Ovarian Hormones, Reward Response, and Binge Eating in Bulimia Nervosa: An Experimental Design

项目总结 人类观察研究表明卵巢激素参与了神经性暴食症的神经生物学 (BN)，特别是暴饮暴食的症状：累积起来，似乎是低雌二醇(E2)或黄体酮 (P4)拮抗的E2与暴饮暴食的增加有关。然而，问题是， 卵巢激素对人类BN症状的影响已从动物研究和从 月经周期中荷尔蒙的推定和测量水平发生的行为。是这样的 观察性研究不能得出因果的、机械的联系。此外，为什么卵巢激素会影响 症状出现或波动未知。鉴于卵巢激素，特别是雌二醇，已经明显 对奖赏处理的影响以及与奖赏有关的神经通路和神经递质(如多巴胺)， 雌激素可能通过影响BN中改变的奖赏过程来影响暴饮暴食。因此，我们 假设BN代表一种激素敏感的表型，这种敏感性表现为受损 奖赏反应(即奖赏相关抑制控制缺陷、奖赏敏感度增强、延迟受损 折扣)在低E2的情况下。因为患有BN的妇女代表了患有BN的人口的一个子组 多巴胺活性降低，这是由E2增强的，低E2可能会促进奖励动机的行为 通过多巴胺的戒断而暴饮暴食。我们提出这项概念验证研究是为了检查我们的总体 假设。我们将完成一个为期3个月的纵向的、与动物相似的人内实验设计 在患有BN(N=10)的女性中直接操作卵巢激素的模型：暂时诱导 使用促性腺激素释放激素激动剂的性腺功能减退症，然后在双盲交叉试验中独立添加E2和P4 举止。在操作的每个阶段，受试者将完成暴饮暴食的症状报告和 行为任务和奖赏加工与奖赏反应问卷。我们将完成以下工作 目的：1)量化E2和P4对患有BN的妇女暴饮暴食的直接影响；2)确定 E2关于奖励反应(例如，延迟折扣)和相关因素(例如，行为抑制)；3)：检查 在补充E2前后，奖赏反应与暴饮暴食之间的联系。如果国阵真的代表 作为一种激素敏感的表型，我们将在激素挑战期间看到暴饮暴食的直接变化。 基于我们之前的工作，我们预计会看到E2的有益作用和P4的加重作用。一个 实验设计是我们能够自信地探索卵巢激素对BN的直接影响的唯一方法。 这一高风险的提议有很大的高回报潜力。目标的成功完成将提供 关于E2和P4是否(以及如何)直接影响BN暴饮暴食的指导。这将提供经验性的 研究人员完成一项更大的、假设驱动的机械性试验所需的方向反过来， 为未来神经内分泌、神经生物学和脑活动的研究提供方向 BN中的函数。

PROJECT SUMMARY Human observational studies suggest ovarian hormones are involved in the neurobiology of bulimia nervosa (BN), specifically the symptom of binge eating: cumulatively, it appears that low estradiol (E2) or progesterone (P4) antagonized E2 are associated with increased binge eating. Problematic however, is that the effect of ovarian hormones on BN symptoms in humans has been inferred from animal studies and from changes in behavior occurring with presumed and measured levels of hormones during the menstrual cycle. Such observational studies cannot conclude a causal, mechanistic link. Moreover, why ovarian hormones influence symptom onset or fluctuation is unknown. Given that ovarian hormones, specifically E2, have pronounced effects on reward processing and neuropathways and neurotransmitters (e.g., dopamine) involved in reward, E2 may influence binge eating through its effect on reward processes that are altered in BN. Thus, we hypothesize BN represents a hormone sensitive phenotype and this sensitivity is displayed as an impaired reward response (i.e., reward-related inhibitory control deficits, heightened reward sensitivity, impaired delay discounting) in the context of low E2. Because women with BN represent a subgroup of the population with reduced dopamine activity, which is enhanced by E2, low E2 may promote reward-motivated behaviors such as binge eating via dopamine withdrawal. We propose this proof-of-concept study to examine our overarching hypothesis. We will complete a 3-month longitudinal, within-person experimental design that parallels animal models to directly manipulate ovarian hormones in females with BN (N = 10): temporarily inducing hypogonadism using a GnRH agonist and then addback E2 and P4 independently in a double-blind cross-over manner. During each phase of the manipulation, subjects will complete symptom reports of binge eating and behavioral tasks and questionnaires of reward processing and reward response. We will complete the following aims: 1): Quantify the direct effect of E2 and P4 on binge eating in women with BN; 2): Determine the effect of E2 on reward response (e.g., delay discounting) and related correlates (e.g., behavioral inhibition); 3): Examine the association between reward response and binge eating before and after E2 addback. If BN truly represents a hormone sensitive phenotype, we will see direct change in binge eating during the hormone challenge. Based on our previous work, we expect to see a beneficial effect of E2 and an exacerbating effect of P4. An experimental design is the only way we can confidently explore the direct impact of ovarian hormones on BN. This high-risk proposal has significant potential for high-reward. Successful completion of the aims will provide guidance in regard to if (and how) E2 and P4 directly affect binge eating in BN. This will provide the empirical direction needed for the investigators to complete a larger, hypothesis-driven mechanistic trial, in turn, providing direction for future research addressing neuroendocrine, neurobiological, and brain activity and function in BN.