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基因中的一种单核苷酸多态性，即缬氨酸（瓦尔）替换为甲硫氨酸（Met）（Val 66 Met），导致人类和小鼠的情绪和认知障碍增加。在围绝经期，即绝经前7-10年，女性的抑郁率急剧上升，其特征是雌激素水平下降和逐渐的非周期性。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中BDNF及其受体TrkB的表达中起着关键作用，海马是一个与焦虑和记忆密切相关的区域。由于缺乏啮齿动物模型，确定围绝经期雌激素周期性的破坏是否有助于Val 66 Met等位基因携带者对抑郁症和焦虑症的更大易感性，以及海马中BDNF信号传导受到阻碍。然而，最近开发的一种新的模型，诱导绝经，通过逐步卵巢停止现在允许复制的围绝经期杂合子Val 66 Met小鼠。因此，这项建议将测试中心假设，即Val 66 Met等位基因的单拷贝加剧了围绝经期期间观察到的情绪和记忆障碍，并导致海马中雌激素介导的BDNF信号传导中断。一个多学科的方法相结合的行为措施，包括开放领域，对象的放置和对象识别和定量原位杂交和光和电子显微镜免疫细胞化学方法的BDNF和TrkB的本地化将测试这一假设。目的1将确定在卵巢切除术诱导的手术绝经后，瓦尔/Met小鼠是否比瓦尔/瓦尔（对照）小鼠经历更大的焦虑和记忆问题以及更少的BDNF信号传导，以及这些作用是否可以通过雌激素替代来逆转。目的2将确定在围绝经期雌激素周期性的破坏是否导致BDNF信号传导减少和焦虑和认知测试中的行为不稳定性增加，所述焦虑和认知测试在瓦尔/Met小鼠中比在瓦尔/瓦尔小鼠中更差。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，最终可能导致针对性别，基因型和生命阶段的个性化临床治疗。 公共卫生相关性：在女性亚群中，焦虑、抑郁和认知功能障碍的发生率在向更年期过渡期间增加（即，围绝经期）。拟议的研究将使用新的啮齿动物模型来确定在围绝经期期间，神经营养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，并同时改变大脑中的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.