Effects of Lead on Cortical Development and Plasticity

铅对皮质发育和可塑性的影响

• 批准号: 7771679
• 负责人: MARY A WILSON
• 金额: $ 32.42万
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7771679
• 关键词: 3 year old; Ablation; Animal Model; Area; Birth; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Child; Childhood; Chronic; Cognitive; Cortical Column; Cyclic AMP; DNA Sequence Rearrangement; Development; Dextromethorphan; 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; 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; Western Blotting; barrel cortex; critical period; disability; hazard; lead exposure; mRNA Expression; neocortical; neurotransmission; novel; osmotic minipump; postnatal; programs; receptor; response; 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）：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。儿童期暴露于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。发育中的大脑对铅毒性的脆弱性在突触发生和活动依赖性皮层可塑性的高峰期最大。该项目利用一个良好的表征动物模型的皮质发育，啮齿动物桶场，以评估铅的发展和活动依赖的细化皮质电路的影响。啮齿类动物躯体感觉皮层的桶场包含一个触须垫的地图，其中离散的神经元簇（称为桶）接收来自单个触须的输入。这种地形图开发产后，和实验操作，如晶须去除在出生后第一周的关键时期修改的结构和地形图的桶场。初步研究表明，新生儿铅暴露损害未成熟的桶皮质柱状加工单位的发展。铅还降低了活动依赖性皮质可塑性的桶场模型中对卵泡消融的可塑性反应。铅可以直接改变多巴胺能神经传递，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。其目标是：1）确定铅诱导的桶大小的变化是否由桶场轴突和树突乔木或神经元数量的减少引起，2）确定铅的作用是否可以被NMDA拮抗剂美沙芬、用FPT III抑制Ras或用咯利普兰抑制PDE 4阻断，3）确定出生后铅暴露是否增加或减少CREB的磷酸化，ERK 1/2或CaMKIV的表达; 4）确定铅暴露是否改变了转录因子Egr 1、生长因子BDNF或突触蛋白I和II在发育中的桶场的基础或诱导表达; 5）确定新生儿卵泡消融后铅暴露对Egr 1、BDNF、突触蛋白I和GAP-43表达的影响。