Effects of Lead on Cortical Development and Plasticity

描述（由申请人提供）：尽管努力减少环境中的铅危害，儿童铅中毒仍然是世界各地的一个主要公共卫生问题。儿童时期接触低水平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。发育中的大脑对铅毒性的易损性在突触发生和活动依赖性皮质可塑性的高峰期是最大的。本项目利用一种具有良好特征的皮层发育动物模型，即啮齿动物的桶场，来评估铅对皮层回路发育和活动依赖性改进的影响。啮齿动物体感皮层的桶状区域包含一幅须丛的地图，在那里，被称为桶状的离散神经元簇接收来自单个须的输入。这张地形图是在出生后形成的，在出生后第一周的关键时期，如去除须等实验性操作可以改变桶状油田的结构和地形图。初步研究表明，新生儿铅暴露会损害未成熟桶状皮质柱状处理单元的发育。在活动依赖的皮质可塑性桶场模型中，铅也降低了对毛囊消融的塑性反应。铅可以直接改变谷氨酸能神经传递，并干扰协调基因表达的下游信号通路。我们假设铅通过改变CREB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。目标是：1)确定铅诱导的脑桶大小变化是否由脑桶区轴突和树突乔木或神经元数量减少引起；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或罗利普兰抑制PDE4阻断；3)确定产后铅暴露是否会增加或减少发育中的脑桶区CREB、ERK1/2或CaMKIV的磷酸化。4)确定铅暴露是否改变了发育中的桶区转录因子Egr1、生长因子BDNF或突触素I和II的基础表达或诱导表达；5)探讨铅暴露对新生儿卵泡消融后Egr1、BDNF、synapsin 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.