BDNF-Estrogen Interactions with Perimenopausal Mood and Cognition

描述（由申请人提供）：脑源性神经营养因子（BDNF）在焦虑、抑郁和认知功能中起重要作用。BDNF基因中缬氨酸（Val）到蛋氨酸（Met）的替换（Val66Met）的单核苷酸多态性导致人类和小鼠的情绪和认知障碍增加。围绝经期是指绝经前的7-10年，以雌激素水平下降和逐渐不周期性为特征。围绝经期的女性抑郁症发病率急剧上升。来自手术停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的表达方面起着关键作用，海马是焦虑和记忆的关键区域。由于缺乏啮齿动物模型，确定围绝经期雌激素周期的破坏是否有助于Val66Met等位基因携带者对抑郁症和焦虑症以及海马BDNF信号传导的更大易感性受到阻碍。然而，最近发展的一种通过逐渐停止卵巢诱导绝经的新模型现在允许在杂合子Val66Met小鼠中复制围绝经期。因此，本研究将验证一个中心假设，即Val66Met等位基因的单个拷贝会加剧围绝经期的情绪和记忆障碍，并导致海马中雌激素介导的BDNF信号通路中断。多学科方法结合行为学测量，包括开放场，物体放置和物体识别，定量原位杂交以及用于定位BDNF和TrkB的光和电镜免疫细胞化学方法，将验证这一假设。目的1将确定，在卵巢切除术引起的手术绝经后，Val/Met小鼠是否比Val/Val（对照）小鼠经历更大的焦虑和记忆问题，以及更少的BDNF信号，以及这些影响是否可以通过雌激素替代来逆转。目的2将确定围绝经期雌激素周期中断是否会导致BDNF信号传导减少，并增加Val/Met小鼠比Val/Val小鼠在焦虑和认知测试中的行为不稳定性。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，最终可能导致根据性别、基因型和生命阶段进行个体化的临床治疗。

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.