Serotonin and the Modulation of Brain Development

描述（由申请人提供）：血清素转运体（SERT）是情绪功能的关键调节剂，在大脑发育期间作为生长调节剂和更成熟大脑中的神经递质发挥作用。它是许多抗抑郁药的主要分子靶点，特别是5-羟色胺选择性再摄取抑制剂（SSRIs），它被用作许多精神疾病的一线治疗。SSRIs增加了多巴胺能神经紧张，这种作用被认为是介导其治疗作用的。奇怪的是，SERT基因表达减少会增加成年人、灵长类动物和啮齿类动物的情感和焦虑样行为的风险。遗传受损的SERT小鼠的异常行为通过早期暴露于SERT阻断剂如氟西汀、氯丙咪嗪和西酞普兰而重现。这些研究结果表明，血清素在大脑系统的成熟，调节成人的情绪功能的关键作用，并提出了一个发展机制，以解释如何低表达SERT启动子等位基因增加精神疾病的脆弱性。此外，这些研究结果表明，胎儿在怀孕期间或儿童早期暴露于SSRIs可能会增加日后患精神疾病的风险。在这个应用程序中，我们提出了几个实验，增加我们的理解的作用，血清素在调节大脑发育。我们研究的“关键时期”的发展是敏感的SERT抑制。我们定义的异常的大脑结构，连接和生理，可能是成年人的异常。我们还确定了行为，解剖学和生理异常，从短暂的，早期暴露于SERT抑制剂的发展轨迹。通过这些研究获得的知识应该会导致更好地了解5-羟色胺在大脑发育过程中的功能，并有助于了解由于SERT功能的发育扰动可能引起的情感和焦虑障碍的潜在病理生理学。血清素的变化可能会影响生命早期大脑的连接方式。这项提案的目的是了解5-羟色胺转运蛋白的抑制如何影响大脑发育和行为。这些结果对怀孕期间抗抑郁药的使用以及理解某些基因变异如何使抑郁症和焦虑症易感具有意义。

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.