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: 7464168
• 负责人: JAY S SCHNEIDER
• 金额: $ 41.39万
• 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/7464168
• 关键词: Acute; Affect; Animals; Area; Astrocytes; Attention; Attenuated; Behavior; Behavioral; Bioinformatics; Brain; Brain Chemistry; Brain Injuries; Candidate Disease Gene; Child; Chronic; Classification; Cognitive; Data; Databases; Development; Dose; Early Intervention; 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; Microarray Analysis; Modification; Molecular; Molecular Profiling; N-Methyl-D-Aspartate Receptors; Neurosciences; Neurotoxins; Numbers; Outcome; Porphobilinogen Synthase; Predisposition; Public Health; Race; Rat Strains; Rattus; Regulatory Pathway; Reporting; Research; Role; Signal Transduction; Socioeconomic Status; Structure; Surveys; Toxic effect; Toxicokinetics; Toxicology; Toxin; base; blood lead; brain behavior; cDNA Arrays; 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）：发育中的大脑是铅的特别脆弱的目标，并导致铅暴露，导致认知和运动缺陷持续到成年。尽管已经研究了铅对发育中的大脑的影响数十年，但我们对遗传背景和环境如何改变铅对神经系统发展和功能的影响的理解存在差距。不同的环境环境可能会对大脑领导的反应产生强大的影响。例如，环境富集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。除了环境外，遗传背景还可以改变发育铅暴露的结果，尽管此时尚未进行系统的检查。因此，我们提出的研究具有以下特定目的：特定目的1。检查遗传背景对海马中铅诱导的行为和分子缺陷的影响。使用基因表达阵列和生物信息学，我们将首先调查海马的正常发育基因表达谱，该结构已知对4种通常用于神经科学或毒理学研究的大鼠菌株中的发育铅毒性敏感。然后，我们将检查发育铅暴露后这些表达曲线的变化。我们假设不同遗传背景的大鼠将对相似的铅暴露具有不同的行为和基因表达反应。从这项研究得出的数据将导致第一个基因表达数据库，以促进铅毒性，并促进我们对可能受到发育铅暴露的代谢，信号传导和调节途径的理解。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。具体目标2。评估不同环境改变与发育铅暴露相关的行为和分子缺陷的程度。这些研究将研究不同住房环境对海马中的空间学习和记忆中铅诱导的缺陷以及初始候选基因表达（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具有更严重的赤字，并且在丰富的环境中饲养的动物，而后者将至少受到部分保护，以防止铅暴露的有害影响，而不管剂量或暴露类型。我们的研究不仅会检查遗传学在影响铅暴露结果中的作用，而且可以证明铅对大脑的影响并非不可变。基于环境富集原理的治疗的早期干预可能被证明可用于减弱至少一些与铅相关的功能缺陷。公共卫生相关性：拟议的研究将提供有关遗传学在影响发育铅暴露结果中作用的新数据，通过评估不同类型和发育铅暴露的水平与遗传变异的相互作用，从而导致脑损伤。此外，检查在不同环境中饲养如何改变与发育铅暴露相关的行为和分子缺陷可能表明，铅对大脑的影响不可变化，并且基于环境富集原理的治疗早期干预可能会被证明可能对减弱至少一些有铅相关的功能缺陷有用。