Environment and Gene Effects on Brain and Behavior

环境和基因对大脑和行为的影响

• 批准号: 8291304
• 负责人: JAY S SCHNEIDER
• 金额: $ 35.06万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291304
• 关键词: Acute; Adult; Affect; Animals; Area; Astrocytes; Attention; Attenuated; Behavior; Behavioral; Bioinformatics; Brain; Brain Chemistry; Brain Injuries; Candidate Disease Gene; Child; Chronic; Cognitive deficits; Data; Databases; Development; Dose; Early treatment; Emotional; Environment; Exposure to; Female; Frequencies; Gender; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Variation; Genotype; Geography; Hippocampus (Brain); Hispanics; Housing; Human; Intervention; Knowledge; Laboratories; Lead; Lead Poisoning; Learning; Memory; Metabolic Pathway; Microarray Analysis; Modification; Molecular; Molecular Profiling; N-Methyl-D-Aspartate Receptors; Neurosciences; Neurotoxins; Outcome; Porphobilinogen Synthase; Predisposition; Race; Rat Strains; Rattus; Regulatory Pathway; Reporting; Research; Role; Signal Pathway; Socioeconomic Status; Structure; Surveys; Toxic effect; Toxicokinetics; Toxicology; Toxin; base; blood lead; brain behavior; cDNA Arrays; environmental enrichment for laboratory animals; gene environment interaction; lead exposure; male; motor deficit; nervous system development; neurochemistry; neurotoxicity; neurotrophic factor; novel; response; sex; social

The developing brain is a particularly vulnerable target for lead with developmental lead exposure resulting in cognitive and motor deficits that persist into adulthood. Although the effects of lead on the developing brain have been studied for decades, there are gaps in our understanding of how genetic background and environment may modify lead's influences on nervous system development and function. Different environmental milieus may have powerful effects on the response of the brain to lead. For example, environmental enrichment could have potential neuroprotective effects against developmental exposure to lead whereas an impoverished environment may exacerbate the neurotoxicity. In addition to environment, genetic background may also modify the outcome from developmental lead exposure, although at this point, this has not been examined systematically. Thus, our proposed research has the following specific aims: Specific Aim 1. Examine the influence of genetic background on lead induced behavioral and molecular deficits in the hippocampus. Using gene expression arrays and bioinformatics, we will first survey the normal developmental gene expression profile for the hippocampus, a structure known to be sensitive to developmental lead toxicity in 4 strains of rats typically used for neuroscience or toxicology studies. We then will examine changes in these expression profiles following developmental lead exposure. We hypothesize that rats of different genetic backgrounds will have different behavioral and gene expression responses to similar lead exposures. Data derived from this study will lead to the first gene expression database for lead toxicity and advance our understanding of the metabolic, signaling and regulatory pathways that may be disturbed by developmental lead exposure. Information on the influence of genetic background on the response to this toxin may help in development of new strategies for intervention. Specific Aim 2. Assess the extent to which different environments modify behavioral and molecular deficits associated with developmental lead exposure. These studies will examine the effects of different housing environments on lead-induced deficits in spatial learning and memory and initial candidate gene expression (i.e., neurotrophic factor and NMDA receptor subtype expression) in the hippocampus. We hypothesize that animals raised in a social but impoverished environment will have more severe deficits and that animals reared in enriched environments and that the latter will be at least partially protected against the detrimental effects of lead exposure regardless of dose or type of exposure. Our research will not only examine the role of genetics in influencing the outcome from lead exposure but may demonstrate that the effects of lead on the brain are not immutable. Early intervention with therapy based on the principles of environmental enrichment might prove useful for attenuating at least some lead-related functional deficits. The proposed research will provide new data on the role of genetics in influencing the outcome from developmental lead exposure by assessing how different types and levels of developmental lead exposure interacts with genetic variation to result in brain damage. Additionally, examination of how rearing in different environments modify behavioral and molecular deficits associated with development lead exposure may demonstrate that the effects of lead on the brain are not immutable and that early intervention with therapy based on the principles of environmental enrichment might prove useful for attenuating at least some lead-related functional deficits.

发育中的大脑是铅的特别脆弱的目标，并导致发育范围的铅暴露导致 认知和运动缺陷一直持续到成年。虽然铅对发育中的大脑的影响 已经研究了数十年，我们对遗传背景和如何 环境可能会改变铅对神经系统发展和功能的影响。不同的 环境环境可能会对大脑对领导的反应产生强大的影响。例如， 环境富集可能具有潜在的神经保护作用，以防止发育暴露在铅中 而贫穷的环境可能会加剧神经毒性。除了环境，遗传 背景还可以改变发展铅暴露的结果，尽管此时， 没有系统地检查。因此，我们拟议的研究具有以下特定目的：特定目标 1。检查遗传背景对铅引起的行为和分子缺陷的影响 海马。使用基因表达阵列和生物信息学，我们将首先调查正常发育 海马的基因表达谱，该结构已知对发育铅毒性敏感 在4种通常用于神经科学或毒理学研究的大鼠菌株中。然后，我们将检查这些变化 发育铅暴露后的表达曲线。我们假设不同遗传的大鼠 背景将对相似的铅暴露具有不同的行为和基因表达反应。数据 从这项研究中得出的将导致第一个基因表达数据库，以促进铅毒性并推动我们的 了解可能受到发展的代谢，信号传导和调节途径 铅接触。遗传背景对这种毒素反应的影响的信息可能有助于 制定新的干预策略。特定目标2。评估不同程度的不同 环境改变了与发育铅暴露有关的行为和分子缺陷。这些 研究将研究不同住房环境对铅诱导的空间学习缺陷的影响 记忆和初始候选基因表达（即神经营养因子和NMDA受体亚型 在海马中表达）。我们假设动物在社会中饲养但贫穷 环境将有更严重的赤字，并且在丰富的环境中饲养的动物，并且 无论剂量或 曝光类型。我们的研究不仅会研究遗传学在影响铅结果中的作用 暴露，但可能表明铅对大脑的影响是不可变的。早期干预 基于环境富集原理的治疗可能对衰减至少一些 与铅相关的功能缺陷。拟议的研究将提供有关遗传学在影响遗传学作用的新数据 通过评估不同类型和水平的发展，发育铅暴露的结果 发育铅暴露与遗传变异相互作用，导致大脑 损害。此外，检查不同环境中的饲养方式 与发育铅暴露相关的行为和分子缺陷可能 证明铅对大脑的影响是不可变的，并且早期 基于环境富集原理的治疗干预可能 事实证明，至少衰减一些与铅相关的功能缺陷有用。