Serotonin, Corpus Callosum, and Autism

血清素、胼胝体和自闭症

• 批准号: 8066425
• 负责人: RICK C.S. LIN
• 金额: $ 30.02万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066425
• 关键词: Address; Affect; Age; American; Anatomy; Animal Model; Antidepressive Agents; Autistic Disorder; Axon; Behavior; Behavioral; Brain; Cell Culture Techniques; Cerebral hemisphere; Child; Citalopram; Clinical; Communities; Corpus Callosum; Data; Deformity; Development; Discipline of Nursing; Disease; Epidemiology; Etiology; Family; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Future; Guidelines; Immunohistochemistry; Individual; Institution; Lead; Learning; Link; Living Costs; Morbidity - disease rate; Mothers; Myelin; Myelin Sheath; Neurodevelopmental Disorder; Oligodendroglia; Perinatal; Perinatal Exposure; Pervasive Development Disorder; Pharmacology; Physiological; Physiology; Play; Population; Pregnancy; Prevalence; Public Policy; Publishing; Rattus; Regulation; Rehabilitation therapy; Research Design; Research Personnel; Role; Scientist; Selective Serotonin Reuptake Inhibitor; Serotonin; Shapes; Societies; System; Tracer; United States; aged; autism spectrum disorder; base; design; malformation; neurochemistry; postnatal; pup; research study; uptake

DESCRIPTION (provided by applicant): Autism spectrum disorder or Autism (ASD) is among one of the most devastating neurodevelopmental disorders in the United States. The most current epidemiological data have suggested that this disorder may affect as many as 1 in 150 children. Unfortunately, the scientific community is at a loss to explain the increased prevalence of this disorder among the American population in recent years. Based on limited neuropathological and fMRI studies, investigators have been able to determine that the most consistent anatomical abnormality in ASD relates to a reduction in the size of the corpus callosum (a major fiber bundle in the brain which connects the two cerebral hemispheres). In the absence of a suitable animal model for ASD, we have learned that serotonin (5HT) plays a critical role during early brain development, and that 5HT synthesis is altered in autistic individuals at early ages. Importantly, our recently published data and other lines of evidence have revealed that brief perinatal exposure of rat pups to the selective serotonin reuptake inhibitor (SSRI), citalopram, can alter uptake of fluorescent tracer from one cerebral hemisphere to another and lead to malformation of myelin sheaths around callosal axons. Hence, our central hypothesis is that abnormal regulation of 5HT during early brain development compromises oligodendrocyte function and interferes with the establishment of normal interhemispheric connections. To address our hypothesis, multi-disciplinary approaches which include anatomy, immunohistochemistry, physiology, pharmacology, behavior, as well as cell culture will be simultaneously conducted from a group of world leading scientists at three different institutions. These studies are designed to define the possible role of serotonin dysregulation in the genesis of autism and related pervasive developmental disorders. We believe that our proposed exploratory studies hold great promise in identifying a future animal model for ASD, and hold the key to linking serotonin dysfunction during early brain development to increased rates of maternal SSRI usage during pregnancy and nursing. Our findings should 1) shape public policy regarding the identification and rehabilitation of individuals with ASD, and 2) help to establish antidepressant treatment guidelines for new and expectant mothers. Neurodevelopmental disorders have a tremendous impact on our society. At present, autism spectrum disorder (ASD) is among one of the most devastating diseases affecting children in terms of prevalence, morbidity, disruption to family life, and cost to the public. According to the most recent epidemiological data, ~ 1 child in 150 suffers from ASD. However, the etiology of this disorder is largely unknown. Interestingly, ASD is characterized by a reduction in the size of the corpus callosum; a sign of underconnectivity between the two cortical hemispheres. Based on our preliminary data and other lines of evidence, we propose that dysfunction of the raphe serotonin (5HT) system during early development may be one of the most important factors contributing to ASD. The most challenging and clinical relevant aspects of this proposal is our attempt to link recent drastic increase of ASD to the increased number of mothers taking antidepressant drugs, namely selective serotonin reuptake inhibitors (SSRIs), during pregnancy and nursing. Hence, our central hypothesis is that abnormal regulation of 5HT during early brain development interferes with myelin formation and the establishment of normal inter-hemispheric connections. The proposed experiments are designed to address this hypothesis by studying anatomical, neurochemical, physiological, and behavioral effects of perinatal citalopram (the most selective SSRI) exposure on rats aged to postnatal days 22 and >90.

