Estrogen Signaling and Synaptogenesis in Hippocampus: The Role of BDNF

海马雌激素信号传导和突触发生：BDNF 的作用

• 批准号: 7407057
• 负责人: Joanna Louise Spencer-Segal
• 金额: $ 4.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2010-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407057
• 关键词: Actins; Address; Affect; Affective; Age-associated memory impairment; Alleles; Antidepressive Agents; Area; Behavior; Brain; Brain Injuries; Brain Part; Brain-Derived Neurotrophic Factor; Cell Line; Cells; Chromosome Pairing; Cognition; Cognition Disorders; Cognitive; Defect; Dementia; Dendritic Spines; Densitometry; Diestrus; End Point; Estradiol; Estrogens; Estrous Cycle; Estrus; Female; Gender; Genes; Genetic; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Hippocampus (Brain); Human; Immunohistochemistry; Immunoperoxidase Technics; Impaired cognition; In Vitro; LIMK1 gene; Label; Laboratories; Learning; Link; Longevity; Measures; Mediating; Mediator of activation protein; Memory; Menopause; Menstrual cycle; Mental Depression; Mental Health; Mental disorders; Modeling; Molecular; Mood Disorders; Moods; Mus; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Ovarian hormone; Pathway interactions; Performance; Phase; Physiological; Placement; Play; Predisposition; Proestrus; Protein Biosynthesis; Proteins; Rattus; Regulation; Reporting; Research; Risk; Rodent; Role; Schizophrenia; Sex Characteristics; Signal Pathway; Signal Transduction; Synapses; Synaptophysin; System; Techniques; Testing; Tissues; Transgenic Organisms; Translations; Variant; Vertebral column; Vesicle; Wild Type Mouse; Woman; age related; brain pathway; cofilin; density; dentate gyrus; depolymerization; hippocampal subregions; immunocytochemistry; in vitro Model; in vivo; interest; memory recognition; methionylmethionine; mouse model; neurotrophic factor; non-genomic; polymerization; presynaptic; protein expression; response; stressor; synaptogenesis; valylvaline; young adult

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.

描述（由申请人提供）：拟议的研究的长期目标是阐明雌二醇增强海马树突状脊柱和突触密度的机制，以及雌性啮齿动物中海马依赖性行为的性能。该提议解决了以下假设：神经营养蛋白，脑衍生的神经营养因子（BDNF）介导雌二醇在海马中的作用。 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突触素。为此，我将使用定量免疫细胞化学在小鼠发酵周期的高和低雌二醇阶段检查小鼠海马中的这些终点。在第二个特定目的中，我将使用BDNF缺乏症的小鼠模型来确定BDNF是否介导了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，在BDNF缺陷型小鼠中是否保留了卵巢激素对上述端点的影响。最后，在第三个特定目标中，我将确定BDNF对于卵巢激素对海马功能的影响是否重要。为了评估BDNF对海马依赖性记忆中先前报道的发情周期波动的贡献，将在雌激素的小鼠和BDNF缺陷小鼠的高和低雌二醇阶段对物体放置记忆进行。雌激素对女性心理健康的影响是由性别易感性的性别差异，卵巢激素对情绪和认知的短期调节以及更年后抑郁症和认知能力下降的增加的影响。拟议的研究将研究卵巢激素对雌性小鼠海马的影响，这是大脑的一部分，涉及抑郁症和痴呆在内的精神疾病。研究将研究BDNF分子在卵巢激素作用中的作用，因为该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脑功能的可能机制，从而影响整个月经周期和寿命的精神疾病和痴呆症的敏感性。