Neuroendocrine and Neuroimaging Endophenotypes in Postpartum Depression

描述（由申请人提供）：作为一名转化医师兼科学家，我的长期研究战略是：发现产后抑郁症（PPD）的神经内分泌和神经影像学内表型，将研究结果转化为基于生物标志物识别PPD高危孕妇的方法，并针对PPD高危妇女的潜在病理生理发展针对性别治疗。抑郁症是育龄妇女疾病负担和因残疾而损失的年数的主要原因35。有产后抑郁症病史的女性，由于未知的原因，在随后的怀孕中患产后抑郁症的风险很高36-38。自杀占产后死亡的20%。性腺类固醇的差异调节，包括神经活性类固醇（NAS）和？-氨基丁酸（GABA）在妊娠晚期和产后通过调节皮质边缘功能连接，可能参与PPD的病理生理。我的试点数据促使我假设PPD与：怀孕期间异常的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）有关。尚未有研究前瞻性地研究围产期性腺激素对PPD中GABA和静息状态功能连通性的影响。我的研究成果将填补这一知识空白，并将推进性腺激素调节的情绪障碍的生物标志物鉴定的科学知识。据我所知，这是PPD中首次联合GABA MRS/静息状态功能连接MRI研究，也是首次研究性类固醇在PD静息状态功能连接（rs-fc）中的作用。特异性目的1：测定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：以前扣带皮层（ACC）为种子区，用磁共振波谱法测量产后HR抑郁和LR非抑郁妇女前扣带皮层（ACC）和皮质边缘rs-fc的GABA/肌酸。我假设：孕酮生物合成/代谢途径的异常，以妊娠期间NAS水平的改变为证据，将与妊娠期间和产后GABA水平的下降有关；妊娠期和产后血浆GABA水平降低与PPD有关；PPD与ACC皮质GABA减少和边缘区ACC rs-fc减少有关。在提出的研究计划中讨论了进一步的假设。NIMH K23是一个桥梁（即培训和指导的途径），让这些早期的研究者发展成为一个独立资助的医生-科学家。K23将提高我在生殖内分泌学方面的知识，重点是开发新的调查技术，并训练我在神经影像学方面研究生殖内分泌系统在抑郁症神经回路中的相互作用，从而阐明生殖通量期间抑郁症的病理生理学，目标是开发针对女性的性别特异性治疗方法。

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.