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

• 批准号: 9223761
• 负责人: Vittorio Gallo
• 金额: $ 21.88万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9223761
• 关键词: ARHGEF5 gene; Adult; Attention deficit hyperactivity disorder; Attenuated; Behavior; Behavior Therapy; Behavioral; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain region; Cells; Cerebral Palsy; Cognitive; Cognitive deficits; Comorbidity; Complex; Coupled; Development; Disinhibition; Electrophysiology (science); Enzymes; Equilibrium; Exposure to; Functional disorder; Future; GABA Receptor; Gene Expression; Genes; Glutamate Receptor; Glutamates; Hippocampus (Brain); Hyperactive behavior; Hyperoxia; Impaired cognition; Impairment; Infant; Infection; Injectable; Injury; Interneurons; Investigation; Lead; Learning; Learning Disabilities; Long-Term Potentiation; Longitudinal Studies; Mediating; Memory; Memory impairment; Modeling; Molecular; Mus; Myelin; Neonatal Brain Injury; Neonatal Hyperoxic Injury; Neurodevelopmental Disability; Neurologic; Neurologic Effect; Neurological outcome; Neuronal Injury; Neurotransmitters; Oxidative Stress; Oxygen; Parvalbumins; Perinatal; Perinatal Brain Injury; Perinatal Hypoxia; Pharmacology; Phenotype; Physiological; Population; Predisposition; Premature Birth; Premature Infant; Property; Protocols documentation; Reactive Oxygen Species; Recovery; Risk Factors; Role; Slice; Structure; Survivors; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Tissues; Validation; Very Low Birth Weight Infant; Viral; Water; adult neurogenesis; antioxidant enzyme; base; cognitive function; cognitive performance; dentate gyrus; efficacy testing; field study; flexibility; gamma-Aminobutyric Acid; improved; insight; motor impairment; mouse model; neonatal exposure; neonate; neural circuit; neurobehavioral; neurobehavioral disorder; neuroblast; neurogenesis; neuron development; neurotransmission; novel; object recognition; optogenetics; oxidative damage; patch clamp; postnatal; premature; public health relevance; receptor; restoration; tiagabine; white matter; white matter damage

 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（由申请人提供）：发育性脑损伤是神经系统后遗症的主要风险因素，包括认知障碍、学习障碍、注意力缺陷/多动障碍和脑瘫。早产新生儿对损伤的敏感性特别高。早产对大脑发育的长期影响的细胞和生理机制知之甚少，特别是对特定神经回路的损害。对早产儿大脑的各种损伤都有助于损伤，但对高组织氧分压或高氧（HO）的神经学效应知之甚少，这与不良的神经学结局相关。早产儿表达的抗氧化酶水平低于足月儿，并且缺乏对分娩时过渡到增加的氧张力所产生的氧化应激的足够防御。我们的围产期HO诱导的脑损伤的小鼠模型，在P6-P8使用短期暴露于高氧分压（80%），显示延迟的白色物质发育，破坏轴突髓鞘的完整性，运动过度活跃和受损的运动协调。早产幸存者的学习障碍和多动表明对记忆形成至关重要的大脑结构受损。海马体是大脑中对认知过程至关重要的结构。由于该脑区在出生后和成年神经发生中以及在重塑/突触可塑性中保持活跃，因此它特别容易受到损伤。我们在海马的初步研究结果表明，围产期HO产生活性氧，减少小白蛋白和GAD 65表达的中间神经元的人口，减少GABA能和去抑制海马兴奋性神经传递。这些神经传递的变化，以及成年齿状回神经发生的减少，伴随着成年记忆和学习缺陷。因此，我们假设HO损害海马神经发生和重塑的长期能力，以及特定海马GABA能回路的发育。这些变化破坏了兴奋性和抑制性（E/I）神经传递之间的平衡，从而降低了突触可塑性和认知性能。我们提出的研究将在两个具体目标中检验这些假设。在目标1中，我们将确定HO如何通过细胞和基因表达的变化来减弱海马的长期神经原性能力。我们还将进行电生理学研究，以确定HO对破坏E/I平衡和长时程增强能力的影响。在目标2中，我们将使用学习、记忆和认知灵活性测试来定义海马重塑改变的行为相关性。最后我们将 确定药物恢复GABA神经传递是否改善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建立HO诱导的细胞变化、GABA能中间神经元功能障碍、长期神经发生和认知缺陷之间的功能关系。这些将为未来的治疗干预提供损伤机制和功能读数的见解。