Identifying the mechanism by which postpartum estrogen withdrawal impacts mesolimbic brain circuitry and motivated behaviors

确定产后雌激素撤退影响中边缘脑回路和动机行为的机制

• 批准号: 10291568
• 负责人: Laura Elizabeth Been
• 金额: $ 43.91万
• 依托单位: HAVERFORD COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291568
• 关键词: Affect; Affective; Anxiety Disorders; Behavior; Behavioral; Binding; Birth; Brain; Child; Childbirth; Complication; Development; Diagnosis; Disease; Dopamine; Drops; Estrogen Receptors; Estrogens; Etiology; Female; Gene Transfer; Genetic Transcription; Goals; Health; Hormonal; Hormones; Laboratories; Lead; Life; Measures; Mediating; Mediator of activation protein; Menopause; Mental disorders; Modeling; Molecular; Mood Disorders; Mothers; Motivation; Mus; Neuronal Plasticity; Neurons; Nucleus Accumbens; Pathway interactions; Perinatal; Periodicity; Pharmacology; Postpartum Period; Postpartum Women; Pregnancy; Pseudopregnancy; Puberty; Public Health; Research; Research Personnel; Rodent; Scanning; Symptoms; Testing; Time; Translations; Ventral Tegmental Area; Viral; Withdrawal; Woman; behavior measurement; behavior test; behavioral phenotyping; brain behavior; brain circuitry; cell type; dopaminergic neuron; experimental study; motivated behavior; neurochemistry; neuromechanism; novel; postsynaptic; prepregnancy; prevent; programs

PROJECT SUMMARY/ABSTRACT Estrogen levels increase dramatically during pregnancy, but quickly plummet to below pre-pregnancy levels after birth and remain suppressed for weeks to months. During this time, approximately 15% of women are diagnosed with a mood and/or anxiety disorder, making postpartum psychological disorders the most common complication associated with childbirth. Although there is strong evidence that the sudden drop in estrogen following birth can lead to an “estrogen withdrawal” state that is related to the symptoms of postpartum psychological disorders, few studies have directly tested the impact of postpartum estrogen withdrawal on the brain, and none have examined the impact of postpartum estrogen withdrawal on the mesolimbic dopamine circuitry. The objective of this proposal is therefore to uncover how postpartum estrogen withdrawal impacts the mesolimbic circuitry and associated motivated behaviors. A hormone-simulated pseudopregnancy model in rodents allows researchers to directly test the impact of estrogen withdrawal on the brain and on behavior. In this model, estrogen withdrawal increases ∆FosB, a mediator of long-term plasticity, in the nucleus accumbens (NAc). Further, this neuroplastic change is associated with deficits in motivated and affective behaviors. The experiments in this proposal will examine a novel neural mechanism for postpartum changes in motivation/affect; specifically, it is proposed that reduced binding at estrogen receptors during postpartum estrogen withdrawal decreases the excitability of ventral tegmental area (VTA) dopamine neurons, resulting in decreased dopamine release into the NAc and an increase in the downstream induction of ∆FosB in the NAc. Aim 1 will test the hypothesis that postpartum estrogen withdrawal decreases dopamine release into the NAc. These experiments will use fast scan cyclic voltammetry to measure dopamine release in the NAc following a hormone-simulated pseudopregnancy. Aim 2 will test the hypothesis that reducing binding at estrogen receptors in the VTA increases DFosB levels in the NAc during the postpartum period. These experiments will use a pharmacological approach to block estrogen receptors in the VTA during estrogen withdrawal, and measure ∆FosB in cell-type-specific neurons in the NAc. Aim 3 will test the hypothesis that increased ΔFosB in the NAc following estrogen withdrawal is required for the decreased motivation seen in estrogen-withdrawn females. These experiments will use a viral-mediated gene transfer approach to prevent ΔFosB-mediated transcription in the NAc during a hormone-simulated pseudopregnancy and measure the impact on motivated behaviors. Taken together, these experiments will uncover how postpartum estrogen withdrawal mechanistically impacts the mesolimbic brain circuitry. Ultimately, this will yield novel information about how peripartum estrogen fluctuations confer heightened vulnerability to psychological disorders.

项目总结/摘要 雌激素水平在怀孕期间急剧增加，但很快就会下降到怀孕前的水平以下 并在数周到数月内保持抑制。在此期间，大约15%的妇女 被诊断患有情绪和/或焦虑症，使产后心理障碍成为最常见的 与分娩有关的并发症。尽管有强有力的证据表明雌激素的突然下降 出生后可能会导致一个“雌激素戒断”的状态，这是有关产后症状 心理障碍，很少有研究直接测试产后雌激素戒断对女性的影响。 没有人研究过产后雌激素戒断对中脑边缘多巴胺的影响， 电路因此，本提案的目的是揭示产后雌激素戒断如何影响 中脑边缘回路和相关的动机行为。 啮齿类动物中的一种模拟假孕模型使研究人员能够直接测试这种影响 对大脑和行为的影响。在这个模型中，雌激素戒断增加了β-FosB， 长期可塑性的介质，在丘脑核（NAc）。此外，这种神经可塑性变化是 与动机和情感行为的缺陷有关。本提案中的实验将检查 产后动机/情感变化的新神经机制;具体而言，建议减少 在产后雌激素戒断过程中，与雌激素受体的结合降低了腹侧海马的兴奋性。 被盖区（VTA）多巴胺神经元，导致减少多巴胺释放到NAc和 增加NAc中的NAPFosB的下游诱导。目的1将检验产后 雌激素戒断会减少多巴胺释放到NAc中。这些实验将使用快速扫描循环 伏安法来测量NAc中的多巴胺释放，随后进行模拟假高潮。目的2 将检验这一假设，即减少VTA中雌激素受体的结合会增加VTA中DFosB水平。 产后期间的NAc。这些实验将使用药理学方法来阻断雌激素 受体在腹侧被盖区在雌激素戒断，并测量NAc中的细胞类型特异性神经元中的FosB。 目的3将检验以下假设，即雌激素戒断后NAc中ΔFosB的增加是维持NAc的稳定性所必需的。 在雌激素戒断的女性中观察到的动机降低。这些实验将使用病毒介导的基因 转移的方法，以防止Δ FosB介导的转录过程中NAc的模拟 pseudopregularity和测量对动机行为的影响。综合起来，这些实验将 揭示产后雌激素戒断如何机械地影响中脑边缘脑回路。 最终，这将产生关于围产期雌激素波动如何提高 易受心理障碍的影响。