【作者】 黄倩；

【导师】 周江宁；

【作者基本信息】 中国科学技术大学 ， 神经生物学， 2008， 博士

【摘要】 基因-环境相互作用在抑郁症的发病中起着重要作用,其中,应激事件是一个非常关键的非遗传因素。数十年的研究揭示出抑郁症的相关病理生理学机制,大致分为两个方向,一是神经化学和神经内分泌假说,认为抑郁症的基础在于大脑内多种化学物质和体内激素的失衡,例如单胺类递质浓度的降低,下丘脑-垂体-肾上腺(HPA)轴过度激活等;另一个是神经网络假说,认为神经重构和神经元活性的改变是这一疾病的基础,其相关的分子包括神经营养/生长因子以及神经粘附因子等。性激素很大程度的参与了抑郁症和应激反应,其机制可能在于它可以调节相关的神经内分泌系统和神经网络相关因子。在这里,我们使用了强迫游泳实验和慢性应激模型,对性激素对应激行为反应的调控作用及其相关分子机制进行了一定的探讨。1.应激过程中3β-diol对行为反应以及CRH转录的类雌激素样作用促肾上腺皮质激素释放激素(CRH)和精氨酸加压素(AVP)作为HPA轴上游的两个神经肽,在应激过程中起着重要作用,它们对于应激的反应也受到性激素的调控。3β-diol是雄激素双氢睾酮(DHT)的代谢产物,然而它本身却不具有雄激素的作用,相反,以前的研究发现它在前列腺中起着类雌激素作用。它可以与雌激素受体结合,促进由雌激素反应元件介导的基因转录。我们用体外转染和体内试验研究了它对于应激相关的行为以及CRH和AVP表达的作用。我们的结果显示,在CHO-K1细胞系中,当转染了雌激素受体时,3β-diol能够显著性的促进CRH和AVP的启劫子活性。慢性给予3β-diol能减少强迫游泳实验中大鼠的静止不动时间,也能促进由强迫游泳引起的CRH mRNA的表达,而急性给予不能产生这一作用。这一结果表明,3β-diol在情感相关行为中起着一定的抗抑郁作用,对于CRH的调控,3β-diol表现出了类雌激素作用。2.慢性应激模型海马和前额叶皮层神经粘附因子的表达:考虑性激素参与我们研究了假手术和去势后雄性大鼠中慢性温和应激引起的行为学和神经粘附因子(NCAM)表达水平的改变。我们发现,慢性应激能显著性降低大鼠前额叶皮层中的NCAM表达,而海马各亚区中的表达不受影响。实验结果揭示了雄激素参与了应激相关的行为反应。在假手术大鼠中,慢性应激能诱导出一个典型的抑郁症表现,即欣快感缺乏,而对于去势后大鼠的欣快感体验行为不产生影响。去势术对于由应激引起的NCAM表达改变不发生作用。因此我们推测,尽管NCAM在慢性应激过程中起了一定的作用,但是它并不介导性激素对于应激相关行为的影响。更多还原

【Abstract】 Critical interactions between genetic and environmental factors - among which stress is one of the most potent non-genomic factors - are involved in the development of mood disorders.Two main hypotheses have been proposed to underlie depression.One is called "chemical hypothesis" which emphasizes neurochemical imbalance as the cause of depression,including altered function of monoamine system and hyperactivity of the hypothalamic-pituitary-adrenal(HPA) axis.The other one,"network hypothesis" emphasized disturbed neural networks as the cause of this disease,with neurotrophins,growth factors and neural cell adhesion molecules as the molecular mechanism.Sex hormones are involved in depression and stress responses,and this may due to their regulation effect on those neurochemical systems and on those moleculars related to neural network.In the present study,we tested this hypothesis using two animal models(the forced swim test and chronic mild stress model).1.An estrogenic effect of 5α-androstane-3β,17β-diol on the behavioral response to stress and on CRH regulation.The gender difference in behavioral and hormonal response to stress is well known,but the underlying mechanism remains elusive.Arginine-vasopressin(AVP) and corticotrophin-releasing hormone(CRH)are two major regulatory peptides in the brain involved in stress regulation.Their response to stress has been shown to be modulated by sex hormones.The androgen metabolite,5α-androstane-3β,17β-diol (3β-diol),has been identified as an estrogenic hormone.It binds to estrogen receptors (ERs)and modulates estrogen response element mediated promoter activities via the ER pathway.The present Study involved in vitro transfection assays to examine whether 3β-dioi can directly modulate CRH and AVP promoter activity.Our results demonstrate that in CHO-K1 cell lines,when ERs were over-expressed,3β-diol could significantly stimulate CRH and AVP promoter activity through an ER pathway.The effect of 3β-diol on the behavioral,the CRH and the AVP response to stress in the rat was also investigated.We found that chronic,but not acute administration of 3β-diol significantly decreased the immobile duration in the forced swim test.In rats exposed to the forced swim test,CRH mRNA expression in the hypothalamus was enhanced by chronic 3β-diol administration,while the AVP mRNA expression was not affected. These results suggest that 3β-diol may play an anti-depressive role in affective behavior and may have a direct effect on CRH expression.2.Expression of the neural cell adhesion molecule(NCAM)in the prefrontal cortex(PFC)and hippocampus of rats subjected to chronic mild stress: considering testicular influence.The effect of chronic mild stress on emotional behavior and on protein levels of NCAM were evaluated in the PFC and hippocampus of intact or castrated male rat brains.Decreased NCAM expression in the prefrontal cortex was found in the rats subjected to stress,while the protein levels in sub-regions of hippocampus remained unchanged.The study explored whether there was a testicular influence on the behavioral response to stress and on the NCAM expression.We found chronic mild stress induced anhedonia in intact,but not castrated male rats.However,castration did not have influence on the stress induced reduction of NCAM expression.These findings indicate that synthesis and expression of NCAM was involved in chronic mild stress,and the effect of castration on stress related behavior was not mediated by the NCAM pathway.更多还原