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: 8105151
• 负责人: JAY S SCHNEIDER
• 金额: $ 41.42万
• 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/8105151
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：发育中的大脑是铅特别脆弱的目标，发育性铅暴露会导致认知和运动缺陷，并持续到成年期。尽管几十年来人们一直在研究铅对大脑发育的影响，但我们对于遗传背景和环境如何改变铅对神经系统发育和功能的影响的理解还存在差距。不同的环境环境可能会对大脑对铅的反应产生强大的影响。例如，丰富的环境可能对铅的发育暴露具有潜在的神经保护作用，而贫困的环境可能会加剧神经毒性。除了环境之外，遗传背景也可能会改变发育期铅暴露的结果，尽管目前尚未对此进行系统研究。因此，我们提出的研究有以下具体目标： 具体目标 1. 检查遗传背景对铅诱导的海马行为和分子缺陷的影响。利用基因表达阵列和生物信息学，我们将首先调查海马体的正常发育基因表达谱，海马体是一种已知对通常用于神经科学或毒理学研究的 4 种大鼠的发育性铅毒性敏感的结构。然后，我们将检查发育铅暴露后这些表达谱的变化。我们假设不同遗传背景的老鼠对相似的铅暴露会有不同的行为和基因表达反应。从这项研究中获得的数据将产生第一个铅毒性基因表达数据库，并增进我们对可能受到发育铅暴露干扰的代谢、信号传导和调节途径的理解。关于遗传背景对该毒素反应的影响的信息可能有助于制定新的干预策略。具体目标 2. 评估不同环境改变与发育性铅暴露相关的行为和分子缺陷的程度。这些研究将探讨不同的居住环境对铅引起的空间学习和记忆缺陷以及海马初始候选基因表达（即神经营养因子和 NMDA 受体亚型表达）的影响。我们假设，在社会但贫困的环境中饲养的动物将有更严重的缺陷，而在富裕的环境中饲养的动物将至少部分地受到保护，免受铅暴露的有害影响，无论暴露的剂量或类型如何。我们的研究不仅将检验遗传学在影响铅暴露结果中的作用，而且可能证明铅对大脑的影响并不是一成不变的。基于环境丰富原则的早期干预治疗可能有助于减轻至少一些与铅相关的功能缺陷。公共健康相关性：拟议的研究将通过评估不同类型和水平的发育性铅暴露如何与遗传变异相互作用而导致脑损伤，从而提供关于遗传学在影响发育性铅暴露结果中的作用的新数据。此外，研究不同环境中的饲养如何改变与发育铅暴露相关的行为和分子缺陷可能会证明铅对大脑的影响不是一成不变的，并且基于环境丰富原则的早期干预治疗可能有助于减轻铅的影响。至少有一些与铅相关的功能缺陷。