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）：脑源性神经营养因子（BDNF）在焦虑、抑郁和认知功能中发挥着重要作用。 BDNF 基因中的单核苷酸多态性，即缬氨酸 (Val) 替换为蛋氨酸 (Met) (Val66Met)，会导致人类和小鼠的情绪和认知障碍增加。女性在围绝经期期间抑郁症发病率急剧上升，围绝经期是绝经前的 7-10 年，其特点是雌激素水平下降和逐渐无周期性。来自经历手术绝经的人类和小鼠的证据表明，雌激素在改善焦虑和记忆功能障碍以及调节海马体中 BDNF 及其受体 TrkB 的表达方面发挥着关键作用，而海马体是与焦虑和记忆密切相关的区域。确定围绝经期期间雌激素周期性的破坏是否会导致 Val66Met 等位基因携带者对抑郁症和焦虑症的易感性增加，并且由于缺乏啮齿动物模型，海马 BDNF 信号传导受到阻碍。然而，最近开发出一种通过逐渐停止卵巢诱导绝经的新模型，现在可以在杂合子 Val66Met 小鼠中复制围绝经期。因此，该提案将检验以下中心假设：Val66Met 等位基因的单个拷贝会加剧围绝经期期间出现的情绪和记忆障碍，并导致海马区雌激素介导的 BDNF 信号破坏。结合行为测量（包括开放场、物体放置和物体识别）以及定量原位杂交以及用于 BDNF 和 TrkB 定位的光和电子显微镜免疫细胞化学方法的多学科方法将检验这一假设。目标 1 将确定在卵巢切除术引起的绝经后，Val/Met 小鼠是否会经历比 Val/Val（对照）小鼠更严重的焦虑和记忆问题以及更少的 BDNF 信号传导，以及这些影响是否可以通过补充雌激素来逆转。目标 2 将确定围绝经期期间雌激素周期性的破坏是否会导致 BDNF 信号减弱以及焦虑和认知测试中的行为不稳定性增加，而 Val/Met 小鼠的焦虑和认知测试行为不稳定性比 Val/Val 小鼠更差。了解 BDNF 基因型和雌激素状态改变对情绪和认知障碍的影响可能最终导致针对性别、基因型和生命阶段的个体化临床治疗。 公共卫生相关性：在女性亚群中，在过渡到更年期（即围绝经期）期间，焦虑、抑郁和认知功能障碍的发生率会增加。拟议的研究将使用新型啮齿动物模型来确定在围绝经期期间，神经营养蛋白脑源性神经营养因子（BDNF）基因的突变是否会加剧焦虑和认知问题，并随之改变大脑中的 BDNF 通讯。这些研究将提供有关情感障碍中雌激素和 BDNF 相互作用的信息，并可能导致改进激素替代疗法以减轻更年期症状。