Serotonin and the Modulation of Brain Development

描述(申请人提供)：5-羟色胺转运体(SERT)是情绪功能的关键调节因子，在大脑发育过程中既是生长调节器，也是更成熟大脑中的神经递质。它是许多抗抑郁药物的主要分子靶点，特别是5-羟色胺选择性再摄取抑制剂(SSRIs)，这些药物被用作治疗许多精神疾病的一线药物。SSRI增加5-羟色胺能张力，这一效应被认为是它们的治疗作用的中介。矛盾的是，在成年人类、灵长类动物和啮齿动物中，SERT基因表达的降低增加了情感和焦虑样行为的风险。遗传受损的SERT小鼠的异常行为可通过早期暴露于SERT阻滞剂如氟西汀、氯丙咪嗪和西酞普兰来重现。这些发现表明，5-羟色胺在调节成人情绪功能的大脑系统成熟过程中发挥了关键作用，并提出了一种发育机制，以解释低表达的SERT启动子等位基因如何增加精神疾病的易感性。此外，这些发现表明，胎儿在怀孕期间或儿童早期接触SSRIs可能会增加以后生活中精神疾病的风险。在这个应用中，我们提出了几个实验，以增加我们对5-羟色胺在调节大脑发育中所起的作用的理解。我们研究对SERT抑制敏感的发育的“关键期”。我们定义了大脑结构、连通性和生理的异常，这些异常可能是成人异常的基础。我们还确定了行为、解剖和生理异常的发展轨迹，这些异常是由于短暂的早期接触SERT抑制剂而引起的。通过这些研究获得的知识应有助于更好地理解5-羟色胺在大脑发育过程中的作用，并有助于了解由于SERT功能发育障碍而可能出现的情感障碍和焦虑障碍的潜在病理生理学。在生命早期，5-羟色胺的变化可能会影响大脑自我连接的方式。这项建议的目标是了解抑制5-羟色胺转运体如何影响大脑发育和行为。这一结果对于在怀孕期间使用抗抑郁药物以及了解某些基因变异如何易患抑郁症和焦虑症具有重要意义。

DESCRIPTION (provided by applicant): The serotonin transporter (SERT) is a critical regulator of emotional function that acts both during brain development as a growth modulator and as a neurotransmitter in the more mature brain. It is the primary molecular target for many antidepressants, especially the serotonin selective reuptake inhibitors (SSRIs), which are used as a first- line treatment for a number of psychiatric conditions. SSRIs increase serotonergic tone, and this effect is thought to mediate their therapeutic actions. Paradoxically, genetically reduced SERT expression increases the risk for affective- and anxiety-like behaviors in adult humans, primates, and rodents. The abnormal behaviors of genetically-impaired SERT mice are recapitulated by early life exposure to SERT-blocking agents such as fluoxetine, clomipramine, and citalopram. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing SERT promoter alleles increase vulnerability to psychiatric disorders. Moreover, these findings suggest that fetal exposure to SSRIs during pregnancy or early childhood may increase the risk of psychiatric disorders later in life. In this application, we propose several experiments that increase our understanding of the role serotonin plays in modulating brain development. We examine "critical periods" of development that are sensitive to SERT inhibition. We define the abnormalities of brain structure, connectivity, and physiology that may underlie the adult abnormalities. We also determine the developmental trajectory of behavioral, anatomical, and physiological abnormalities that arise from brief, early exposure to SERT inhibitors. The resulting knowledge obtained by these studies should lead to a better understanding of how serotonin functions during brain development and help inform the underlying pathophysiology of affective and anxiety disorders that may arise due to developmental perturbations in SERT function. Changes in serotonin may affect the way the brain wires itself together during early life. The goal of this proposal is to understand how inhibition of the serotonin transporter affects brain development and behavior. The results have implications for the use of antidepressants during pregnancy and for understanding how certain gene variants predispose to depression and anxiety disorders.