Postnatal Brain Susceptibility to Intermittent Hypoxia

描述（由申请人提供）：阻塞性睡眠呼吸暂停综合征（OSA）是 一种常见的疾病， 年龄与动态大脑发育有关， 获得重要的神经认知功能。OSA的特征在于： 睡眠期间反复发作缺氧，如果不治疗， 有明显的神经认知疾病，如过度不安， 易怒，智力表现下降，注意力集中，学习和 警惕然而，慢性间歇性缺氧的相对贡献 (CIH)儿童中OSA相关的神经认知功能障碍仍不清楚。 在成年大鼠中，CIII曲线模拟在大鼠中观察到的间歇性缺氧， 睡眠中的OSA患者导致空间 学习和记忆力以及诱导长期 海马CA 1区的增强作用。这些神经行为和 生理变化与发展中的解剖学变化相关， 皮质-海马区，我们发现这种解剖学上的变化 在出生后发育的幼鼠中尤为突出， 与儿童中美国的高峰患病率相吻合，这表明 大脑成熟期是CIH最脆弱的时期。因此我们 假设CIH对记忆和学习的不利影响 在这个高度脆弱的发展时期， 长期持续，甚至在CIH之后很久， 曝光已经停止。此外，这些神经认知缺陷将 与平行的电生理学改变相关， 的CA 1区域的长时程增强（LTP）的特征。 海马，以及正常离子型谷氨酸受体的破坏 在皮质和海马内的表达和结合特征。我们 建议：（1）研究CIH对以下方面的短期和长期影响 行为模式和水迷宫任务的获得和保持。(2)到 评估CIH对LTP特征的短期和长期影响， 海马体的CA 1区。(3)确定NMDA谷氨酸的变化 受体在新皮层和海马的表达和结合特征 与CIH相关的区域，以及长期恢复后;（4）确定 是否在发育的关键脆弱期暴露于CIH 将引起时间依赖性的神经胶质和神经干细胞增殖， 皮质和海马区。这些研究将描述伴随治疗的特征 CIH诱导啮齿动物发育过程中结构和表型变化 OSA的模型，并提供初步见解CIH在短期内的作用 和美国儿童长期神经行为发病率。

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.