COCAINE INDUCED DISTURBANCES OF MOUSE BRAIN DEVELOPMENT

可卡因引起小鼠大脑发育障碍

• 批准号: 2121271
• 负责人: BARRY E KOSOFSKY
• 金额: $ 11.23万
• 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/2121271
• 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

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.

今天在美国出生的婴儿中，有5-15％的婴儿暴露于 子宫内可卡因。 “裂缝孩子”有很多结果， 产前和产后因素影响移植的表达 可卡因效应。 临床研究表明，单一的最佳 产前可卡因作用的标记，包括产后发育 在受影响儿童的一部分中看到的妥协是胎儿的损害 和产后大脑的生长。 我们在小鼠中开发了一种动物模型 产前可卡因暴露，使我们能够解离直接 可卡因从间接改变胎儿脑发育的影响 与可卡因诱导的营养不良有关的影响。 我们发现 移植可卡因暴露会独立损害胎儿的大脑和身体 增长，导致瞬态和永久行为干扰 在暴露的后代，并导致新皮质的永久改变 细胞结构。 我们提出了实验，以研究 这些增长的决定因素，相关和机制， 行为和神经病理学的变化。 我们将使用这些措施来 确定在妊娠更严格的妊娠期间是否使用可卡因 时期或较低剂量足以产生胎儿的改变 生长和产后行为，看看这些特征是否可以 解离。 我们建议实验以识别和定量改变 在新皮层结构中：对量化的细胞结构分析 体感皮质的“枪管场”，包括皮质的测量 厚度，细胞密度以及解剖标记的表征 这反映了解剖学成熟和精度的改变 这个新皮层区域的组织 可卡因暴露。 我们提出了一系列绘制神经元的实验 激活以识别那些大脑结构和神经系统 可卡因暴露的小鼠的成年小鼠改变了，这与 特定的行为障碍在阻塞二阶时明显 厌恶条件。 从这些动物研究中获得的信息应该 导致有关妊娠暴露于可卡因的临床见解 人类，促进了改进的诊断，治疗和预防之一 我们社会中发育残疾的不断升级。