Environment and Gene Effects on Brain and Behavior

发育中的大脑是铅的一个特别脆弱的目标，发育中的铅暴露导致 认知和运动缺陷持续到成年。虽然铅对大脑发育的影响 已经研究了几十年，我们对遗传背景和 环境可能改变铅对神经系统发育和功能的影响。不同 环境环境可能对大脑对铅的反应有强大的影响。例如，在一个示例中， 环境富集可能对发育期铅暴露具有潜在的神经保护作用 而贫瘠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期铅暴露的结果，尽管在这一点上， 没有被系统地检查过。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行为和分子缺陷的影响， 海马体。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的 海马体的基因表达谱，海马体是一种已知对发育铅毒性敏感的结构。 在通常用于神经科学或毒理学研究的4种大鼠品系中。然后，我们将研究这些变化 发育期铅暴露后的表达谱。我们假设不同基因的老鼠 不同背景的人对类似的铅暴露会有不同的行为和基因表达反应。数据 从这项研究中得出的结论将导致第一个铅毒性基因表达数据库，并推进我们的研究。 了解代谢，信号传导和调节途径，可能会受到干扰的发展 铅暴露。关于遗传背景对这种毒素反应的影响的信息可能有助于 制定新的干预战略。具体目标2。评估在多大程度上 环境改变与发育铅暴露相关的行为和分子缺陷。这些 研究将探讨不同的居住环境对铅诱导的空间学习缺陷的影响 以及记忆和初始候选基因表达（即，神经营养因子和NMDA受体亚型 在海马体中表达）。我们假设在社会环境中长大的动物 环境将有更严重的赤字，动物饲养在丰富的环境中， 后者将至少部分地免受铅暴露的有害影响，无论剂量或 暴露的类型。我们的研究不仅将研究遗传学在影响铅的结果中的作用， 这可能表明铅对大脑的影响不是一成不变的。早期干预 基于环境富集原理的治疗可能被证明对于减弱至少一些 铅相关的功能缺陷。这项拟议中的研究将为遗传学在影响人类健康方面的作用提供新的数据。 通过评估不同类型和水平的铅暴露 发育期铅暴露与遗传变异相互作用， 损害此外，研究在不同环境中饲养如何改变 与发育期铅暴露相关的行为和分子缺陷可能 证明铅对大脑的影响不是一成不变的， 基于环境丰富原则的治疗干预可能 证明可用于减弱至少一些与铅相关的功能缺陷。

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.