Dexamethasone (DEX) 是一種合成的強效醣皮質類固醇，可促進肺泡內的表面張力素合成，加速肺泡發育並具有抗發炎的作用，已廣泛地被使用於預防早產兒慢性肺病的發生。然而，臨床報告顯示早產兒使用 DEX 會引起許多的副作用，包括抑制早產兒個體生長，以及影響神經發育與認知功能等。但早期 DEX 暴露後是否由於個體生長受抑制，進而導致神經發育及認知功能改變到目前仍是未知的。因此我們建立新生仔鼠 DEX 使用模式，連續 3 天給予新生仔鼠逐天遞減劑量的 DEX，探討早期 DEX 暴露，對於海馬迴神經突觸塑性的表現及認知功能缺損與個體生長遲緩之間的關聯性。首先利用電氣電生理方法證實，經早期 DEX 暴露後，在 5 周大的大鼠海馬迴 CA1 區域給予低頻電刺激或由 (S)-3,5-Dihydroxyphenylglycine (DHPG) 活化第一類代謝型麩胺酸受體 (metabotropic glutamate receptor, mGluR) 皆明顯促進長期抑制現象 (long-term depression, LTD) 的誘發；反之，短暫高頻電刺激所誘發之長期增益現象 (long-term potentiation, LTP) 的表現卻受到抑制。且神經突觸塑性的改變，主要是與突觸後緻密區 (postsynaptic density, PSD) 內 Ca2+/calmodulin-dependent protein kinase II (CaMKII) 中 threonine 286 位置磷酸化的程度增加及第一型蛋白去磷酸酶 (protein phosphatase1, PP1) 的活性受抑制有關。此外，在新奇事物探索及被動迴避試驗中，我們也發現早期 DEX 暴露，會造成後期學習能力降低及記憶表現的缺損。我們透過減少母鼠哺育仔鼠數目，使個體生長較趨近於正常發育情形，來探討是否減緩早期 DEX 暴露後所造成神經突觸塑性及認知缺損。結果發現減少母鼠哺育仔鼠數目，可顯著的減低因早期 DEX 暴露所造成的海馬迴 CA1 區域突觸塑性及記憶缺損傷害，而不影響母鼠哺乳及照護的行為。並由免疫化學染色等結果，發現早期 DEX 暴露不會影響海馬迴 CA1 區域興奮性及抑制性神經元的型態及數目。顯示生長遲緩可能在早期 DEX 暴露所導致成長後海馬迴神經突觸塑性及功能改變中扮演重要的角色。
早期 DEX 暴露除了影響海馬迴 CA1 區域突觸塑性的表現及記憶形成外，由於 DEX 是一種強效的皮質固醇可影響全身系統，因此我們也想釐清早期 DEX 暴露是否也影響日後個體的壓力反應調節能力。利用急性壓力模式，我們發現於早期 DEX 暴露組與控制組的 5 週大鼠相比，較易引發高程度的下視丘─腦下垂體─腎上腺內分泌軸 (hypothalamic-pituitary-adreneal axis, HPA axis) 反應，血中的促腎上腺素皮質醇 (adrenocorticotropic hormone, ACTH) 及皮質酮 (corticosterone, CORT) 濃度增加，且對於壓力的感受性增強。然而，位於下視丘的室旁核 (paraventricular nucleus, PVN) 為主要釋放促腎上腺皮質激素釋放荷爾蒙 (corticotrophin-releasing hormone, CRH)，在早期 DEX 暴露組及控制組的表現並無明顯差異。利用 DEX 抑制試驗測試下視丘─腦下垂體─腎上腺內分泌軸的負向調控機制，我們發現早期 DEX 暴露的大鼠對於壓力的負向調控有缺損。另外，在即時聚合酶連鎖反應實驗中，也發現早期 DEX 暴露可增加下視丘的室旁核區內精胺酸血管加壓素的 (arginine vasopressin, AVP) mRNA 表現量。總結，早期 DEX 暴露，不但會影響神經突觸塑性和認知功能的表現，也會改變神經內分泌系統對於壓力的反應，增加日後發生為精神及心理疾病的風險。

Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used to prevent chronic lung disease (CLD) by facilitating surfactant synthesis in pulmonary alveolus and anti-inflammatory effects in preterm infants. Even though such a treatment lessens preterm infants’ morbidity of CLD, the disadvantage of this treatment is that retards preterm infants’ somatic growth and may result in long-lasting neurodevelopmental deficits in later life. Using a schedule of tapering doses of DEX similar to that used in premature infants, we developed a rat model and examined whether the lasting influence of neonatal DEX treatment on hippocampal synaptic plasticity and memory performance are correlated with the deficits in somatic growth. We confirmed that neonatal DEX exposure switched the direction of synaptic plasticity in hippocampal CA1 region, favoring low-frequency stimulation- and group I metabotropic glutamate receptor agonist (S)-3,5,-dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD), and opposing the induction of long-term potentiation (LTP) by high-frequency stimulation in the adolescent period. The effects of DEX on LTP and LTD were correlated with an increase in the autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) at threonine-286 and a decrease in the protein phosphatase 1 (PP1) expression. Neonatal DEX treatment also resulted in a disruption of memory retention subjected to object recognition task and passive avoidance learning. The adverse effects of neonatal DEX treatment on hippocampal synaptic plasticity and memory performance of the animals from litters culled to 4 pups were significantly less than those for the 8 pup litters. However, there was no significant difference in maternal care between groups. Neonatal DEX exposure did not affect the number or morphology of hippocapal CA1 pyramidal neurons and parvalbumin interneurons at 5 weeks old. These results suggest that growth retardation plays a crucial role in the DEX-induced long-lasting influence of hippocampal synaptic plasticity and function.
We also examined the effects of neonatal DEX exposure on stress response of rats in later life. We found that response of the hypothalamic-pituitary-adreneal axis (HPA axis) to acute restraint stress is greater in neonatal DEX-exposeed rats than age-matched saline-exposed control rats. Acute restraint stress induced higher plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) concentration in neonatal DEX-exposed rats compared with saline-exposed control rats at 5 weeks old. However, the increased levels of corticotrophin-releasing hormone (CRH) in hypothalamic paraventricular nucleus (PVN) were similar between groups. Neonatal DEX-exposed rats demonstrated an impaired negative-feedback regulation of stress response by using the DEX suppression test. Moreover, arginine vasopressin (AVP) mRNA expression was significantly higher in the hypothalamic PVN of neonatal DEX-exposed rats compared to SAL-exposed rat at 5 weeks old. Together these results suggest that neonatal DEX exposure may alter the function of neuroendocrine stress response system that enhances risk to develop psychopathology later in life.

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