Estrogen Signaling and Synaptogenesis in Hippocampus: The Role of BDNF

描述（由申请人提供）：本研究的长期目标是阐明雌二醇增强雌性啮齿动物海马树突棘和突触密度以及海马依赖行为表现的机制。该建议提出了神经营养因子，脑源性神经营养因子（BDNF）介导雌二醇在海马中的作用的假设。在第一个具体目标中，我将描述小鼠海马对卵巢激素生理水平的反应，使用之前证明雌二醇在体外和/或体内增加的终点：蛋白质翻译介质Akt的激活，肌动蛋白解聚介质LIMK的激活，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查小鼠发情周期中雌二醇高和低阶段小鼠海马中的这些终点。在第二个具体目标中，我将使用BDNF缺乏的小鼠模型确定BDNF是否介导卵巢激素对这些终点的影响。使用与第一个目标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缺陷小鼠中卵巢激素对上述终点的影响是否保留。最后，在第三个具体目标中，我将确定BDNF对卵巢激素对海马功能的影响是否重要。为了评估BDNF对先前报道的海马依赖性记忆的发情周期波动的贡献，将在发情周期的高雌二醇和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体现在对精神障碍的易感性、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等方面的性别差异。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，与抑郁症和痴呆症等精神疾病有关。这些研究将检查BDNF分子在卵巢激素作用中的作用，因为这种分子以前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学卵巢激素调节大脑功能的可能机制，影响整个月经周期和生命周期对精神疾病和痴呆的易感性。

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.