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）：尽管努力减少环境中的潜在客户危害，但童年铅中毒仍然是全世界主要的公共卫生问题。儿童期暴露于低水平的铅可以永久降低智力，但是这种影响的神经生物学机制尚不清楚。在突触发生和活性依赖性皮质可塑性的峰值期间，发育中的大脑易于引起毒性的脆弱性是最大的。该项目利用了啮齿动物桶形的皮质发育的良好特征动物模型，以评估铅对皮质回路的发育和活动依赖性细化的影响。啮齿动物体感皮层的桶形场包含一张晶须垫的地图，其中神经元的离散簇（称为枪管）从单个晶须中接收输入。该地形图会在产后发展，并在产后第一个周的关键时期（在关键时期清除晶须）的实验操作修改了枪管场的结构和地形图。初步研究表明，新生儿铅暴露会损害未成熟桶皮层中柱状加工单元的发展。铅还降低了活性依赖性皮质可塑性的枪管场模型中对卵泡消融的塑性反应。铅可以直接改变谷氨酸能神经传递，并干扰坐标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展。目的是：1）确定铅诱导的枪管大小的变化是否是由于枪管场轴突和树突状轴向或神经元数的减少引起在发育中的枪管场中增加或减少CREB，ERK1/2或CAMKIV的磷酸化，4），以确定铅暴露在发育场中的转录因子EGR1，生长因子BDNF，orsynapsin I和II的转录因子EGR1的基础或诱导表达是否改变； 5）确定新生儿卵泡消融后的铅暴露对EGR1，BDNF，Sytapsin I和GAP-43表达的影响。