COCAINE INDUCED DISTURBANCES OF MOUSE BRAIN DEVELOPMENT

可卡因引起小鼠大脑发育障碍

• 批准号: 2634031
• 负责人: BARRY E KOSOFSKY
• 金额: $ 11.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2634031
• 关键词: animal developmental psychology; behavior test; biomarker; brain mapping; cocaine; developmental neurobiology; disease /disorder model; dosage; embryo /fetus toxicology; histogenesis; histopathology; laboratory mouse; neuropsychology; placental transfer; prenatal growth disorder; vibrissae

Between 5-15% of infants born in urban America today have been exposed to cocaine in utero. There is a spectrum of outcomes for "crack kids", with prenatal and postnatal factors influencing the expression of transplacental cocaine effects. Clinical studies have suggested that the single best marker for prenatal cocaine effects, including the postnatal developmental compromise seen in a subset of affected children, is impairment of fetal and postnatal brain growth. We have developed an animal model, in mice, of prenatal cocaine exposure which has allowed us to dissociate the direct effects of cocaine in altering fetal brain development, from the indirect effects associated with cocaine-induced malnutrition. We find that transplacental cocaine exposure independently impairs fetal brain and body growth, results in transient as well as permanent behavioral disturbances in exposed offspring, and results in permanent alterations in neocortical cytoarchitecture. We have proposed experiments to investigate the determinants, correlates and mechanisms underlying these growth, behavioral, and neuropathologic changes. We will use these measures to determine whether cocaine administered during a more restricted gestational period, or at a lower dose, is sufficient to produce alterations in fetal growth and postnatal behavior, and to see whether these features can be dissociated. We propose experiments to identify and quantitate alterations in neocortical structure: a quantitative cytoarchitectonic analysis of the "barrel field" of somatosensory cortex, including measures of cortical thickness, cell density as well as characterization of anatomic markers which reflect alterations in the maturation and precision of anatomic organization of this neocortical region consequent to transplacental cocaine exposure. We propose a series of experiments to map neuronal activation to identify those brain structures and neural systems which are altered in cocaine exposed mice as adults, and which correlate with specific behavioral impairments evident in blocking of second-order aversive conditioning. Information gained from these animal studies should lead to clinical insights regarding gestational exposure to cocaine in humans, fostering improved diagnostics, treatment and prevention of one of the escalating causes of developmental disability in our society.

今天在美国城市出生的婴儿中有5%-15%接触过 子宫内的可卡因。对于“聪明的孩子”来说，有一系列的结果， 影响胎盘蛋白表达的产前和产后因素 可卡因效应。临床研究表明，单一的最好的 产前可卡因效应的标志，包括出生后发育 在一组受影响的儿童中看到的损害，是胎儿的损害 以及出生后的大脑发育。我们已经开发出一种动物模型，在小鼠身上， 产前接触可卡因使我们能够将 可卡因对胎儿大脑发育的影响 与可卡因引起的营养不良有关的影响。我们发现 经胎盘接触可卡因独立损害胎儿大脑和身体 发育，导致暂时性和永久性的行为障碍 在暴露的后代中，并导致新皮质永久性改变 细胞结构。我们已经提出了一些实验来研究 这些增长背后的决定因素、关联和机制， 行为和神经病理改变。我们将利用这些措施来 确定可卡因是否在更严格的妊娠期使用 周期，或在较低的剂量下，足以引起胎儿的改变 生长和出生后行为，并看看这些特征是否可以 解体了。我们建议进行实验来识别和量化变化。 在新皮质结构中：一种定量的细胞构筑分析 躯体感觉皮质的“桶状视野”，包括皮质的测量 厚度、细胞密度以及解剖标记的特征 反映了解剖学的成熟度和精确度的变化 经胎盘引起的这个新皮质区域的组织 接触可卡因。我们提出了一系列实验来映射神经元 激活以识别那些大脑结构和神经系统 在成年后暴露于可卡因的小鼠中发生变化，并与 在二阶阻断中明显的特定行为障碍 厌恶的条件反射。从这些动物研究中获得的信息应该 导致对怀孕期间接触可卡因的临床洞察 人类，促进改进诊断、治疗和预防其中一种 我们社会中不断升级的发展性残疾的原因。