Effects of Lead on Cortical Development and Plasticity

描述(由申请人提供)：儿童铅中毒仍然是世界各地的一个主要公共卫生问题，尽管努力减少环境中的铅危害。儿童时期接触低水平的铅会永久性地降低智力，但这种影响的神经生物学机制尚不清楚。发育中的大脑在突触发生和活性依赖的皮质可塑性的高峰期对铅毒性的易感性最大。该项目利用一种具有良好特性的皮质发育动物模型--啮齿动物桶野，来评估铅对皮质环路的发育和依赖活动的精细化的影响。啮齿动物躯体感觉皮层的桶状区域包含一张胡须垫地图，在该地图中，离散的神经元簇(称为桶)接受来自个别胡须的输入。这张地形图是在出生后发展起来的，在出生后第一周的关键时期进行的胡须去除等实验操作改变了桶形场的结构和地形图。初步研究表明，新生儿铅暴露会损害未成熟桶状皮质中柱状加工单位的发育。在依赖活性的皮质可塑性的桶形场模型中，铅也降低了对毛囊消融的可塑性反应。铅可以直接改变谷氨酸能神经传递，干扰下游协调基因表达的信号通路。我们假设铅通过改变CREB的磷酸化和已知在发育和可塑性中起作用的基因的表达来损害皮质柱的发育。其目的是：1)确定铅引起的桶大小的改变是否是由于桶野轴突和树突或神经元数量的减少所致；2)确定铅的作用是否可以被NMDA拮抗剂右美沙芬、FPT III抑制RAS或用罗利普兰抑制PDE4所阻断；3)确定出生后铅暴露是否增加或减少发育中桶野中CREB、ERK1/2或CaMKIV的磷酸化；4)确定铅暴露是否改变发育中桶野转录因子Egr1、生长因子BDNF或突触素I和II的基础或诱导表达；5)探讨铅暴露对新生鼠卵泡切除后Egr1、BDNF、突触素I和GAP-43表达的影响。

DESCRIPTION (provided by applicant): Childhood lead poisoning persists as a major public health problem throughout the world, despite efforts to reduce lead hazards in the environment. Childhood exposure to low-level lead can permanently reduce intelligence, but the neurobiologic mechanism for this effect is unknown. The vulnerability of the developing brain to lead toxicity is maximal during the peak of synaptogenesis and activity-dependent cortical plasticity. This project utilizes a well-characterized animal model of cortical development, the rodent barrel field, to evaluate the effects of lead on the development and activity-dependent refinement of cortical circuitry. The barrel field of rodent somatosensory cortex contains a map of the whisker pad in which discrete clusters of neurons, called barrels, receive input from individual whiskers. This topographic map develops postnatally, and experimental manipulations such as whisker removal during a critical period in the first postnatal week modify the structure and topographic map of the barrel field. Preliminary studies have shown that neonatal lead exposure impairs the development of columnar processing units in immature barrel cortex. Lead also decreases the plastic response to follicle ablation in the barrel field model of activity-dependent cortical plasticity. Lead can directly alter glutamatergic neurotransmission and interfere with downstream signaling pathways that coordinate gene expression. We hypothesize that lead impairs the development of cortical columns by altering CREB phosphorylation and the expression of genes that are known to play a role in development and plasticity. The aims are: 1) to determine whether lead-induced changes in barrel size are caused by reduction in barrel field axonal and dendritic arbors or neuronal number, 2) to determine whether the effects of lead can be blocked by the NMDA antagonist dextromethorphan, inhibition of Ras with FPT III, or inhibition of PDE4 with rolipram, 3) to determine whether postnatal lead exposure increases or decreases phosphorylation of CREB, ERK1/2 or CaMKIV in the developing barrel field, 4) to determine whether lead exposure alters basal or inducible expression of the transcription factor Egr1, the growth factor BDNF, orsynapsin I and II in the developing barrel field; 5) to determine the effect of lead exposure on Egr1, BDNF, synapsin I and GAP-43 expression after neonatal follicle ablation.