Neuroendocrine and Neuroimaging Endophenotypes in Postpartum Depression

描述（由申请人提供）：我的长期研究战略作为一个翻译医生，科学家的职业生涯是：发现产后抑郁症（PPD）的神经内分泌和神经影像内表型，翻译结果，开发方法，以确定孕妇在最高风险的发展PPD的基础上生物标志物和开发针对潜在的病理生理学的性别特异性治疗妇女在发展PPD的高风险。抑郁症是疾病负担的主要原因，也是育龄妇女残疾的主要原因35。有PPD病史的妇女，由于未知原因，在随后的怀孕中发展PPD的风险很高36-38。自杀占产后死亡人数的20%。性腺类固醇的差异调节，包括神经活性类固醇（NAS）和？妊娠晚期和产后氨基丁酸（GABA）通过调节皮质边缘功能连接，可能参与PPD的病理生理过程。我的试验数据促使我假设PPD与妊娠期间异常的NAS和GABA调节以及产后异常的皮质GABA和静息状态功能连接（rs-fc）相关。没有研究前瞻性地研究围产期性腺类固醇对PPD中GABA和静息状态功能连接的影响。我的研究结果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志物鉴定的科学知识。据我所知，这是第一个联合GABA MRS/静息态功能连接MRI研究PPD和第一个调查的作用，性类固醇在静息态功能连接（rs-fc）在PD。具体目的1：测定妊娠晚期和产后PPD低危（LR）和高危（HR）人群的血浆NAS和GABA水平。具体目标二：采用磁共振波谱技术，以前扣带皮层（ACC）为种子区，测量HR抑郁和LR非抑郁的产后妇女的前扣带皮层（ACC）和皮质边缘rs-fc的皮质GABA/肌酸。我假设：孕激素的生物合成/代谢途径的异常（由妊娠期间改变的NAS水平证明）将与HR组中妊娠期间和产后的GABA水平降低相关; HR组中妊娠期间和产后的血浆GABA水平降低将与PPD相关; PPD与ACC中皮质GABA降低和边缘区ACC rs-fc降低相关。在拟议的研究计划中讨论了进一步的假设。NIMH K23是这个早期研究者发展成为独立资助的医生-科学家的桥梁（即培训和指导途径）。K23将提高我对生殖内分泌学的认识，重点是开发新的调查技术，并训练我进行神经成像，以调查生殖内分泌系统对抑郁症神经回路的相互作用，从而阐明抑郁症的病理生理学在生殖流动时期，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.