Prenatal Corticosteroid Impact on Hippocampus

描述（由申请人提供）：皮质类固醇治疗广泛用于妊娠晚期预防早产新生儿呼吸窘迫综合征。这种疗法的一个疗程没有长期的有害影响。然而，经常使用多个疗程的皮质类固醇治疗和长期的皮质类固醇升高。动物数据表明，在怀孕的最后三分之一期间，长期的产前皮质类固醇增加可能会对大脑发育产生不利影响，特别是海马相关功能，如学习和记忆。本研究的目的是建立一个产前或产后早期多疗程皮质类固醇给药的大鼠模型，以确定反复皮质类固醇治疗对海马功能（出生后在海马相关癫痫易感性、体内行为和学习测试中进行测试）和形态学（通过神经元增殖、体视神经元计数和神经元死亡率进行评估）的影响。该提案将进一步调查不产生有害影响的这类皮质类固醇剂量与另一种阈下产后影响（发热性癫痫发作）的影响之间可能存在协同作用的可能性。这两个因素的协同作用将导致对海马功能和结构的不利影响（“双重打击”假说）。最后，实验将确定是否可以通过将受影响的后代暴露于丰富的环境中来改善反复皮质类固醇治疗的有害影响。方法包括产前给药皮质类固醇、kainic酸诱导的癫痫发作、海马点燃、开放场、单杠和升高+迷宫试验、用BrdU标记新生神经元、荧光染色凋亡/坏死神经元、使用光和共聚焦显微镜在海马中进行体视神经元计数，以及将大鼠暴露于丰富的环境中。这项建议的数据对于确定多疗程产前皮质类固醇治疗的长期不良影响以及改善这些影响对后代的影响至关重要。

DESCRIPTION (provided by applicant): Corticosteroid therapy is widely used during the third trimester of pregnancy to prevent respiratory distress syndrome in prematurely born neonates. A single course of this therapy has no long-term harmful effects. However, multiple courses of corticosteroid therapy with long-lasting elevations of corticosteroids are frequently used. Animal data indicate that long-term prenatal corticosteroid increases during the last third of pregnancy may adversely affect brain development, especially hippocampus-associated functions such as learning and memory. The purpose of this proposal is to establish a rat model of prenatal or early postnatal multiple-course corticosteroid administration to determine the effects of repeated corticosteroid therapy on hippocampal function (tested postnatally in hippocampal- related seizure susceptibility, behavioral and learning tests in vivo) and morphology (assessed using neuronal proliferation, stereological neuronal counts, and rate of neuronal death). The proposal will further investigate the possibility that there may be a synergy between the effects of such doses of corticosteroids that do not produce harmful effects and the effects of another subthreshold postnatal impact (a febrile seizure). The synergy of these two factors will then result in adverse effects on hippocampal function and structure ("two-hit" hypothesis). Finally, the experiments will determine whether the harmful effects of repeated corticosteroid treatment may be ameliorated by the exposure of the affected offspring to an enriched environment. Methods include prenatal administration of corticosteroids, kainic acid-induced seizures, hippocampal kindling, open field, horizontal bar and elevated plus maze tests, labeling of newly born neurons with BrdU, fluorescent staining for apoptotic/necrotic neurons, stereological neuronal counts in the hippocampus using light and confocal microscopy, and the exposure of the rats to an enriched environment. The data of this proposal will be critical for determining long-term adverse effects of multiple course prenatal corticosteroid therapy and for the ameliorating these effects in the offspring.