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

 描述(申请人提供)：发育性脑损伤是神经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。早产儿对伤害的易感性尤其高。早产对大脑发育的长期影响的细胞和生理机制，特别是对特定神经回路的损害，目前还知之甚少。对早产儿大脑的各种侮辱都会导致损伤，但人们对高组织氧分压或高氧(HO)的神经影响知之甚少，这与神经预后不良有关。早产儿的抗氧化酶水平低于足月儿，并且缺乏足够的防御系统来抵御分娩时氧分压升高引起的氧化应激。我们的围产期HO诱发脑损伤的小鼠模型，在P6-P8短期暴露于高氧分压(80%)，显示白质发育延迟，轴突髓鞘完整性破坏，运动多动和运动协调受损。早产幸存者的学习障碍和多动症表明，对记忆形成至关重要的大脑结构受到了损害。海马体是认知过程的中心大脑结构。由于这一大脑区域在出生后和成人的神经发生以及重塑/突触可塑性方面保持活跃，因此特别容易受到侮辱。我们在海马区的初步发现表明，围产期HO产生活性氧，减少表达小白蛋白和GAD65的中间神经元群体，减少GABA能，并抑制谷氨酸能兴奋性神经传递。神经传递的这些变化，加上成人齿状回神经发生的减少，伴随着成人记忆和学习障碍。因此，我们假设，HO损害了海马区神经发生和重塑的长期能力，以及特定海马区GABA能回路的发展。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，从而降低了突触的可塑性和认知能力。我们提议的研究将在两个具体目标上检验这些假设。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体的长期神经生成能力。我们还将进行电生理研究，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、记忆和认知灵活性的测试来确定海马体重塑改变的行为相关性。最后，我们会 确定GABA神经传递的药理学恢复是否改善HO损伤后的E/I平衡和认知能力。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障碍之间的功能关系。这些将为未来的治疗干预提供对损伤机制的洞察和功能读数。

 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.