BDNF-Estrogen Interactions with Perimenopausal Mood and Cognition

BDNF-雌激素与围绝经期情绪和认知的相互作用

• 批准号: 8095064
• 负责人: Teresa A Milner
• 金额: $ 22.53万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095064
• 关键词: Address; Alleles; Animals; Anxiety; Anxiety Disorders; Area; Behavior; Behavioral; Biological Markers; Boxing; Brain; Brain-Derived Neurotrophic Factor; Caucasians; Caucasoid Race; Clinical Treatment; Codon Nucleotides; Cognition; Cognition Disorders; Cognitive; Communication; Development; Drops; Electrons; Estrogen Replacements; Estrogens; Female; Functional disorder; Genes; Genetic Polymorphism; Genotype; Goals; Graafian Follicles; Heterozygote; Hippocampus (Brain); Hormone replacement therapy; Hormones; Human; Impaired cognition; In Situ Hybridization; Incidence; Individual; Lead; Life; Light; Link; Measures; Mediating; Memory; Memory Disorders; Memory impairment; Menopausal Symptom; Menopause; Mental Depression; Messenger RNA; Methionine; Methods; Microscopic; Modeling; Molecular; Mood Disorders; Moods; Mus; Mutation; Neurotrophic Tyrosine Kinase Receptor Type 2; Operative Surgical Procedures; Outcome; Ovarian; Ovariectomy; Perimenopause; Periodicity; Phenotype; Phosphorylation; Play; Population; Postmenopause; Predisposition; Productivity; Protocols documentation; Quality of life; Replacement Therapy; Risk; Rodent; Rodent Model; Role; Signal Transduction; Single Nucleotide Polymorphism; Staging; Synapses; Testing; Valine; Vertebral column; Woman; behavior measurement; chemical reduction; cognitive function; design; experience; falls; immunocytochemistry; improved; interdisciplinary approach; mRNA Expression; neurotrophic factor; neurotropin; novel; object recognition; presynaptic; research study; sex

DESCRIPTION (provided by applicant): Brain derived neurotrophic factor (BDNF) is importantly involved in anxiety, depression and cognitive function. A single nucleotide polymorphism, a valine (Val) to methionine (Met) substitution (Val66Met) in the BDNF gene, results in increased mood and cognitive disorders in both humans and mice. Depression rates rise sharply in women during perimenopause, which is the 7-10 year period before menopause characterized by declining estrogen levels and gradual acyclicity. Evidence from humans and mice that have undergone surgical menopause indicate that estrogen plays a critical role ameliorating anxiety and memory dysfunctions and in modulating the expression of BDNF and its receptor TrkB in the hippocampus, a region critically involved in anxiety and memory. Determining whether disruption of estrogen cyclicity during perimenopause contributes to the greater susceptibility of carriers of Val66Met allele to depression and anxiety disorders and BDNF signaling in the hippocampus has been hampered due to a lack of a rodent model. However, the recent development of a novel model that induces menopause through gradual ovarian cessation now allows for the replication of the perimenopausal period in heterozygote Val66Met mice. Therefore, this proposal will test the central hypothesis that a single copy of Val66Met allele intensifies the mood and memory disorders seen during perimenopause and leads to disruption of BDNF signaling mediated by estrogen in the hippocampus. A multidisciplinary approach combining behavioral measures including open field, object placement and object recognition and quantitative in situ hybridization and light and electron microscopic immunocytochemical methods for the localization of BDNF and TrkB will test this hypothesis. Aim 1 will determine if, after surgical menopause induced by ovariectomy, Val/Met mice experience even greater anxiety and memory problems and less BDNF signaling that Val/Val (control) mice and if these effects can be reversed by estrogen replacement. Aim 2 will determine if during perimenopause disruption of estrogen cyclicity leads to reduced BDNF signaling and increased behavioral instability in anxiety and cognitive tests that are worse in Val/Met than Val/Val mice. Understanding the impact of BDNF genotype and altered estrogen status on mood and cognitive disorders could ultimately lead to clinical treatments that are individualized for sex, genotype and life stage. PUBLIC HEALTH RELEVANCE: In a subpopulation of women, the incidences of anxiety, depression and cognitive dysfunction increase during the transition to menopause (i.e., perimenopause). The proposed studies will use novel rodent models to determine if, during perimenopause, a mutation in the neurotropin brain derived neurotrophic factor (BDNF) gene exacerbates anxiety and cognitive problems and concomitantly alters BDNF communication in the brain. These studies will provide information on the interaction of estrogen and BDNF in affective disorders and could lead to improved hormone replacement therapies to alleviate menopausal symptoms.

描述（由申请人提供）：脑衍生的神经营养因子（BDNF）重要地参与了焦虑，抑郁和认知功能。 BDNF基因中的单个核苷酸多态性，甲氨酸（Val）替代（Val66met），导致人类和小鼠的情绪和认知障碍增加。跨期女性的抑郁率急剧上升，这是更年期的7-10年，其特征是雌激素水平下降和逐渐的超循环。经过手术更年期的人类和小鼠的证据表明，雌激素起着至关重要的作用来缓解焦虑和记忆功能障碍，并调节BDNF及其受体TRKB在海马中的表达，这是一个严重涉及焦虑和记忆的地区。确定雌激素环境中雌激素环节的破坏是否有助于val66met等位基因对抑郁症和焦虑症和海马中BDNF信号的敏感性更大，这是由于缺乏啮齿动物而受到阻碍。然而，最近通过逐渐卵巢戒烟诱导更年期的新型模型的发展现在可以复制杂合子val66met小鼠中的围绝经期。因此，该提案将检验中心假设，即val66met等位基因的单个副本加强了围栏期间看到的情绪和记忆障碍，并导致海马中雌激素介导的BDNF信号传导破坏。一种多学科方法，结合了行为措施，包括开放场，对象放置和对象识别以及定量杂交，光和电子显微镜免疫细胞化学方法用于BDNF和TRKB的定位将检验此假设。 AIM 1将确定在卵巢切除术引起的外科绝经后，Val/MET小鼠是否会经历更大的焦虑和记忆问题，而BDNF信号更少表明Val/Val（对照）小鼠以及是否可以通过雌激素替代来逆转这些作用。 AIM 2将确定雌激素循环性的破坏期间是否会导致BDNF信号传导降低，并且在焦虑和认知测试中的行为不稳定性增加，而在Val/MET中的认知测试比Val/Val小鼠差。了解BDNF基因型和改变雌激素对情绪和认知障碍的影响最终可能导致临床治疗，这些临床治疗是个性化的，基因型和生命阶段。 公共卫生相关性：在妇女的亚群中，焦虑，抑郁和认知功能障碍的发生率在过渡到更年期的过程（即，围绝经期）。拟议的研究将使用新颖的啮齿动物模型来确定神经支出脑衍生的神经营养因子（BDNF）基因是否加剧了焦虑和认知问题，并同时改变了大脑中的BDNF通讯。这些研究将提供有关雌激素和BDNF在情感障碍中相互作用的信息，并可能导致改善激素替代疗法以减轻绝经症状。