BDNF-Estrogen Interactions with Perimenopausal Mood and Cognition

描述(申请人提供)：脑源性神经营养因子(BDNF)与焦虑、抑郁和认知功能密切相关。BDNF基因中的单核苷酸多态，即Valine(Val)到Met(Met)替换(Val66Met)，会导致人类和小鼠情绪和认知障碍的增加。围绝经期妇女的抑郁率急剧上升，这是绝经前的7-10年，以雌激素水平下降和逐渐无周期为特征。来自人类和经历过手术绝经的小鼠的证据表明，雌激素在改善焦虑和记忆障碍以及调节BDNF及其受体TrkB在海马区的表达方面发挥着关键作用，海马区是与焦虑和记忆密切相关的区域。确定围绝经期雌激素循环性的中断是否导致Val66Met等位基因携带者更容易患抑郁症和焦虑症，以及海马区BDNF信号转导因缺乏啮齿动物模型而受到阻碍。然而，最近开发的一种通过逐渐停止卵巢来诱导更年期的新模型现在允许在杂合子Val66Met小鼠中复制围绝经期。因此，这项提议将检验核心假设，即Val66Met等位基因的单一拷贝会加剧围绝经期出现的情绪和记忆障碍，并导致由雌激素介导的海马区BDNF信号中断。一种结合行为测量(包括开阔场地、物体放置和物体识别)以及定量原位杂交和光镜和电子显微镜免疫细胞化学方法定位BDNF和TrkB的多学科方法将检验这一假说。目的1将确定在卵巢切除引起的手术绝经后，Val/Met小鼠是否经历更严重的焦虑和记忆问题，以及BDNF信号是否比Val/Val(对照)小鼠更少，以及这些影响是否可以被雌激素替代逆转。目的2将确定围绝经期雌激素周期的中断是否会导致BDNF信号的减少和焦虑和认知测试中行为不稳定性的增加，而Val/Met小鼠的情况比Val/Val小鼠更差。了解BDNF基因和雌激素状态改变对情绪和认知障碍的影响，最终可能导致针对性别、基因和生命阶段进行个性化的临床治疗。 公共卫生相关性：在妇女亚群中，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增加。这项拟议的研究将使用新的啮齿动物模型来确定，在围绝经期，神经促进素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，并伴随着改变BDNF在大脑中的沟通。这些研究将提供有关雌激素和脑源性神经营养因子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缓解更年期症状。

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.