描述（由申请人提供）：自闭症谱系障碍或自闭症（ASD）是美国最具破坏性的神经发育障碍之一。当前最新的流行病学数据表明，这种疾病可能影响150名儿童中的1个。不幸的是，科学界无法解释近年来美国人群中这种疾病的患病率的增加。基于有限的神经病理学和功能磁共振成像研究，研究人员能够确定ASD中最一致的解剖异常与call体大小的降低有关（大脑中的主要纤维束，它连接了两个脑半球）。在没有适合ASD的动物模型的情况下，我们了解到5-羟色胺（5HT）在早期大脑发育过程中起着至关重要的作用，并且在早期自闭症个体中，5HT合成发生了变化。重要的是，我们最近发表的数据和其他证据表明，大鼠幼崽对选择性5-羟色胺再摄取抑制剂（SSRI）的短暂围产期暴露可以改变荧光示踪剂从一个脑半球的吸收，并导致另一个骨蛋白垫子周围的骨髓蛋白鞘膜畸形。因此，我们的中心假设是，早期大脑发育期间5HT的异常调节损害了少突胶质细胞功能，并干扰了建立正常的半球间连接。为了解决我们的假设，包括解剖学，免疫组织化学，生理学，药理学，行为以及细胞培养在内的多学科方法以及细胞培养将同时从三个不同机构的世界领先的科学家那里进行。这些研究旨在定义5-羟色胺失调在自闭症起源和相关普遍发育障碍中的可能作用。我们认为，我们提出的探索性研究在确定ASD的未来动物模型方面具有巨大的希望，并掌握了早期大脑发育期间5-羟色胺功能障碍的关键，与在怀孕和护理期间的孕产妇SSRI使用率提高。我们的发现应1）制定有关ASD患者识别和康复的公共政策，以及2）帮助为新的和预期的母亲制定抗抑郁治疗指南。神经发育障碍对我们的社会产生了巨大影响。目前，自闭症谱系障碍（ASD）是影响儿童的最毁灭性疾病之一，在患病率，发病率，对家庭生活中的破坏以及对公众的成本。根据最新的流行病学数据，约有150名儿童患有ASD。但是，这种疾病的病因在很大程度上是未知的。有趣的是，ASD的特征是call体的大小降低。两个皮质半球之间连接不足的迹象。根据我们的初步数据和其他证据，我们建议在早期开发过程中Raphe 5-羟色胺（5HT）系统的功能障碍可能是导致ASD的最重要因素之一。该提案的最具挑战性和临床相关的方面是，我们试图将ASD最近的急剧增加与服用抗抑郁药的母亲的数量增加，即在怀孕和护理期间选择性羟色胺再摄取抑制剂（SSRIS）。因此，我们的核心假设是，早期大脑发育过程中5HT的异常调节会干扰髓磷脂的形成和正常的半球间连接的建立。该提出的实验旨在通过研究围产期西妥约优兰（最选择性SSRI）对年龄到产后22和> 90的大鼠的解剖学，神经化学，生理和行为影响来解决这一假设。

项目成果

Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats.

• DOI: 10.3389/fncel.2013.00067
• 发表时间: 2013
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Zhang J;Dennis KA;Darling RD;Alzghoul L;Paul IA;Simpson KL;Lin RC
• 通讯作者: Lin RC

Perinatal citalopram exposure selectively increases locus ceruleus circuit function in male rats.

• DOI: 10.1523/jneurosci.3736-11.2011
• 发表时间: 2011-11-16
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Darling RD;Alzghoul L;Zhang J;Khatri N;Paul IA;Simpson KL;Lin RC
• 通讯作者: Lin RC