Examining the Effects of Estradiol on Neural and Molecular Response to Rewards in Perimenopausal-Onset Anhedonia and Psychosis

项目摘要 情感障碍在女性中非常普遍，并与显著的发病率和 死亡率，特别是在生殖过渡时期， 绝经揭开情感障碍的病理生理学是具有挑战性的， 抑郁综合征是异质性的并且具有多种病因。因此，研究旨在 鉴定生物标志物以改善易感性和病程的预测，以及 情感障碍的治疗反应产生了不一致的结果。我们建议 通过研究最初出现在更年期的症状来应对这一挑战 因此有一个共同的内分泌触发。我们认为，研究一个相对 具有相似的症状发作生物学机制的同质组参与者将 增加阐明围绝经期发病症状的发病机制的可能性。这 该提案将使用同步正电子发射断层扫描和功能磁 磁共振成像（PET-MR）检查奖励相关纹状体激活之间的关系 通过fMRI测量和通过[11 C]雷氯必利PET测量的强直性和阶段性纹状体DA活性， 不同严重程度的围绝经期发病（PO）妇女的跨诊断样本 快感缺乏和精神病具体目标1将检查PO快感缺失与 功能磁共振成像和强直性脊柱炎测量精神病症状严重程度和奖励相关纹状体激活 和通过[11 C]雷氯必利PET测量的阶段性纹状体DA活性。具体目标2将检查 与安慰剂相比，雌二醇给药引起的快感缺乏减少之间的关系，以及 与奖励处理相关的PET-MR指标的变化。具体目标3将审查关系 与安慰剂相比，雌二醇引起的PO精神病降低与PET-MR变化之间 与奖励处理相关的指标。我们的核心假设是中脑边缘多巴胺 PO快感缺失和精神病患者的奖赏加工过程中， 雌二醇给药将与神经对奖赏反应的正常化相关 通过fMRI和PET测量纹状体多巴胺功能， 通过fMRI和PET测量的纹状体功能变化将与 PO后快感缺乏和精神病症状严重程度的变化。该项目的成果将 增加我们对更年期快感缺乏和精神病脆弱性的理解 过渡，并有可能提供经过验证的分子成像靶点，以供未来使用 围绝经期发作的精神疾病的新疗法的机制临床试验。

Project Summary Affective disorders are highly prevalent in women and associated with significant morbidity and mortality, particularly during times of reproductive transition, including the transition to menopause. Unraveling the pathophysiology of affective disorders is challenging because depressive syndromes are heterogeneous and have diverse etiologies. Thus, studies aimed at identifying biomarkers to improve the prediction of susceptibility and illness course as well as treatment response in affective disorders have yielded inconsistent results. We propose to address this challenge by studying symptoms that initially present during the menopause transition and thus have a common endocrine trigger. We believe that studying a relatively homogeneous group of participants with similar biological mechanisms of symptom onset will increase the likelihood of elucidating the pathogenesis of perimenopausal-onset symptoms. This proposal will use simultaneous positron emission tomography and functional magnetic resonance imaging (PET-MR) to examine relations between reward-related striatal activation measured by fMRI and tonic and phasic striatal DA activity measured by [11C]raclopride PET in a transdiagnostic sample of women with varying severities of perimenopausal-onset (PO) anhedonia and psychosis. Specific Aim 1 will examine associations between PO anhedonia and psychosis symptom severity and reward-related striatal activation measured by fMRI and tonic and phasic striatal DA activity measured by [11C]raclopride PET. Specific Aim 2 will examine relations between anhedonia reductions due to estradiol administration, relative to placebo, and changes in PET-MR metrics related to reward processing. Specific Aim 3 will examine relations between PO psychosis reductions due to estradiol, relative to placebo, and changes in PET-MR metrics related to reward processing. Our central hypotheses are that the mesolimbic dopamine system is impaired during reward processing in PO anhedonia and psychosis, that the effects of estradiol administration will be associated with normalization of neural responses to rewards measured by fMRI and striatal dopamine functioning measured by PET, and that the degree of change in striatal functioning measured by fMRI and PET will be associated with the magnitude of change in PO anhedonia and psychosis symptom severity. The results of this project will increase our understanding of anhedonia and psychosis vulnerability during the menopause transition and have the potential to deliver validated molecular imaging targets to use in future mechanistic clinical trials of novel treatments for perimenopausal-onset psychiatric disorders.