Long-term adverse effects of neonatal dexamethasone treatment in female rat

• Main Authors: Chiu, Hui-Fang, 邱惠芳
• Other Authors: Lu, Kwok-Tung
• Format: Others
• Language: en_US
• Online Access: http://ndltd.ncl.edu.tw/handle/3u53q7

博士 === 國立臺灣師範大學 === 生命科學系 === 106 === Synthetic glucocorticoid dexamethasone (DEX) has been widely used as an anti-inflammatory agent and also used to treat respiratory distress syndrome in preterm infants. Previous studies suggested that neonatal DEX treatment (NDT) could alter brain development and cognitive function. Hippocampus is a critical brain area for both spatial and associative learning and memory. Amygdala is an essential region for regulating emotional response and behavior. Both hippocampus and amygdala are also the important components of the limbic system, which exhibit a tight association with mental disorders such as major depression and anxiety disorder. Previous NDT studies often focused on its influence with the male rats only. Because females are more vulnerable to the psychological stress and have higher susceptibility of having mental disorders, it is important and worthy to study the possible long-term adverse effect on female animals. In order to investigate the effects of NDT on the hippocampal and amygdaloid function in female rats, the experimental subjects received subcutaneous injections of a tapering dose of DEX (0.5 mg/kg, 0.3 mg/kg and 0.1 mg/kg) from postnatal day 1 to day 3 (PND1~3). In vitro electrophysiological recording, inhibitory avoidance (IA) and forced swimming test (FST) were used to evaluate the hippocampal and amygdaloid function, particularly the spatial and emotional memory function at juvenile (6 weeks old) and adult (10 weeks old) female rats. We found that NDT could alter high frequency stimulation (HFS) which would induce hippocampal and amygdaloid long-term potentiation (LTP) formation. The expression level of hippocampal and amygdaloid estrogen receptor alpha (ER) was significantly repressed in NDT female rats. The results of this study also showed that NDT blocked IA learning in juvenile NDT female rats which did not sustain to the adulthood. No significant difference in the retention latencies was found between NDT and SAL groups in adult female rats. The long-term adverse effects of NDT on amygdaloid function in both juvenile and adult NDT female rats were investigated by forced swimming test (FST). The FST results demonstrated that the depression-like behaviors were increased in both juvenile and adult NDT female rats as compared with the control group of SAL animals. By using locomotor activity monitoring, we can also study the possible toxic effect of NDT on motor function and spontaneous behavior. The total horizontal distance movement did not reveal any significant difference between the NDT and the control animals. Clearly, the normal HFS induced long-term potentiation (LTP) formation in hippocampus and amygdala would be blocked in juvenile and adult NDT animals. Suprafusion of estradiol could partially restore the hippocampal and amygdaloid LTP formation in NDT female rats, as the systemic administration (6 weeks old or 10 weeks old consecutive four days; 0.25 mg/kg/day; subcutaneous injection) of estradiol could partially attenuate depression-like behavior in both juvenile and adult NDT female rats. More interestingly, our chromation immunoprecipitation (ChIP) results revealed that the level of H3K9 acetylation was significantly decreased in the hippocampus of NDT female rats. Co-administration of HDAC inhibitor trichostatin A (TSA) could restore the expression of hippocampal ER expression in NDT female rats. In addition, TSA was also found to partially restore the hippocampal LTP formation and rescue the hippocampal spatial memory function on IA test in the NDT juvenile female rats. In conclusion, our results strongly suggested that NDT could elicit some long-term adverse effects on the hippocampus and amygdala in NDT female rats, and it is correlated to the decline of H3K9 acetylation, which resulted in the decrease of hippocampal and amygdaloid ER expression. Co-administration of TSA or systemic injection of estradiol could partially restore the hippocampal and amygdaloid function in NDT female rats. These results suggested that the hippocampal and amygdaloid level is closely related to the mechanism that causes ERα to incur the adverse effect of NDT female rats, which might result in adverse consequences in adult age.