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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要怀孕期间雌激素水平急剧增加，但很快就会降至孕前水平以下大约 15% 的女性在产后数周至数月内处于压抑状态。被诊断患有情绪和/或焦虑障碍，使产后心理障碍成为最常见的尽管有强有力的证据表明雌激素突然下降。产后可能会导致“雌激素戒断”状态，这与产后症状有关心理障碍方面，很少有研究直接测试产后雌激素戒断对心理障碍的影响。大脑，并且没有人检查产后雌激素戒断对中脑边缘多巴胺的影响因此，该提案的目的是揭示产后雌激素戒断的影响。中脑边缘回路和相关的动机行为。啮齿类动物的激素模拟假怀孕模型使研究人员能够直接测试其影响雌激素戒断对大脑和行为的影响在该模型中，雌激素戒断会增加 ΔFosB，a。伏隔核（NAc）中的长期可塑性调节剂此外，这种神经可塑性变化是。本提案中的实验将检查与动机和情感行为缺陷相关的问题。具体来说，建议减少产后动机/情感变化的新神经机制；产后雌激素撤退期间与雌激素受体的结合降低了腹侧的兴奋性被盖区 (VTA) 多巴胺神经元，导致 NAc 中的多巴胺释放减少， NAc 中 ΔFosB 下游诱导的增加将检验产后的假设。雌激素撤退会减少 NAc 中多巴胺的释放。这些实验将使用快速循环扫描。伏安法测量激素模拟假妊娠后 NAc 中多巴胺的释放。将检验以下假设：减少 VTA 中雌激素受体的结合会增加 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。雌激素撤退期间 VTA 中的受体，并测量 NAc 中细胞类型特异性神经元中的 ΔFosB。目标 3 将检验以下假设：雌激素撤退后 NAc 中的 ΔFosB 增加是在雌激素缺乏的女性中观察到动力下降。这些实验将使用病毒介导的基因。在激素模拟过程中防止NAc中ΔFosB介导的转录的转移方法综上所述，这些实验将检测假怀孕并测量其对动机行为的影响。揭示产后雌激素撤退如何机械地影响中脑边缘大脑回路。最终，这将产生有关围产期雌激素波动如何影响的新信息容易遭受心理障碍。