Preclinical evidence suggests that the actions of ovarian steroid hormones and brain-derived neurotrophic factor (BDNF) are highly convergent on brain function. Studies in humanized mice document an interaction between estrus cycle-related changes in estradiol secretion and BDNF Val⁶⁶Met genotype on measures of hippocampal function and anxiety-like behavior. We believe our multimodal imaging data provide the first demonstration in women that the effects of the BDNF Val/Met polymorphism on hippocampal function are selectively modulated by estradiol. In a 6-month pharmacological hormone manipulation protocol, healthy, regularly menstruating, asymptomatic women completed positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans while performing the n-back working memory task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist, leuprolide acetate; leuprolide plus estradiol; and leuprolide plus progesterone. For each of the three hormone conditions, a discovery data set was obtained with oxygen-15 water regional cerebral blood flow PET in 39 healthy women genotyped for BDNF Val⁶⁶Met, and a confirmatory data set was obtained with fMRI in 27 women. Our results, in close agreement across the two imaging platforms, demonstrate an ovarian hormone-by-BDNF interaction on working memory-related hippocampal function (PET: F_2,37=9.11, P=0.00026 uncorrected, P=0.05, familywise error corrected with small volume correction; fMRI: F_2,25=5.43, P=0.01, uncorrected) that reflects differential hippocampal recruitment in Met carriers but only in the presence of estradiol. These findings have clinical relevance for understanding the neurobiological basis of individual differences in the cognitive and behavioral effects of ovarian steroids in women, and may provide a neurogenetic framework for understanding neuropsychiatric disorders related to reproductive hormones as well as illnesses with sex differences in disease expression and course.

中文翻译：

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脑源性神经营养因子 Val66Met 基因型和卵巢类固醇相互作用调节女性工作记忆相关的海马功能：一项多模式神经影像学研究。

临床前证据表明，卵巢类固醇激素和脑源性神经营养因子 (BDNF) 的作用对脑功能高度集中。^{对人源化小鼠的研究记录了发情周期相关的雌二醇分泌变化与 BDNF Val 66}之间的相互作用Met 基因型对海马功能和焦虑样行为的测量。我们相信我们的多模态成像数据首次在女性中证明了 BDNF Val/Met 多态性对海马功能的影响是由雌二醇选择性调节的。在为期 6 个月的药理学激素操作方案中，健康、定期月经、无症状的女性在三种激素条件下执行 n-back 工作记忆任务时完成正电子发射断层扫描 (PET) 和功能磁共振成像 (fMRI) 扫描：卵巢抑制诱导通过促性腺激素释放激素激动剂醋酸亮丙瑞林；亮丙瑞林加雌二醇；和亮丙瑞林加黄体酮。对于三种激素情况中的每一种，⁶⁶ Met，并在 27 名女性中使用 fMRI 获得了验证数据集。我们的结果在两个成像平台上非常一致，证明了卵巢激素与 BDNF 的相互作用对工作记忆相关的海马功能的影响（PET：F 2,37 ₌ 9.11，P = 0.00026 未校正，P = 0.05，家庭错误校正小体积校正；fMRI：F _2,25=5.43，P=0.01，未校正）反映了 Met 携带者海马募集的差异，但仅在雌二醇存在的情况下。这些发现对于了解女性卵巢类固醇对认知和行为影响的个体差异的神经生物学基础具有临床相关性，并可能为理解与生殖激素相关的神经精神疾病以及疾病表现和性别差异的疾病提供神经遗传学框架。课程。