing interneuron populations, reduces GABA-ergic and disinhibits glutamatergic excitatory neurotransmission. These changes in neurotransmission, together with reduced adult dentate gyrus neurogenesis, are accompanied by adult memory and learning deficits. We therefore hypothesize that HO impairs the long-term capacity of the hippocampus for neurogenesis and remodeling, as well as development of specific hippocampal GABAergic circuitry. These changes disrupt the balance between excitatory and inhibitory (E/I) neurotransmission, which reduces synaptic plasticity and cognitive performance. Our proposed studies will test these hypotheses in two Specific Aims. In Aim 1, we will determine how HO attenuates the long-term neurogenic capacity of the hippocampus through cellular and gene expression changes. We will also perform electrophysiological studies to determine the effects of HO on disrupting E/I balance and the capacity for long-term potentiation. In Aim 2, we will define behavioral correlates of altered hippocampal remodeling, using tests of learning, memory and cognitive flexibility. Finally, we will determine whether pharmacological restoration of GABA neurotransmission improves E/I balance and cognitive performance following HO injury. Our study will establish functional relationships between HO-induced cellular changes, GABAergic interneuron dysfunction, long-term neurogenesis and cognitive deficits in a developmental model of neuronal injury. These will provide insights into injury mechanisms and functional readouts for future therapeutic intervention.
 描述(由适用提供):发育性脑损伤是神经系统后遗症的主要危险因素,包括认知障碍,学习障碍,注意力缺陷/多动障碍和脑瘫。对受伤的敏感性在过早出生的新生儿中特别高。早产对脑发育的长期后果的基础和物理机制知之甚少,特别是对特定神经元电路的损害。对早产大脑的多种侮辱会导致损伤,但对高组织氧张力或高氧(HO)的神经系统作用知之甚少,这与不良的神经系统结局有关。早产婴儿的抗氧化酶比期婴儿的抗氧化剂水平较低,并且缺乏适当的防御能力来抵抗氧化物胁迫,这是由于过渡到递送时氧气张力增加而产生的。我们的小鼠围产期HO诱导的脑损伤的小鼠模型使用短期暴露于P6-P8处的高氧张力(80%),显示了延迟的白质发育,轴突髓磷脂的完整性破坏,运动多动症和运动配位受损。在早产的生存中学习障碍和多动症表明对记忆形成至关重要的脑结构的损害。海马是一种大脑结构,是认知处理的核心。由于该大脑区域在产后和成人神经发生以及重塑/突触可塑性中保持活跃,因此特别容易受到侮辱。我们在海马中的初步发现表明,围产期HO会产生活性氧,减少表达白细胞蛋白酶和GAD65表达的中间神经元间种群,减少GABA饮食,并减少Gaba-offic和Disimibhib grutamatergic兴奋性兴奋性兴奋性兴奋性神经传递。因此,神经传递的这些变化,以及减少的成年齿状回神经发生,因此,我们假设HO会损害海马对神经发生和重塑的长期能力,并损害了特定的海马Gabaergagaergic回路。这些变化破坏了兴奋和抑制性(E/I)神经传递之间的平衡,从而降低了合成可塑性和认知性能。我们提出的研究将以两个具体目标来检验这些假设。 AIM 1,我们将确定HO如何通过细胞和基因表达变化来减轻海马的长期神经源能力。我们还将进行电生理研究,以确定HO对E/I平衡的影响以及长期潜力的能力。在AIM 2中,我们将使用学习,记忆和认知灵活性的测试来定义改变海马重塑的行为相关性。最后,我们会的 确定GABA神经传递的药理恢复是否可以改善HO损伤后的E/I平衡和认知表现。我们的研究将在神经元损伤的发育模型中,将在HO诱导的细胞变化,GABA能中神经元功能障碍,长期神经发生和认知缺陷之间建立功能关系。这些将为未来的治疗干预提供对伤害机制和功能读数的见解。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据

数据更新时间:2024-06-01

Vittorio Gallo的其他基金

Administrative Core
行政核心
  • 批准号:
    10454191
    10454191
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
Renovation of Core Laboratories for the DC Intellectual and Developmental Disabilities Research Center
华盛顿特区智力与发育障碍研究中心核心实验室改造
  • 批准号:
    10374284
    10374284
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
District of Columbia Intellectual and Developmental Disabilities Research Center (DC-IDDRC)
哥伦比亚特区智力与发育障碍研究中心 (DC-IDDRC)
  • 批准号:
    10237679
    10237679
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
District of Columbia Intellectual and Developmental Disabilities Research Center (DC-IDDRC)
哥伦比亚特区智力与发育障碍研究中心 (DC-IDDRC)
  • 批准号:
    10454190
    10454190
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10237680
    10237680
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10686079
    10686079
  • 财政年份:
    2021
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
Endotelin-1 role in development and regeneration
Endotelin-1 在发育和再生中的作用
  • 批准号:
    10246490
    10246490
  • 财政年份:
    2020
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
Endotelin-1 role in development and regeneration
Endotelin-1 在发育和再生中的作用
  • 批准号:
    10451772
    10451772
  • 财政年份:
    2020
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
Neural basis of locomotor dysfunction in Down Syndrome
唐氏综合症运动功能障碍的神经基础
  • 批准号:
    10091905
    10091905
  • 财政年份:
    2020
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:
Endotelin-1 role in development and regeneration
Endotelin-1 在发育和再生中的作用
  • 批准号:
    10027098
    10027098
  • 财政年份:
    2020
  • 资助金额:
    $ 26.25万
    $ 26.25万
  • 项目类别:

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