Steroid-induced Neuroplasticity in the Brain

该实验室的工作重点是压力和性腺类固醇对大脑的影响。1.尽管30多年来人们已经知道反复应激可引起海马锥体神经元顶树突的戏剧性重塑，特别是在CA3亚区，但关于短期、短暂应激的影响的研究相对较少。我们发现，在男性，但不是女性，一个单一的手术事件导致顶端CA3锥体神经元树突的长度急剧缩短，最多两个月后就能检测到。摘除睾丸的效果与假手术不同，提示存在应激和睾酮的相互作用；并且不会通过暴露于饮用水中合成的糖皮质激素地塞米松而导致循环中糖皮质激素浓度的瞬时增加而再现，这只会导致CA3树突状分支的瞬时截断。我们假设手术后观察到的持续的树突状细胞重塑包括最初手术相关的肾上腺糖皮质激素分泌的激活和随后的炎症/修复相关的反应。为了验证这一假设，我们将检验最初短暂接触糖皮质激素对大鼠的形态影响，无论是否有随后实验诱导的炎症。2.在细胞水平上，应激下调了雄激素调节的ERK特异性磷酸酶DUSP6的表达。有趣的是，大脑中睾酮的主要代谢物5a雄烷3a 17üdiol(Adiol)在正常男性循环中发现的Adiol浓度范围内逆转了应激对DUSP6的影响。在女性中，压力的影响似乎涉及不同的机制，部分是通过糖皮质激素抑制G蛋白偶联雌激素受体(GPER)信号发挥作用。我们将通过DUSP6、GPER和相关的应激调节蛋白的表达和活性，在体内检测应激和糖皮质激素治疗的效果，无论是否伴随性腺类固醇暴露。我们将探索压力和性腺类固醇在调节大脑miRNA表达方面相互作用的假设。3.环境中的人造化学物质可能会模仿荷尔蒙的作用，从而扰乱动物生存所需的行为。我们以前曾报道过世界上使用最广泛的化学物质之一，双酚A(BPA)，在很低的剂量水平下就会损害雌激素诱导的海马区突触发生。在组织培养条件下，我们发现BPA是大脑中GPER激活的有力拮抗剂，对神经元GPER信号产生应激性抑制。我们将比较双酚A和常用双酚A替代品的效果，后者对大脑的影响迄今尚未得到测试，将这些化合物在体内对GPER信号的影响与它们对海马神经元形态和认知行为的影响相关联。

Work in this laboratory focuses on the effects of stress and gonadal steroids in the brain. 1.Although it has been known for more than 30 years that repeated stress can induce dramatic remodelling of hippocampal pyramidal neuron apical dendrites, particularly in the CA3 sub-field, there has been a relative paucity of studies on the effects of short term, transient stress. We have found that in males, but not females, a single surgical event produces a dramatic reduction in the length of apical CA3 pyramidal neuron dendrites, detectable up to two months later. The effects of orchidectomy differ from those of sham operation, suggesting a stress x testosterone interaction; and are not reproduced by transiently increasing circulating glucocorticoid concentrations, via exposure to the synthetic glucocorticoid dexamethasone in the drinking water, which elicits only a transient truncation of CA3 dendritic branching. We hypothesize that that the lasting dendritic remodelling observed after surgery involves both the initial surgery-associated activation of adrenal glucocorticoid secretion and subsequent inflammation/repair associated responses. To test this hypothesis, we will examine the morphological effects in rats of an initial brief glucocorticoid exposure, with or without subsequent experimentally-induced inflammation. 2.At the cellular level, stress down-regulates expression of dual specificity phosphatase 6 (DUSP6), an androgen-regulated ERK-specific phosphatase. Interestingly, the primary metabolite of testosterone in the brain, 5a androstane 3a 17ß diol (Adiol) reverses the effects of stress on DUSP6, within the range of circulating Adiol concentrations found in normal males. In females, effects of stress appear to involve different mechanisms, acting in part via glucocorticoid inhibition of G protein coupled estrogen receptor (GPER) signaling. We will examine the effects of stress and glucocorticoid treatment in vivo, with or without concomitant gonadal steroid exposure, in terms of the expression and activity of DUSP6, GPER and related stress-regulated proteins. We will explore the hypothesis that stress and gonadal steroids interact in regulating miRNA expression in the brain. 3.Man-made chemicals in the environment may mimic hormone action, thereby disrupting the behaviors that animals need for survival. We previously reported that one of the most widely used chemicals in the world, bisphenol A (BPA), impairs estrogen induced synaptogenesis in the hippocampus at very low dose levels. Under tissue culture conditions, we have found that BPA is a potent antagonist of GPER activation in the brain, producing a stress-like inhibition of neuronal GPER signaling. We will compare BPA's effects to those of commonly used BPA alternatives, whose effects on the brain have so far not been tested, correlating the in vivo effects of these compounds on GPER signaling with their effects on hippocampal neuronal morphology and cognitive behavior.