Neuroendocrine and Neuroimaging Endophenotypes in Postpartum Depression

描述(由申请者提供)：我作为一名翻译内科医生兼科学家职业生涯的长期研究战略是：发现产后抑郁(PPD)的神经内分泌和神经成像内表型，将研究结果转化为开发方法，基于生物标记物识别患有PPD最高风险的孕妇，并针对PPD高危女性的潜在病理生理开发针对性别的治疗方法。抑郁症是导致育龄妇女疾病负担和伤残年数减少的主要原因35。有产后抑郁病史的妇女，由于不明原因，患产后抑郁的风险很高，再次怀孕36-38岁。自杀占产后死亡的高达20%39。性腺类固醇激素，包括神经活性类固醇(NAS)和-氨基丁酸(GABA)在妊娠晚期和产后的差异调节，可能通过调节皮质边缘功能连接参与PPD的病理生理学。我的试点数据促使我假设PPD与以下因素有关：怀孕期间NAS和GABA调节异常，以及产后皮质GABA和静息状态功能连接(RS-FC)异常。没有研究前瞻性地调查围产期性腺类固醇对PPD患者GABA和静息状态功能连接性的影响。我的研究发现将填补这一知识空白，并将推进性腺类固醇调节情绪障碍生物标记物识别的科学知识。据我所知，这是第一个PPD的GABA MRS/静息状态功能连接MRI联合研究，也是第一个研究性类固醇在PD的静息状态功能连接(RS-FC)中的作用。目的1：检测PPD低危(LR)和高危(HR)孕妇妊娠晚期和产后血浆NAS和GABA水平。具体目的2：以扣带回前部皮质(ACC)为种子区，测定HR抑郁和LR非抑郁产后妇女的皮质GABA/肌酸比值和皮质边缘rS-Fc。我假设：孕酮生物合成/代谢途径的异常，表现为妊娠期NAS水平的变化，将与妊娠期和产后HR队列中GABA水平的下降有关；HR队列中妊娠和产后血浆GABA水平的下降将与PPD相关；PPD与ACC中皮质GABA的下降和边缘区域的ACC-Fc下降有关。在拟议的研究计划中还讨论了进一步的假设。NIMH K23是这位早期研究人员发展成为独立资助的内科科学家的桥梁(即培训和指导的途径)。K23将提高我对生殖内分泌学的知识，重点是开发新的调查技术，并培训我在神经成像方面研究抑郁症中生殖内分泌系统与神经回路的相互作用，从而阐明生殖流动期间抑郁症的病理生理，目标是开发针对女性性别的治疗方法。

DESCRIPTION (provided by applicant): My long-term research strategy for a career as a translational physician-scientist is to: discover neuroendocrine and neuroimaging endophenotypes in postpartum depression (PPD), translate findings to develop methods to identify pregnant women at highest risk of developing PPD based on biological markers and develop gender-specific treatments targeted to underlying pathophysiology in women at high-risk of developing PPD. Depression is the leading cause of disease burden and years lost to disability for women in their childbearing years35. Women with a history of PPD, for unknown reasons, are at high risk of developing PPD with subsequent pregnancies 36-38. Suicide accounts for up to 20% of postpartum deaths39. Differential regulation of gonadal steroids, including neuroactive steroids (NAS), and ?-aminobutyric acid (GABA) during late pregnancy and the postpartum, via modulation of corticolimbic functional connectivity, may be involved in the pathophysiology of PPD. My pilot data prompted me to hypothesize that PPD is associated with: abnormal NAS and GABA regulation during pregnancy and abnormal postpartum cortical GABA and resting-state functional connectivity (rs-fc). No study has prospectively investigated the effect of perinatal gonadal steroids on GABA and resting-state functional connectivity in PPD. My research findings will fill this knowledge gap and will advance scientific knowledge of biomarker identification in gonadal steroid-modulated mood disorders. To my knowledge, it is the first combined GABA MRS/resting-state functional connectivity MRI study in PPD and the first to investigate the role of sex steroids in resting-state functional connectivity (rs-fc) in PD. Specific Aim 1: To measure plasma NAS and GABA in late pregnancy and in the postpartum in those at low-risk (LR) and high-risk (HR) for PPD. Specific Aim 2: To measure cortical GABA/Creatine with magnetic resonance spectroscopy in the anterior cingulate cortex (ACC) and corticolimbic rs-fc in HR depressed and LR non- depressed postpartum women using the ACC as a seed area. I hypothesize that: abnormalities in the biosynthetic/metabolic pathway of progesterone, evidenced by altered NAS levels during pregnancy will be associated with decreased GABA levels during pregnancy and in the postpartum in the HR cohort; decreased plasma GABA levels in HR cohort both during pregnancy and the postpartum will be associated with PPD; PPD is associated with decreased cortical GABA in the ACC and decreased ACC rs-fc with limbic areas. Further hypotheses are discussed in the proposed research plan. The NIMH K23 is the bridge (i.e. pathway for training and mentorship) for this early stage investigator to develop into an independently-funded physician- scientist. The K23 will advance my knowledge of reproductive endocrinology with an emphasis on developing novel investigative techniques and train me in neuroimaging to investigate the interactions of the reproductive endocrine system on neural circuitry in depression so to elucidate the pathophysiology of depression during times of reproductive flux with the goal of developing gender-specific treatments in women.