利用大白鼠模式探討新生期投予 Dexamethsone 對成年期憂鬱行為的影響 The effects of neonatal dexmethasone treatment on depressive-like behavior in adult rats

Date
2013
Authors
許惠喻
Hsu Hui-Yu
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Abstract
人類於新生期所面對的心理或生理壓力,會對成年期的情緒表達或生理狀況產生深遠的影響。 Dexamethasone ( DEX ) 是一種人工合成醣皮質激素,在臨床上常用於治療早產兒因肺部發育不良而引發的呼吸窘迫症現象,可提高早產兒的存活率,但近期的研究卻顯示高劑量以及長期的使用卻可能對其產生不良的影響。在動物模式中,大鼠新生期投予 DEX 可能導致其青少年期空間記憶產生障礙,亦會干擾海馬迴 ( hippocampus ) 中長期增益效應 (long-term potentiation, LTP) 的形成。而這些不良影響在成年時逐漸得到改善。然而先前本實驗室的研究卻顯示,新生時期投予DEX的成年大鼠在強迫游泳行為(forced swimming test, FST )模式中會產生類憂鬱行為的反應。顯示新生期DEX的投予對動物面臨急性壓力時的反應具有長期影響。然而,此現象涉及哪些神經投射路徑的調控與分子路徑的活化,是值得深入探討的議題。因此,本研究利用Wistar大鼠,模擬臨床上投藥的方式,於出生後第一至第三天,以皮下注射的方式的投予遞減劑量的DEX (0.5 mg/kg, 0.3 mg/kg and 0.1 mg/kg),於動物八週齡時進行各項行為實驗,以西方墨點法 (western blotting)與中樞投予 ERK抑制劑,釐清 DEX投予對情緒記憶的分子機制所造成的改變。並利用胞外電生理探討其對相關神經投射路徑活性的影響。研究結果發現,在FST行為模式中,新生期投予DEX的動物不游動的時間明顯較長,且杏仁核ERK磷酸化程度顯著的高於控制組動物。ERK 抑制劑的投予能有效降低DEX組動物不游動的時間,顯示ERK的磷酸化程度與動物不游動的時間具有高度的正相關性。胞外電生理記錄結果發現,以高頻電刺激誘發的LTP訊號,新生期DEX組大鼠在視丘投射至側杏仁核的神經訊號值明顯高於控制組大鼠,當利用ERK磷酸化抑制劑灌流後,能使神經路徑過度活化的現象回復,顯示此路徑中 ERK磷酸化的程度在調控動物面臨急性壓力時的生理反應扮演重要角色。本研究結果有助於瞭解新生期DEX的投予對動物成年期時面臨急性壓力時,神經投射路徑與分子活性的影響,並提供研究急性壓力反應的調控機制與臨床治療藥物開發的參考。
Numerous literatures indicate that stress exposed and medication experience in early postnatal can produce subtle changes in brain maturation, which will resulted in long-lasting behavioral changes when they were exposed to novelty stress in the later period of life. Synthetic glucocorticoid dexamethasone (DEX) is frequently used to lessen the progression of chronic lung disease in premature infants. Recent studies suggest that neonatal DEX treatment impair brain development and cognitive functions. In this study, forced swimming test (FST) were applied to evaluate the effect of neonatal DEX treatment on amygdale function in adulthood. Rats were subjected to receive subcutaneous injection of tapering doses of DEX (0.5 mg/kg, 0.3 mg/kg and 0.1mg/kg) from postnatal day 1 to 3 (PN1~PN3). Behavior test were took place at the age 8 weeks. Since previous studies shown that the immobility behavior during FST was regulated by MAPK signal pathway in amygdale, the MAPK/ERK phosphorylation in amygdale were investigated. Several researches imply that thalamic paraventricular nucleus (PVN) is activated by acute stress and the project to forebrain structures such as amygdale implicated in processing stress-related information. Possibility of neonatal DEX treatment effect on neurocircuit participates in the depression-like behaviors was studied by extracellular recording. Our results showed increasing of the immobility time in neonatal DEX treatment rats comparing with control group. Western blot analysis also showed that the amygdala phospho-ERK level in neonatal DEX treatment rats was higher than that in control rats. Intra-cerebroventricular infusion of ERK inhibitor PD98059 suppressed immobility time of neonatal DEX treatment rats during FST. No significant different in amygdale phospho-ERK level between each group which infused with PD98059. The high frequency stimulation induced LTP was significantly greater in neonatal DEX treatment rats than in control rats. These results suggest that DEX treatment in the neonatal period can induce a long-lasting synaptic plasticity effect in the circuit from the paraventricular thalamic nucleus to the lateral nucleus of amygdale, and ERK activation might be involved in the formation of depression-like behaviors.
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Keywords
Dexamethasone, Extracellular signal-regulated kinases, HPA軸, 長期增益效應, 高台暴露, 強迫游泳, 杏仁核, Dexamethasone, Extracellular signal-regulated kinases, hypothalamo–pituitary–adrenal axis (HPA axis), long-term potentiation, exposed of flat-top, forced swimming test, amygdale
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