Abstract：
Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer\'s disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aβ plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aβ deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.
摘要：
新生儿缺氧缺血性脑病（HIE）导致死亡率和神经系统发病率，包括具有复杂神经病理学的认知不良。胆碱能基底前脑的损伤及其大脑皮层的丰富神经支配也可能导致认知病理学。尚不确定与成人认知相关的神经变性相关的基因是否会使新生儿HIE后的结局恶化。我们假设，由新生儿HI引起的小鼠新皮质损伤是由持续的胆碱能神经支配和与认知结果相关的中间神经元（IN）病理引起的，并由与阿尔茨海默病相关的基因加剧。我们在出生后第10天（P10）对非转基因（nTg）C57Bl6小鼠和转基因（Tg）表达人突变体淀粉样前体蛋白（APP-瑞典变体）和突变体早老素（PS1-ΔE9）的小鼠进行了Rice-VannucciHI模型。具有假手术的nTg和Tg小鼠是对照。视觉辨别(VD)进行认知测试。皮质和海马胆碱能轴突和IN病理和Aβ斑块，分别通过胆碱乙酰转移酶（ChAT）和6E10抗体的免疫组织化学鉴定，计数为P210。简单的ChAT+轴突肿胀存在于所有的假手术组和HI组;Tg小鼠有更多的比他们的nTg对应物,但HI不影响APP/PS1Tg小鼠轴突肿胀的数量。相比之下,复杂的ChAT神经炎簇（NC）仅发生在Tg小鼠中；HI增加了负担。特定区域中ChAT簇的丰度与VD降低相关。内嗅皮层（EC）中磨损ChATINs的频率在Tgshams中相对于其nTg对应物增加，但HI消除了这种差异。EC的胆碱能IN病理与NC数相关。HI不会加剧APP/PS1Tg小鼠的Aβ沉积，也不与其他指标相关。成年APP/PS1Tg小鼠具有明显的皮质胆碱能轴突和ECChATIN病理；新生儿HI加剧了某些病理，并与VD相关。新生儿HI引起的认知缺陷和皮质神经病理学的机制可能受遗传风险的调节。也许考虑了结果的一些可变性。
