Effects of Lead on Cortical Development and Plasticity

铅对皮质发育和可塑性的影响

• 批准号: 7218650
• 负责人: MARY A WILSON
• 金额: $ 33.29万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-03 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218650
• 关键词: Ablation; Age-Years; Animal Model; Area; Birth; Brain; Brain-Derived Neurotrophic Factor; CDKN1A gene; CREB1 gene; Child; Childhood; Chronic; Cognitive; Condition; Cortical Column; Cyclic AMP; DNA Sequence Rearrangement; Development; Dextromethorphan; Disruption; Dose; Environment; Excision; Exposure to; Gene Expression; Genes; Genetic Transcription; Glutamates; Golgi Apparatus; Growth Associated Protein 43; Growth Factor; Impaired cognition; In Situ Hybridization; Individual; Intelligence; Label; Lead; Lead Poisoning; MEKs; Maintenance; Maps; Measures; Methods; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neonatal; Neurons; Numbers; Oils; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Plastics; Play; Process; Proteins; Public Health; Rattus; Relative (related person); Research Personnel; Rodent; Role; Rolipram; Sampling; Signal Pathway; Signal Transduction; Somatosensory Cortex; Structure; Synapses; Synapsin I; Synapsin II; Vibrissae; Week; Western Blotting; barrel cortex; critical developmental period; disability; hazard; lead exposure; mRNA Expression; neocortical; neurotransmission; novel; oncoprotein p21; osmotic minipump; postnatal; programs; receptor; response; size; subcutaneous; synaptogenesis; transcription factor

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.

描述（由申请人提供）：尽管人们努力减少环境中的铅危害，但儿童铅中毒仍然是全世界的一个主要公共卫生问题。儿童时期接触低浓度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。发育中的大脑对铅毒性的脆弱性在突触发生和活动依赖性皮质可塑性的高峰期达到最大。该项目利用特征明确的皮质发育动物模型（啮齿动物桶状场）来评估铅对皮质回路发育和活动依赖性细化的影响。啮齿动物体感皮层的桶状区域包含胡须垫的地图，其中离散的神经元簇（称为桶）接收来自各个胡须的输入。该地形图是在出生后形成的，在出生后第一周的关键时期进行的实验操作（例如去除晶须）会改变桶状区域的结构和地形图。初步研究表明，新生儿铅暴露会损害未成熟的桶状皮层中柱状处理单元的发育。铅还会降低活动依赖性皮层可塑性的桶状场模型中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发挥作用的基因的表达来损害皮质柱的发育。目的是：1) 确定铅引起的桶大小变化是否是由桶区轴突和树突乔木或神经元数量减少引起的，2) 确定铅的影响是否可以被 NMDA 拮抗剂右美沙芬阻断，抑制用 FPT III 抑制 Ras，或用咯利普兰抑制 PDE4，3) 以确定出生后铅暴露是否会增加或减少 CREB、ERK1/2 或 CaMKIV 的磷酸化4) 确定铅暴露是否会改变发育中的桶状区域中转录因子 Egr1、生长因子 BDNF、orsynapsin I 和 II 的基础或诱导表达； 5)确定铅暴露对新生儿卵泡消融后Egr1、BDNF、突触蛋白I和GAP-43表达的影响。