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：
7999281
负责人：
JAY A GINGRICH
金额：
$ 34.93万
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 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7999281
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）：5-羟色胺转运蛋白（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更成熟的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标，尤其是5-羟色胺选择性再摄取抑制剂（SSRIS），用于多种精神疾病的第一线治疗。 SSRI会增加血清素能的语调，这种作用被认为可以介导他们的治疗作用。矛盾的是，遗传降低的SERT表达增加了成年人，灵长类动物和啮齿动物中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寿命暴露于Sert阻断药（例如氟西汀，氯米帕明和Citalopram）概括。这些发现表明5-羟色胺在调节成年人情绪功能的大脑系统成熟中的关键作用，并提出了一种发展机制来解释低表达SERT启动子等位基因如何增加对精神疾病的脆弱性。此外，这些发现表明，胎儿在怀孕或幼儿期间暴露于SSRIS可能会增加生命后期精神疾病的风险。在此应用中，我们提出了几项实验，以增加对5-羟色胺在调节大脑发育中所起的作用的理解。我们检查了对SERT抑制敏感的发展的“关键时期”。我们定义了可能是成人异常的基础的大脑结构，连通性和生理学的异常。我们还确定了由短暂的早期暴露于SERT抑制剂引起的行为，解剖和生理异常的发育轨迹。这些研究获得的最终知识应更好地理解脑部发育过程中的血清素功能，并有助于告知由于Sert功能中发育扰动而可能引起的情感和焦虑症的潜在病理生理学。 5-羟色胺的变化可能会影响大脑在早期的启动方式。该提案的目的是了解抑制5-羟色胺转运蛋白如何影响大脑发育和行为。结果对怀孕期间抗抑郁药的使用有影响，并了解某些基因变异如何使抑郁症和焦虑症易感性。