Prenatal Corticosteroid Impact on Hippocampus

描述(申请人提供)：皮质类固醇疗法广泛应用于妊娠晚期，以预防早产儿呼吸窘迫综合征。这种疗法只需一个疗程，就没有长期的有害影响。然而，多疗程的皮质类固醇治疗与长期的皮质类固醇激素升高是经常使用的。动物数据表明，在怀孕的最后三分之一期间，产前皮质类固醇的长期增加可能会对大脑发育产生不利影响，特别是学习和记忆等与海马体相关的功能。本研究的目的是建立一种出生前或出生后早期多疗程皮质类固醇治疗的大鼠模型，以确定重复皮质类固醇治疗对海马区功能(生后在海马区相关的癫痫敏感性、行为和学习测试中进行测试)和形态(通过神经元增殖、立体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这种剂量的不会产生有害影响的皮质类固醇的影响与另一种阈值以下的出生后影响(发烧发作)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会对海马区的功能和结构产生不利影响(两次打击假说)。最后，实验将确定反复皮质类固醇治疗的有害影响是否可以通过将受影响的后代暴露在丰富的环境中而得到改善。方法包括产前给予皮质类固醇激素、海人酸致癫痫发作、点燃海马区、开阔、单杠和高架+迷宫试验、用BrdU标记新生神经元、对凋亡/坏死神经元进行荧光染色、用光学和共聚焦显微镜进行海马神经元立体计数，以及将大鼠暴露在丰富的环境中。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反应以及改善后代的这些影响至关重要。

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.