Role of epigenetics on long-lasting behavioral and gene-expression changes following neonate exposure to antidepressants

表观遗传学对新生儿接触抗抑郁药后长期行为和基因表达变化的作用

• 批准号: 9976550
• 负责人: Loren Keith Henry
• 金额: $ 20.56万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9976550
• 关键词: ATAC-seq; Address; Adolescent; Adult; Animals; Antidepressive Agents; Anxiety; Behavior; Behavioral; Centers of Research Excellence; ChIP-seq; Chromatin; Chronic; Citalopram; Climacteric; DNA Methylation; Development; Disease; Embryonic Development; Epigenetic Process; Exposure to; Fetal Development; Fetus; Gene Expression; Gene Targeting; Genes; Grant; Health; Hippocampus (Brain); Homeostasis; Human; Knock-out; Long-Term Effects; Mediating; Mental Depression; Mental disorders; Methods; Midbrain structure; Molecular Target; Mothers; Mus; Neonatal; Neuraxis; Neurologic; Neurons; Pharmaceutical Preparations; Physiological; Placenta; Play; Point Mutation; Population; Predisposition; Pregnancy; Pregnant Women; RNA; RNA analysis; Risk; Rodent; Rodent Model; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Structure; Testing; Third Pregnancy Trimester; Time; Transgenic Mice; Work; behavior change; behavioral outcome; bisulfite sequencing; differential expression; early life exposure; epigenomics; genome-wide; histone modification; mRNA Expression; mature animal; methylome; mutant; neonate; neurotransmission; novel; prenatal exposure; resilience; reuptake; serotonin transporter; stress resilience; stressor; transcriptome sequencing

ABSTRACT Depression and anxiety are prevalent during pregnancy and commonly treated with serotonin selective reuptake inhibitor (SSRI) antidepressants. These drugs pass freely from mother to placenta and alter the serotonergic homeostasis in the developing fetus. However, serotonin acts as a trophic factor during embryogenesis and plays an important role in structural development of the central nervous system which has led to a number of studies investigating the short and long-term consequences to the fetus. Multiple rodent models have demonstrated that neonate exposure to SSRIs during a developmentally sensitive time frame equivalent to the 3rd trimester of human pregnancy leads to long-lasting behavioral changes associated with anxiety and depression. These behavioral outcomes in the absence of continued exposure to the SSRI suggests a drug-mediated impact on development through an epigenetic mechanism. This study will investigate this assumption through use a novel transgenic mouse that harbors a mutant serotonin transporter that renders the mouse insensitive to many SSRIs while maintaining normal serotonin transporter and homeostasis. Mice will be evaluated for changes in gene expression, epigenetic marks, and behavior just after SSRI treatment and/or as adult animals. The SSRI-insensitive mouse will provide a critical control to eliminate background effects and pinpoint relevant targets that underlie this phenomenon. Identified targets can then be explored in human populations with the intent of providing a clear understanding of risks involved with SSRI- treatment during pregnancy.

摘要 抑郁和焦虑在怀孕期间很普遍，通常用选择性5-羟色胺治疗 重摄取抑制剂(SSRI)抗抑郁药。这些药物可以自由地从母亲传给胎盘，并改变 发育中胎儿的5-羟色胺能动态平衡。然而，5-羟色胺在体内扮演营养因子的角色 胚胎发生，在中枢神经系统的结构发育中起着重要作用 导致了一些研究，调查了这种药物对胎儿的短期和长期后果。多只啮齿动物 模型已经证明，在发育敏感的时间段内，新生儿接触SSRIs 相当于人类怀孕晚期会导致长期的行为变化，与 焦虑和抑郁。在没有持续暴露于SSRI的情况下，这些行为结果 暗示药物通过表观遗传机制对发育产生影响。这项研究将 通过使用携带突变的5-羟色胺转运体的新型转基因小鼠来研究这一假设 这使得小鼠对许多SSRI不敏感，同时保持正常的5-羟色胺转运体和 动态平衡。之后将对小鼠的基因表达、表观遗传标记和行为的变化进行评估 SSRI治疗和/或作为成年动物。SSRI不敏感的鼠标将提供关键的控制，以消除 背景效果，并准确地指出这一现象背后的相关目标。然后，确定的目标可以 在人群中进行探索，目的是提供对SSRI所涉及的风险的明确了解- 怀孕期间的治疗。