Postnatal Brain Susceptibility to Intermittent Hypoxia

产后大脑对间歇性缺氧的易感性

• 批准号: 6460272
• 负责人: David Gozal
• 金额: $ 35.75万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460272
• 关键词: age difference; behavioral /social science research tag; cell proliferation; cerebral cortex; cerebral ischemia /hypoxia; developmental neurobiology; disease /disorder model; glutamate receptor; hippocampus; infant animal; laboratory rat; learning; long term potentiation; nerve stem cell; neuropsychological tests; neurotoxicology; respiratory airflow disorder; respiratory hypoxia; sleep apnea

DESCRIPTION (provided by applicant): Obstructive sleep apnea syndrome (OSA) is a frequent condition affecting up to 2 percent of the pediatric population at ages that are characteristically associated with dynamic brain development and acquisition of important neurocognitive functions. OSA is characterized by repeated episodes of hypoxia during sleep, and when untreated it is associated with significant neurocognitive morbidities such as excessive restlessness and irritability, diminished intellectual performance, attention span, learning and vigilance. However, the relative contributions of chronic intermittent hypoxia (CIH) to OSA-associated neurocognitive dysfunction in children remain unclear. In adult rats, a CIII profile that mimics the intermittent hypoxia observed in patients with OSA during sleep leads to substantial reductions in spatial learning and retention as well as diminished ability to induce long-term potentiation in the CA1 region of the hippocampus. These neurobehavioral and physiological alterations correlate with anatomical changes developing in cortico-hippocampal regions., and we have found that such anatomical changes are particularly prominent in developing rat pups at post-natal ages that coincide with the peak prevalence of USA in children, suggesting that this period of brain maturation is uniquely vulnerable to CIH. We therefore hypothesized that the detrimental effects of CIH on memory and learning performances during this highly vulnerable developmental period are long-lasting, and will be manifest even during adulthood, long after the CIH exposure has ceased. Furthermore, these neurocognitive deficits will be associated and correlated with parallel electrophysiological alterations in the characteristics of long-term potentiation (LTP) of the CAl region of the hippocampus, as well as with disruption of normal ionotropic glutamate receptor expression and binding characteristics within the cortex and hippocampus. We propose to: (1) examine the short-term and long-term consequences of CIH on behavioral patterning and on water maze task acquisition and retention. (2) To assess the short-term and long-lasting effects of CIH on LTP characteristics of the CA1 region of the hippocampus.; (3) To establish changes in NMDA glutamate receptor expression and binding characteristics in neocortical and hippocampal regions associated with CIH, and following long-term recovery; (4) To determine whether exposure to CIH during a critically-vulnerable period of development will elicit time-dependent glial and neuronal stem cell proliferation within cortical and hippocampal regions. These studies will characterize concomitant structural and phenotypic changes induced by CIH in a developmental rodent model of OSA, and provide initial insights into the role of CIH in short-term and long-term neurobehavioral morbidity of USA in children.

描述（由申请人提供）：阻塞性睡眠呼吸暂停综合症（OSA）为 经常影响多达2％儿科人口的状况 与动态大脑发育以及 获取重要的神经认知功能。 OSA的特征是 睡眠期间缺氧的重复发作，当未经处理时，它与之相关 具有明显的神经认知性病，例如过度躁动和 易怒，智力表现降低，注意力跨度，学习和 警觉。但是，慢性间歇性缺氧的相对贡献 （CIH）儿童与OSA相关的神经认知功能障碍尚不清楚。 在成年大鼠中，模仿间歇性缺氧的CIII轮廓 睡眠期间OSA的患者可大大减少空间 学习和保留以及诱导长期诱导的能力 海马的CA1区域的增强。这些神经行为和 生理改变与解剖学变化相关 Cortico-Hampocampal区域。我们发现这种解剖学变化 在产后年龄的大鼠幼崽中特别突出 与儿童中美国的峰值患病率一致，这表明这是 大脑成熟时期非常容易受到CIH的影响。因此，我们 假设CIH对记忆和学习的有害影响 在这个高度脆弱的发展时期的表现是 持久，即使在CIH之后很久以后，也会表现出来 暴露停止了。此外，这些神经认知缺陷将是 相关并与平行的电生理变化相关 长期增强（LTP）的特征 海马以及正常离子谷氨酸受体的破坏 皮质和海马中的表达和结合特征。我们 建议：（1）检查CIH的短期和长期后果 行为模式以及水迷宫任务的获取和保留。 （2）至 评估CIH对LTP特征的短期和长期影响 海马的CA1区。 （3）建立NMDA谷氨酸的变化 新皮质和海马的受体表达和结合特征 与CIH相关的区域以及长期恢复后； （4）确定 是否在批判性发展期间接触CIH 将引起时间依赖性的神经胶质和神经元干细胞增殖 皮质和海马区域。这些研究将表征伴随 CIH在发育啮齿动物中引起的结构和表型变化 OSA模型，并提供有关CIH在短期中的作用的初步见解 和美国儿童的长期神经行为发病率。