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CIRCADIAN SYSTEM AND PRENATAL COCAINE IN ZEBRAFISH

斑马鱼的昼夜节律系统和产前可卡因

基本信息

批准号：
8445305
负责人：
IRINA V. ZHDANOVA
金额：
$ 29.96万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445305
关键词：
Address Adult Affect Age Animals Area Attenuated Behavioral Biological Blood Vessels Brain Bromodeoxyuridine Cell Cycle Cell Proliferation Cell division Circadian Rhythms Cocaine Cocaine Dependence Complementary DNA Confocal Microscopy Control Groups Cyclin A Cyclin-Dependent Kinases Data Development Dopamine Dose Embryo Embryonic Development Evaluation Fertilization Fetal Cocaine Exposure Fishes Forebrain Development Funding Future Gender Gene Expression Genes Genetic Genetic Transcription Genetic Variation Goals Growth Health High Pressure Liquid Chromatography Hormonal Hormones Individual Individual Differences Lead Light Limbic System Link Maintenance Mammals Melatonin Melatonin Receptors Messenger RNA Methods Molecular Morphology Motor Activity Nature Neurons Outcome Pattern Pharmaceutical Preparations Phase Physiologic pulse Physiological Physiological Processes Preventive Process Regulation Research Resources Reverse Transcriptase Polymerase Chain Reaction Rewards Role S Phase Sampling Signal Transduction Sleep Somatotropin Staging Staining method Stains Structure System Systems Development Techniques Telencephalon Testing Therapeutic Time Transgenic Organisms Tubulin Up-Regulation Vascular blood supply Withdrawal Work Zebrafish aged base brain size brain volume circadian pacemaker cocaine exposure combat critical period design dopamine transporter genetic analysis genetic strain improved insight neurogenesis neuron development neuronal patterning novel therapeutic intervention prenatal prevent prophylactic response sample collection

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed project is to establish the role of the circadian system in the prenatal effects of cocaine exposure during a critical period of embryonic brain development in a diurnal vertebrate, zebrafish. These studies will be based on the results of the previous 3-year funding period, which established a reciprocal relationship between the cocaine and zebrafish clock system, found that melatonin can counteract the effects of cocaine on brain development, identified two strains with contrasting effects of cocaine on circadian system and behavioral effects of cocaine, and characterized the behavioral and molecular effects of cocaine and cocaine withdrawal in adult and aged zebrafish of both genders. The continuation of this research will specifically focus on characterization of the effects of cocaine and circadian clock system on brain development, and address the hypothesis that reciprocal interaction between the two is due to their contrasting effects on neuronal proliferation during early stages of brain formation. The Specific Aims will address: 1) In-depth characterization of the effects of early cocaine and melatonin exposure on zebrafish brain development and gene expression; 2) An impact of the earlier identified genetic variation in circadian response to cocaine on the effects of prenatal cocaine and melatonin exposure; 3) The role of circadian deficits in the prenatal brain development and effects of cocaine, and whether exogenous melatonin can counteract these effects. Zebrafish will be exposed to cocaine during the major periods of cortical (pallium) and limbic system (dorsomedial and dorsolateral telencephalon) development, synchronized with either the nighttime or daytime circadian phase. Melatonin will be administered prior to cocaine at different circadian phases, in embryos with normal and deficient circadian system. The brain size, cell division rate, dopamine levels, expression of the circadian genes and those encoding for the melatonin receptors, dopamine transporter, cyclin-dependent kinases, cyclin A and growth hormone will be evaluated throughout development and maturation. The time of development and integrity of the neuronal ensembles will be evaluated in transgenic fish with fluorescent markers for alpha-1-tubulin and f-spondin. The cocaine-induced changes in the locomotor activity and sleep will be documented during early post-natal period. Understanding the role of the circadian factors in brain development and mechanisms through which they attenuate prenatal effects of cocaine, should help to design preventive and therapeutic strategies to counteract prenatal cocaine impact on early brain development or subsequent changes in brain functions.

描述（由申请人提供）：拟议项目的目标是在昼夜活动的脊椎动物斑马鱼胚胎大脑发育的关键时期，确定昼夜节律系统在可卡因暴露的产前影响中的作用。这些研究将基于前3年资助期的结果，这些结果建立了可卡因和斑马鱼时钟系统之间的相互关系，发现褪黑激素可以抵消可卡因对大脑发育的影响，确定了可卡因对昼夜节律系统和可卡因对行为影响的两种毒株。研究了可卡因和可卡因戒断对成年和老年斑马鱼的行为和分子效应。本研究的继续将特别关注可卡因和生物钟系统对大脑发育的影响的特征，并解决两者之间的相互作用是由于它们在大脑形成早期阶段对神经元增殖的不同影响的假设。具体目标将解决：1)深入表征早期可卡因和褪黑激素暴露对斑马鱼大脑发育和基因表达的影响；2)早期发现的可卡因昼夜反应遗传变异对产前可卡因和褪黑激素暴露的影响；3)昼夜节律缺陷在产前脑发育中的作用和可卡因的影响，以及外源性褪黑激素是否可以抵消这些影响。斑马鱼将在皮层（苍白质）和边缘系统（背内侧和背外侧端脑）发育的主要时期暴露于可卡因，与夜间或白天的昼夜节律阶段同步。褪黑素将在不同的昼夜节律阶段，在正常和缺乏昼夜节律系统的胚胎中施用于可卡因之前。大脑大小、细胞分裂率、多巴胺水平、昼夜节律基因的表达以及褪黑激素受体、多巴胺转运体、周期蛋白依赖激酶、周期蛋白A和生长激素的编码将在整个发育和成熟过程中进行评估。用α -1-微管蛋白和f-spondin荧光标记来评价转基因鱼神经元群的发育时间和完整性。可卡因引起的运动活动和睡眠的变化将在产后早期被记录下来。了解昼夜节律因素在大脑发育中的作用，以及它们减弱可卡因产前影响的机制，应该有助于设计预防和治疗策略，以抵消产前可卡因对早期大脑发育或随后大脑功能变化的影响。