Steroid-induced Neuroplasticity in the Brain

类固醇诱导的大脑神经可塑性

• 批准号: RGPIN-2020-04706
• 负责人: MacLusky, Neil
• 金额: $ 3.42万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746256
• 关键词: Steroid; induced; Neuroplasticity; Brain

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.

这个实验室的工作重点是压力和性腺类固醇对大脑的影响。1.虽然它已经知道了超过30年，反复的压力可以诱导海马锥体神经元顶端树突，特别是在CA 3子字段的显着重塑，一直是一个相对缺乏的短期，短暂的压力的影响的研究。我们已经发现，在男性，但不是女性，一个单一的手术事件产生了显着减少顶端CA 3锥体神经元树突的长度，可检测到长达两个月后。肾上腺皮质切除术的效果不同于假手术，提示应激X睾酮相互作用;并且通过暴露于饮用水中的合成糖皮质激素地塞米松而瞬时增加循环糖皮质激素浓度不会再现，这仅导致CA 3树突状分支的瞬时截短。我们假设，术后观察到的持续树突状重塑涉及肾上腺糖皮质激素分泌的初始手术相关激活和随后的炎症/修复相关反应。为了验证这一假设，我们将检查大鼠最初短暂暴露于糖皮质激素的形态学效应，有或没有随后的实验诱导的炎症。2.在细胞水平，应激下调了雄激素调节的ERK特异性磷酸酶DUSP 6的表达。有趣的是，睾酮在大脑中的主要代谢产物5a雄甾烷3a 17 β二醇（Adiol）在正常男性中发现的循环Adiol浓度范围内逆转了应激对DUSP 6的影响。在女性中，压力的影响似乎涉及不同的机制，部分通过糖皮质激素抑制G蛋白偶联雌激素受体（GPER）信号传导。我们将研究应激和糖皮质激素治疗在体内的影响，伴随或不伴随性腺类固醇暴露，在DUSP 6，GPER和相关的应激调节蛋白的表达和活性。我们将探讨压力和性腺类固醇在调节大脑中miRNA表达中相互作用的假设。3.环境中的人造化学物质可能会模仿激素的作用，从而扰乱动物生存所需的行为。我们以前报道过，世界上最广泛使用的化学物质之一双酚A（BPA）在非常低的剂量水平下会损害雌激素诱导的海马突触发生。在组织培养条件下，我们发现BPA是脑中GPER激活的有效拮抗剂，对神经元GPER信号传导产生应激样抑制。我们将比较BPA的影响，那些常用的BPA替代品，其对大脑的影响迄今尚未被测试，相关的体内这些化合物对GPER信号的影响，其对海马神经元形态和认知行为。