Postnatal Brain Susceptibility to Intermittent Hypoxia

描述(申请人提供)：阻塞性睡眠呼吸暂停综合征(OSA) 一种常见的疾病，影响多达2%的儿科人口 年龄与动态的大脑发育和 获得重要的神经认知功能。OSA的特点是 睡眠期间反复出现低氧，如果不进行治疗，与此相关 有严重的神经认知疾病，如过度躁动和 易怒，智力表现减退，注意力持续时间，学习和 保持警惕。然而，慢性间歇性低氧的相对贡献 (CIH)到阻塞性睡眠呼吸暂停综合征(OSA)相关的儿童神经认知功能障碍仍不清楚。 在成年大鼠中，模拟观察到的间歇性低氧的CIII轮廓 睡眠中患有阻塞性睡眠呼吸暂停综合征的患者导致空间运动能力显著下降 学习和保持以及诱导长期学习的能力减弱 海马区CA1区的增强。这些神经行为和 生理变化与人体的解剖变化有关 皮质-海马区。我们发现这种解剖学变化 在幼鼠出生后发育的过程中尤为突出 与美国儿童患病率的峰值不谋而合，这表明这 大脑成熟期特别容易受到脑出血的影响。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育期内的表现是 持续很长时间，甚至在成年后很久都会表现出来 风险敞口已经停止。此外，这些神经认知缺陷将是 与平行的电生理改变相关和相互关联 大鼠脑CA1区长时程增强的特征 海马区，以及正常的离子型谷氨酸受体的破坏 大脑皮质和海马区的表达和结合特征。我们 建议：(1)研究CIH的短期和长期后果 行为模式和水迷宫任务的习得和保持。(2)至 评估CIH对LTP特性的短期和长期影响 海马的CA1区；(3)建立NMDA谷氨酸的变化 新皮质和海马区受体的表达及结合特性 与CIH相关的区域，以及在长期恢复之后；(4)确定 在极度脆弱的发展时期接触三氯环己烷 将在体内诱导时间依赖性的神经胶质和神经元干细胞增殖 大脑皮层和海马区。这些研究将描述伴随的 CIH对发育期啮齿动物结构和表型的影响 OSA模型，并对CIH在短期内的作用提供初步见解 和美国儿童神经行为的长期发病率。

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.