Serotonin and the Modulation of Brain Development

血清素和大脑发育的调节

基本信息

批准号：
8197718
负责人：
JAY A GINGRICH
金额：
$ 35.19万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197718
关键词：
Address Adolescent Adult Affect Affective Age Age of Onset Alcoholism Alleles Amygdaloid structure Analysis of Variance Animals Anorexia Nervosa Anterior Antidepressive Agents Antisocial Personality Disorder Anxiety Anxiety Disorders Area Autistic Disorder Behavior Behavioral Behavioral Paradigm Birth Rate Brain Brain region Butyric Acids Cells Citalopram Clomipramine Code Collaborations Corpus striatum structure Data Dendrites Desipramine Development Disease Doctor of Philosophy Dorsal Doxycycline Drug Kinetics Electrodes Electrophysiology (science)Embryo Emotional Etiology Event Exhibits Exposure to Extinction (Psychology)Female Fluoxetine Functional disorder Gene Expression Genes Genetic Genetic Variation Genotype Glutamate Receptor Goals Golgi Apparatus Growth Growth Factor Heterozygote Hippocampus (Brain)Hydroxyindoleacetic Acid Investigation Knock-out Knowledge Laboratories Lead Learning Length Life Link Maps Measurement Measures Mediating Mental Depression Mental disorders Methaqualone Microelectrodes Molecular Target Monoamine Oxidase A Monoamine Oxidase Inhibitors Mood Disorders Morphology Mus Neuraxis Neuroanatomy Neurotransmitters Obsessive-Compulsive Disorder Occupations Pathway interactions Pattern Perinatal Perinatal Exposure Pharmacodynamics Phenotype Physiological Physiology Play Polymerase Chain Reaction Predisposition Pregnancy Primates Principal Investigator Promoter Regions Publications Published Comment Publishing Radial Repression Research Personnel Response to stimulus physiology Risk Rodent Role Scanning Selective Serotonin Reuptake Inhibitor Serotonin Short-Term Memory Signal Transduction Specific qualifier value Specificity Staining method Stains Stress Structure Suggestion Survival Rate Swimming System Testing Tetracyclines Therapeutic Time Training Trans-Activators United States National Institutes of Health Variant Work Writing arm axonal guidance base brain morphology carbon fiber cingulate cortex conditioned fear critical period early childhood early life exposure experience gamma-Aminobutyric Acid genetic manipulation genetic variant in vivo inhibitor/antagonist interest knowledge of results male morris water maze neuropathology neuropsychiatry noradrenaline transporter offspring postnatal programs promoter research study response serotonin transporter tool

项目摘要

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.

描述（由申请人提供）：血清素转运蛋白（SERT）是情绪功能的关键调节剂，在大脑发育过程中充当生长调节剂，并在更成熟的大脑中充当神经递质。它是许多抗抑郁药的主要分子靶点，尤其是选择性血清素再摄取抑制剂（SSRI），它被用作许多精神疾病的一线治疗。 SSRIs 会增加血清素能张力，这种效应被认为可以调节其治疗作用。矛盾的是，SERT 表达基因减少会增加成年人、灵长类动物和啮齿类动物出现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生命早期接触 SERT 阻断剂（如氟西汀、氯米帕明和西酞普兰）来重现。这些发现表明，血清素在调节成人情绪功能的大脑系统成熟中发挥着关键作用，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脆弱性。此外，这些研究结果表明，胎儿在怀孕期间或幼儿期接触 SSRIs 可能会增加以后患精神疾病的风险。在此应用中，我们提出了几个实验，以加深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”。我们定义了可能构成成人异常的大脑结构、连接性和生理学的异常。我们还确定了因短暂、早期接触 SERT 抑制剂而引起的行为、解剖和生理异常的发育轨迹。这些研究获得的知识应该有助于更好地理解血清素在大脑发育过程中如何发挥作用，并有助于了解由于 SERT 功能的发育扰动而可能出现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。该提案的目的是了解抑制血清素转运蛋白如何影响大脑发育和行为。这些结果对于怀孕期间使用抗抑郁药以及了解某些基因变异如何导致抑郁症和焦虑症具有重要意义。