Estrogen Signaling and Synaptogenesis in Hippocampus: The Role of BDNF

描述(申请人提供)：这项拟议研究的长期目标是阐明雌二醇提高雌性啮齿动物海马树突棘和突触密度以及海马区依赖行为表现的机制。这一建议解决了神经营养素，即脑源性神经营养因子(BDNF)，在海马体中介导雌二醇作用的假设。在第一个特定目标中，我将利用先前在体外和/或体内大鼠海马体中被雌二醇增加的终点，来表征小鼠海马区对卵巢激素生理水平的反应：激活蛋白翻译中介Akt，激活肌动蛋白解聚中介LIMK，以及突触前囊泡蛋白Synaptophysin的表达。为了做到这一点，我将使用定量免疫细胞化学来检测小鼠发情周期中雌激素水平高和低的小鼠海马体中的这些终点。在第二个具体目标中，我将使用BDNF缺乏的小鼠模型来确定BDNF是否介导了卵巢激素对这些终结点的影响。使用与第一个目的相同的定量免疫细胞化学技术，我将确定与野生型小鼠相比，BDNF缺陷小鼠是否保留了卵巢激素对上述终点的影响。最后，在第三个具体目标中，我将确定BDNF是否在卵巢激素对海马体功能的影响中起重要作用。为了评估BDNF对先前报道的发情周期波动在海马体依赖记忆中的作用，我们将在发情周期的高、低雌二醇阶段对野生型小鼠和BDNF缺陷小鼠进行物体放置记忆。雌激素对女性心理健康的影响表现在对精神障碍的易感性方面存在性别差异，卵巢激素对情绪和认知的短期调节，以及绝经后抑郁和认知能力下降的风险增加。这项拟议的研究将调查卵巢激素对雌性小鼠海马体的影响，海马体是大脑的一部分，与包括抑郁症和痴呆症在内的精神疾病有关。这项研究将研究BDNF分子在卵巢激素影响中的作用，因为该分子以前曾与包括抑郁症在内的精神疾病有关。这些发现将揭示自然和药理卵巢激素调节大脑功能的可能机制，影响月经周期和寿命期间精神疾病和痴呆症的易感性。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to elucidate the mechanisms by which estradiol enhances hippocampal dendritic spine and synapse density and performance of hippocampus-dependent behaviors in female rodents. This proposal addresses the hypothesis that the neurotrophin, brain-derived neurotrophic factor (BDNF), mediates estradiol's actions in the hippocampus. In the first specific aim, I will to characterize the response of the mouse hippocampus to physiologic levels of ovarian hormones, using endpoints previously demonstrated to be increased by estradiol in vitro and/or in vivo rat hippocampus: activation of the mediator of protein translation Akt, activation of the mediator of actin depolymerization LIMK, and expression of the presynaptic vesicle protein synaptophysin. To do this, I will use quantitative immunocytochemistry to examine these endpoints in the mouse hippocampus at high- and low- estradiol phases of the mouse estrous cycle. In the second specific aim, I will determine whether BDNF mediates the effects of ovarian hormones on these endpoints using a mouse model of BDNF deficiency. Using the same quantitative immunocytochemical techniques as in the first aim, I will determine whether the effects of ovarian hormones on the above endpoints are preserved in BDNF-deficient mice compared to wild-type mice. Finally, in the third specific aim, I will determine whether BDNF is important for the effects of ovarian hormones on hippocampal function. To assess the contribution of BDNF to previously reported estrus cycle fluctuations in hippocampus-dependent memory, object placement memory will be performed on wild-type mice and BDNF-deficient mice at high- and low- estradiol phases of the estrus cycle. The influence of estrogens on mental health in women is suggested by gender differences in susceptibility to mental disorders, short-term modulation of mood and cognition by ovarian hormones, and increased risk of depression and cognitive decline after menopause. The proposed studies will investigate the effects of ovarian hormones on the female mouse hippocampus, a part of the brain implicated in psychiatric disorders including depression and dementia. The studies will examine the role of the BDNF molecule in the effects of ovarian hormones, as this molecule has previously been linked to psychiatric disorders including depression. The findings will reveal possible mechanisms by which natural and pharmacological ovarian hormones modulate brain function, influencing susceptibility to psychiatric disorders and dementia across the menstrual cycle and lifespan.