GXE and Cognitive Impairment

铅是一种重金属，在美国和全球范围内引起了极大的公共卫生关注。除了其特征明确的发育神经毒性外，累积铅暴露对成年人也具有神经毒性，并可导致成年人加速、持续的认知能力下降。载脂蛋白E基因（ApoE）在人类中以三种多态性等位基因（ε2、ε3、ε4）存在; ApoE -ε3等位基因（以下简称ApoE 3）是最常见的等位基因。ApoE-ε4等位基因（以下简称为ApoE 4）与阿尔茨海默病风险增加相关，并且即使在没有阿尔茨海默病病理的情况下也会加速认知衰退。海马体是大脑中对学习和记忆，特别是空间学习至关重要的区域。成体海马神经发生是海马齿状回中的成体神经干细胞导致海马中成体神经元的产生和功能整合的过程。这些成人出生的神经元可以影响依赖于海马的学习和记忆。虽然成人神经发生是由各种细胞外刺激，由环境，和神经毒物，包括铅和乙醇调制，有一个缺乏的信息有关的基因-环境相互作用（GXE）对成人神经发生的影响。本研究的重点是铅-遗传背景相互作用对成人神经发生和海马依赖性学习记忆的影响。

Lead is a heavy metal of great public health concern in the US and globally. In addition to its well- characterized developmental neurotoxicity, cumulative lead exposure is also neurotoxic to adults and can lead to accelerated, persistent cognitive decline in adult humans. The apolipoprotein E gene (ApoE) exists as three polymorphic alleles in humans (ε2, ε3, ε4); the ApoE -ε3 allele (simplified as ApoE3 hereafter) is the most common allele. The ApoE-ε4 allele (simplified as ApoE4 hereafter) is associated with increased risk for Alzheimer’s disease, and accelerated cognitive decline even in the absence of Alzheimer’s disease pathology. The hippocampus is a region of the brain critical for learning and memory, especially spatial learning. Adult hippocampal neurogenesis is the process whereby adult neural stem cells in the dentate gyrus of the hippocampus leads to the generation and functional integration of adult-born neurons in the hippocampus. These adult-born neurons can influence hippocampus-dependent learning and memory. Although adult neurogenesis is modulated by various extracellular stimuli, by the environment, and by neurotoxicants including lead and ethanol, there is a paucity of information regarding the effect of gene-environment interactions (GxE) on adult neurogenesis. This proposal focuses on the effect of lead-genetic background interactions on adult neurogenesis and hippocampus-dependent learning and memory.