Prenatal stress and antidepressants effects on offspring brain development

 描述（由申请人提供）：越来越多的孕妇被处方选择性5-羟色胺（5-HT）再摄取抑制剂（SSRI）抗抑郁药，以治疗怀孕期间的抑郁症。最近，妊娠早期SSRI治疗与后代生活中不良反应的风险增加有关，例如自闭症谱系障碍（ASD）。上述治疗不能避免不良反应，因为未经治疗的抑郁症和相关的母体压力会影响后代的神经功能结局。此外，流行病学研究不能明确区分药物与母体疾病对发育中的后代大脑的影响。这个项目的目标是机械地分离短期和长期 使用小鼠模型研究母体应激和SSRIs对胎儿脑发育和成人功能的影响。第一个目标是确定胎儿大脑暴露于SSRIs及其代谢物的具体参数，包括胎龄、剂量、暴露持续时间和药物特性的影响。为此目的提出的实验利用了新开发的研究胎盘药物转运的方法;这种独特的专业知识将使我们能够测量母亲和胎儿之间的双向药物转运，以及妊娠不同阶段的胎盘药物积累和代谢。第二个目的是研究产前暴露于母体压力和常用的SSRIs（单独和组合）对胎儿脑结构，神经化学和多巴胺能和丘脑皮质神经元通路形成的影响。实验结合了联合收割机新的高分辨率全胎脑扩散磁共振成像（与约翰霍普金斯大学的Irina Burd博士合作），生物化学和免疫组织化学，以研究暴露时间和持续时间对原位结构和神经元回路形成的影响。第三个目标是确定母体压力和SSRI暴露在不同时期的妊娠对成年后代脑功能的长期影响。拟议的实验使用高度时间分辨微透析的最新进展（与加州大学洛杉矶分校的Anne Andrews博士合作）来确定清醒的成年男性和女性后代腹侧海马体中基础和刺激的细胞外5-HT水平的变化。 与公共卫生的相关性：拟议的研究解决了调查妊娠期间母体压力/抑郁和/或其药物治疗引起的胎儿发育风险的迫切需要，同时进一步定义了影响母体、胎盘和胎儿大脑之间复杂生物相互作用的产前敏感期。从长远来看，这项研究有望改善风险评估，并有助于为孕妇及其后代制定更安全的治疗策略。

 DESCRIPTION (provided by applicant): Increasing numbers of pregnant women are prescribed selective serotonin (5-HT) reuptake inhibitor (SSRI) antidepressants to treat depression during pregnancy. SSRI treatment in early pregnancy has recently been associated with increased risk of adverse effects such as autism spectrum disorder (ASD) later in offspring life. Adverse effects are not avoided by foregoing therapy, as untreated depression and the associated maternal stress affect offspring neurological outcomes. Additionally, epidemiological studies cannot clearly separate medication from maternal disease effects on the developing offspring brain. The goal of this project is to dissociate mechanistically the short- and long-term effects of exposure to maternal stress and to SSRIs on fetal brain development and adult function using a mouse model. The first aim determines the specific parameters of fetal brain exposure to SSRIs and their metabolites, including influence of gestational age, dosage, duration of exposure and identity of the drug. Experiments proposed in this aim take advantage of a newly developed methodology for studying placental drug transport; this unique expertise will permit us to measure bi-directional drug transport between mother and fetus, as well as placental drug accumulation and metabolism at different stages of pregnancy. The second aim investigates the effect of prenatal exposure to maternal stress and commonly used SSRIs (alone and in combination) on fetal brain structure, neurochemistry and serotonergic and thalamocortical neuronal pathway formation. Experiments combine new high-resolution whole fetal brain diffusion magnetic resonance imaging (in collaboration with Dr Irina Burd at Johns Hopkins University), biochemistry and immunohistochemistry to investigate the effects of timing and duration of exposure on structure and neuronal circuit formation in situ. The third aim determines the long-term effects of maternal stress and SSRI exposure at different times of gestation on adult offspring brain function. The proposed experiments use recent advances in highly time-resolved microdialysis (in collaboration with Dr Anne Andrews at UCLA) to determine changes in basal and stimulated extracellular 5-HT levels in ventral hippocampus in awake adult male and female offspring. Relevance to public health: The proposed studies address an urgent need for the investigation of fetal developmental risks that stem from maternal stress/depression and/or its pharmacological treatment during pregnancy, while further defining prenatal sensitive periods that influence complex biological interactions between the mother, placenta and fetal brain. In the long term this research is expected to lead to improved risk assessment, and to help to develop safer therapeutic strategies for pregnant women and their offspring.