Hypothermic Protection in Neocortex Is Topographic and Laminar, Seizure Unmitigating, and Partially Rescues Neurons Depleted of RNA Splicing Protein Rbfox3/NeuN in Neonatal Hypoxic-Ischemic Male Piglets.
Hypothermic Protection in Neocortex Is Topographic and Laminar, Seizure Unmitigating, and Partially Rescues Neurons Depleted of RNA Splicing Protein Rbfox3/NeuN in Neonatal Hypoxic-Ischemic Male Piglets.
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低温对新生儿脑病的影响可能在新皮质的地形和细胞病理学上有所不同，其表现可能受到癫痫发作的影响，从而改变神经病理学的严重程度、分布和类型。我们开发了一种缺氧缺血（HI）脑病和体温过低（HT）的新生仔猪生存模型，并采用连续脑电图（cEEG）检查癫痫发作。新生雄性仔猪接受 HI-常温 (NT)、HI-HT、假 NT 或假 HT 治疗。随机未用药的假仔猪和 HI 仔猪在恢复期间接受了 cEEG。生存期为 2-7 天。对不同新皮质区域的正常和病理神经元进行计数，通过细胞结构和连接组学进行鉴定，使用苏木精和伊红染色以及 RNA 结合 FOX-1 同源物 3 (Rbfox3/NeuN) 的免疫组织化学。确定了缉获负担。相对于假 NT 和假 HT 仔猪，HI-NT 仔猪的正常/总神经元比率降低，缺血坏死/总神经元比率增加，前后运动、体感和额叶皮质的严重程度不同。 HT 减弱了新皮质神经病理学。 HT 保护在下顶叶皮层第三层最为突出。 Rbfox3 免疫反应性将皮质神经元区分为：Rbfox3 阳性/正常、Rbfox3 阳性/缺血性坏死和 Rbfox3 耗尽。与假 NT 仔猪相比，HI 仔猪在第 II 层和第 III 层中 Rbfox3 耗尽/总神经元比率增加。 HT 部分挽救了神经元 Rbfox3 耗竭。 HI-NT 和 HI-HT 仔猪的癫痫发作负担相似。我们得出的结论是，新生 HI 仔猪新皮质具有：(1) 外侧裂易受 HI 和癫痫发作的影响； (2) 功能不同区域的有限神经元细胞病理学库与 HT 的保护机制有关； (3) 较高的癫痫发作负担，对 HT 不敏感，这与体感皮层中更多的全层缺血坏死神经元相关； (4)对HT敏感的病理性RNA剪接蛋白核耗竭。这项工作表明，HT 对新生儿 HI 中新皮质的保护是地形和层状的，不会缓解癫痫发作，并恢复 RNA 剪接因子的神经元消耗。
The effects of hypothermia on neonatal encephalopathy may vary topographically and cytopathologically in the neocortex with manifestations potentially influenced by seizures that alter the severity, distribution, and type of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia (HT) with continuous electroencephalography (cEEG) for seizures. Neonatal male piglets received HI-normothermia (NT), HI-HT, sham-NT, or sham-HT treatments. Randomized unmedicated sham and HI piglets underwent cEEG during recovery. Survival was 2–7 days. Normal and pathological neurons were counted in different neocortical areas, identified by cytoarchitecture and connectomics, using hematoxylin and eosin staining and immunohistochemistry for RNA-binding FOX-1 homolog 3 (Rbfox3/NeuN). Seizure burden was determined. HI-NT piglets had a reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to sham-NT and sham-HT piglets with differing severities in the anterior and posterior motor, somatosensory, and frontal cortices. Neocortical neuropathology was attenuated by HT. HT protection was prominent in layer III of the inferior parietal cortex. Rbfox3 immunoreactivity distinguished cortical neurons as: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had an increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT piglets. Neuronal Rbfox3 depletion was partly rescued by HT. Seizure burdens in HI-NT and HI-HT piglets were similar. We conclude that the neonatal HI piglet neocortex has: (1) suprasylvian vulnerability to HI and seizures; (2) a limited neuronal cytopathological repertoire in functionally different regions that engages protective mechanisms with HT; (3) higher seizure burden, insensitive to HT, that is correlated with more panlaminar ischemic-necrotic neurons in the somatosensory cortex; and (4) pathological RNA splicing protein nuclear depletion that is sensitive to HT. This work demonstrates that HT protection of the neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores neuronal depletion of RNA splicing factor.
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