Postnatal Brain Susceptibility to Intermittent Hypoxia

产后大脑对间歇性缺氧的易感性

• 批准号: 6858757
• 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/6858757
• 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征 (OSA) 是 影响多达 2% 儿科人口的常见病症 与大脑动态发育相关的年龄 获得重要的神经认知功能。 OSA 的特点是 睡眠期间反复发生缺氧，如果不治疗，则与 患有严重的神经认知疾病，例如过度烦躁和 烦躁、智力表现下降、注意力持续时间、学习和 警觉。然而，慢性间歇性缺氧的相对贡献 (CIH) 与儿童 OSA 相关的神经认知功能障碍的关系仍不清楚。 在成年大鼠中，CIII 曲线模拟了在大鼠中观察到的间歇性缺氧。 OSA 患者在睡眠期间会导致空间 学习和记忆力以及诱导长期学习的能力下降 海马 CA1 区增强。这些神经行为和 生理变化与解剖学变化相关 皮质海马区，我们发现这种解剖学变化 在出生后年龄的大鼠幼崽的发育中尤其突出 与美国儿童患病率高峰相吻合，表明这 大脑成熟期特别容易受到 CIH 的影响。我们因此 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，甚至在成年期、CIH 发生后很久也会表现出来 曝光已停止。此外，这些神经认知缺陷将 与平行的电生理改变相关并相关 CA1区的长时程增强（LTP）特征 海马体，以及正常离子型谷氨酸受体的破坏 皮质和海马内的表达和结合特征。我们 建议： (1) 审查 CIH 对经济的短期和长期影响 行为模式以及水迷宫任务获取和保留。 (2) 至 评估 CIH 对 LTP 特征的短期和长期影响 海马体 CA1 区； (3) 确定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的区域； (4) 确定 是否在发育极其脆弱的时期暴露于 CIH 将引起时间依赖性神经胶质细胞和神经元干细胞增殖 皮质和海马区。这些研究将描述伴随的 CIH 在发育啮齿动物中引起的结构和表型变化 OSA 模型，并提供对 CIH 在短期内的作用的初步见解 以及美国儿童的长期神经行为发病率。