Environment and Gene Effects on Brain and Behavior

描述(申请人提供)：发育中的大脑是铅的一个特别脆弱的目标，发育中的铅暴露会导致认知和运动障碍，并持续到成年。虽然铅对大脑发育的影响已经研究了几十年，但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，我们的理解还存在差距。不同的环境环境可能会对大脑对铅的反应产生强烈的影响。例如，环境富集物可能对发育过程中的铅暴露具有潜在的神经保护作用，而贫穷的环境可能会加剧神经毒性。除了环境，遗传背景也可能改变发育铅暴露的结果，尽管在这一点上，这还没有得到系统的研究。因此，我们提出的研究有以下具体目的：具体目的1.检测遗传背景对铅诱导的海马区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，海马体是已知对发育铅毒性敏感的4个品系的大鼠，通常用于神经科学或毒理学研究。然后，我们将研究发育铅暴露后这些表达谱的变化。我们假设，不同遗传背景的大鼠对相似的铅暴露会有不同的行为和基因表达反应。这项研究的数据将导致第一个铅毒性的基因表达数据库，并促进我们对发育铅暴露可能干扰的代谢、信号和调控途径的理解。关于遗传背景对这种毒素反应的影响的信息可能有助于开发新的干预策略。具体目标2.评估不同环境对与发育铅暴露相关的行为和分子缺陷的影响程度。这些研究将考察不同居住环境对铅诱导的空间学习和记忆障碍以及海马区初始候选基因表达(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，而在丰富的环境中饲养的动物将至少部分免受铅暴露的有害影响，无论剂量或暴露类型。我们的研究不仅将考察遗传学在影响铅暴露结果中的作用，还可能证明铅对大脑的影响并不是一成不变的。基于环境富集化原则的早期干预疗法可能对减轻至少部分与铅有关的功能缺陷有用。与公共健康相关：拟议的研究将通过评估不同类型和水平的发育铅暴露如何与遗传变异相互作用导致脑损伤，提供关于遗传学在影响发育铅暴露结果方面的作用的新数据。此外，对在不同环境中成长如何改变与发育铅暴露相关的行为和分子缺陷的研究可能会表明，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可能被证明对减轻至少部分与铅有关的功能缺陷是有用的。

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.