Prenatal stress and antidepressants effects on offspring brain development

产前压力和抗抑郁药物对后代大脑发育的影响

• 批准号: 9927684
• 负责人: Alexandre Bonnin
• 金额: $ 41.67万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927684
• 关键词: Address; Adult; Adult Children; Adverse effects; Affect; Age; Antidepressive Agents; Anxiety; Axon; Behavior; Biochemistry; Biogenic Amines; Biological; Blood Circulation; Brain; Chronic; Collaborations; Complex; Development; Diffusion Magnetic Resonance Imaging; Disease; Dose; Drug Exposure; Drug Transport; Experimental Designs; Exposure to; Female; Fetus; Gestational Age; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); Human; Immunohistochemistry; In Situ; Investigation; Kinetics; Lead; Life; Long-Term Effects; Measures; Mental Depression; Mental disorders; Metabolism; Methodological Studies; Methodology; Microdialysis; Mothers; Mus; Neurological outcome; Neurons; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Placenta; Pregnancy; Pregnant Women; Public Health; Research; Resolution; Risk; Risk Assessment; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Stress; Structural defect; Structure; Testing; Therapeutic; Time; Universities; antepartum depression; antidepressant effect; autism spectrum disorder; awake; depressive symptoms; dosage; drinking water; early pregnancy; epidemiology study; experimental study; extracellular; fetal; fetal blood; forced swim test; improved; in vivo; in vivo evaluation; inhibitor/antagonist; male; maternal depression; maternal stress; mouse model; neurochemistry; neuronal circuitry; neurotransmission; offspring; postnatal; pregnant; prenatal; prenatal exposure; prenatal stress; public health relevance; reuptake; stem

 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.

 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。第三个目标确定母体压力和妊娠不同时间接触SSRI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。

项目成果

In Utero Exposure to Citalopram Mitigates Maternal Stress Effects on Fetal Brain Development.

在子宫内接触西酞普兰可减轻母体压力对胎儿大脑发育的影响。

• DOI: 10.1021/acschemneuro.9b00180
• 发表时间: 2019
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Velasquez,JuanC;Zhao,Qiuying;Chan,Yen;Galindo,LigiaCM;Simasotchi,Christelle;Wu,Dan;Hou,Zhipeng;Herod,SkylaM;Oberlander,TimF;Gil,Sophie;Fournier,Thierry;Burd,Irina;Andrews,AnneM;Bonnin,Alexandre
• 通讯作者: Bonnin,Alexandre

Effect of Maternal ±Citalopram Exposure on P11 Expression and Neurogenesis in the Mouse Fetal Brain.

• DOI: 10.1021/acschemneuro.6b00339
• 发表时间: 2017-05-17
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: King JR;Velasquez JC;Torii M;Bonnin A
• 通讯作者: Bonnin A

Simultaneous serotonin and dopamine monitoring across timescales by rapid pulse voltammetry with partial least squares regression.

• DOI: 10.1007/s00216-021-03665-1
• 发表时间: 2021-11
• 期刊: Analytical and bioanalytical chemistry
• 影响因子: 4.3
• 作者: Movassaghi CS;Perrotta KA;Yang H;Iyer R;Cheng X;Dagher M;Fillol MA;Andrews AM
• 通讯作者: Andrews AM

Disrupted placental serotonin synthetic pathway and increased placental serotonin: Potential implications in the pathogenesis of human fetal growth restriction.

胎盘血清素合成途径中断和胎盘血清素增加：对人类胎儿生长受限发病机制的潜在影响。

• DOI: 10.1016/j.placenta.2019.05.012
• 发表时间: 2019
• 期刊: Placenta
• 影响因子: 3.8
• 作者: Ranzil,Suveena;Ellery,Stacey;Walker,DavidW;Vaillancourt,Cathy;Alfaidy,Nadia;Bonnin,Alexander;Borg,Anthony;Wallace,EuanM;Ebeling,PeterR;Erwich,JanJaap;Murthi,Padma
• 通讯作者: Murthi,Padma

Prenatal disruption of blood-brain barrier formation via cyclooxygenase activation leads to lifelong brain inflammation.

• DOI: 10.1073/pnas.2113310119
• 发表时间: 2022-04-12
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1