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，在大脑发育过程中作为生长调节剂和成熟大脑中的神经递质起作用。它是许多抗抑郁药的主要分子靶点，尤其是血清素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增加血清素能张力，这种效应被认为是介导其治疗作用。矛盾的是，在成年人、灵长类动物和啮齿动物中，基因上SERT表达减少会增加情感和焦虑样行为的风险。基因受损的SERT小鼠的异常行为可以通过早期暴露于SERT阻断剂（如氟西汀、氯丙咪嗪和西酞普兰）中重现。这些发现表明血清素在调节成人情绪功能的脑系统成熟中起着关键作用，并提出了一种发育机制来解释低表达SERT启动子等位基因如何增加对精神疾病的易感性。此外，这些研究结果表明，胎儿在怀孕期间或幼儿期接触SSRIs可能会增加以后生活中患精神疾病的风险。在这个应用中，我们提出了几个实验来增加我们对血清素在调节大脑发育中的作用的理解。我们研究了对SERT抑制敏感的发育“关键时期”。我们定义异常的大脑结构，连通性和生理，可能是成人异常的基础。我们还确定了由于短暂、早期暴露于SERT抑制剂而引起的行为、解剖和生理异常的发育轨迹。通过这些研究获得的知识将有助于更好地理解血清素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。5 -羟色胺的变化可能会影响早期大脑的连接方式。这项提议的目的是了解抑制血清素转运体如何影响大脑发育和行为。研究结果对怀孕期间使用抗抑郁药以及了解某些基因变异如何易患抑郁症和焦虑症具有启示意义。

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.