Environment and Gene Effects on Brain and Behavior

环境和基因对大脑和行为的影响

• 批准号: 8584042
• 负责人: JAY S SCHNEIDER
• 金额: $ 45.17万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584042
• 关键词: Aberrant DNA Methylation; Adult; Affect; Animals; Behavior; Behavioral; Binding Proteins; Brain; Cognition; Cognitive; Cognitive deficits; Cytosine; DNA Methylation; DNA Methylation Regulation; DNA Methyltransferase; DNA Modification Methylases; Data; Development; Elderly; Epigenetic Process; Exposure to; Female; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Grant; Hippocampus (Brain); Hormonal; Individual; Intervention; Lead; Learning; Life; Long-Term Effects; Maintenance; Mediating; Memory; Methylation; Modification; Molecular; Outcome; Play; Populations at Risk; Predisposition; Prefrontal Cortex; Process; Public Health; Rat Strains; Rattus; Regulation; Research; Resistance; Rest; Risk; Role; System; Time; Toxic Environmental Substances; Work; base; behavior influence; blood lead; brain behavior; cognitive function; early life exposure; environmental enrichment for laboratory animals; experience; frontal lobe; gene environment interaction; genome-wide; improved; insight; lead exposure; male; memory process; promoter; protein expression; public health relevance; relating to nervous system; remediation; response; sex; stressor

DESCRIPTION (provided by applicant): An important way in which developmental Pb exposure may influence cognitive development and later life cognitive functioning is through epigenetic modifications and specifically, through modulating DNA methylation. Recent studies show that DNA methylation in the adult brain is highly dynamic and that the dynamic regulation of methylation in the prefrontal cortex (PFC) and hippocampus together play integral roles in memory formation, consolidation, and maintenance. Preliminary data show that DNA methylation in PFC and hippocampus are affected by developmental Pb exposure under resting conditions and during learning and memory, interfering with normal dynamic regulation of methylation and gene transcription necessary during learning and memory, leading to cognitive deficits. These effects of Pb appear to be expressed differently in males and females, are influenced by developmental timing of Pb exposure, and may be modified by individual genetic makeup through strain-specific epigenetic influences. Our long-term goal is to understand how developmental Pb exposure exerts long-term effects on the brain and behavior. The objective here, which is our next step in pursuit of these goals, is to better understand epigenetic effects of Pb on the brain and how these effects influence behavior. Our goal is to determine how low level Pb exposure affects dynamic methylation of specific genes in PFC and hippocampus during learning and memory and the extent to which these effects contribute to cognitive deficits in males and females and in different strains of rats. Our central hypothesis, is that Pb exposure will alter the dynamic regulation of DNA methylation of key learning/memory related genes in the PFC and hippocampus and that this epigenetic influence of Pb will vary by sex and strain. The objectives of this research will be accomplished by pursuing the following aims: 1) Determine effects of low level Pb exposure on the dynamic modulation of DNA methylation during learning and memory and examine how these effects influence behavior and cognition-related gene expression in males and females in a strain identified by us to be highly susceptible to the effects of Pb (Long Evans) and a strain relatively resistant (Sprague Dawley). Our hypothesis is that there will be aberrant dynamic DNA methylation resulting in abnormal modulation of learning/memory-related genes with associated cognitive deficits and these effects will be modified by sex and strain; 2) Determine the extent to which pharmacological modulation of DNA methylation influences cognitive outcomes in Pb-exposed animals and modulates learning/memory-related gene expression. We postulate that aberrant DNA methylation can be pharmacologically manipulated, potentially re-setting Pb-induced changes and positively influencing cognitive outcome. The proposed studies extend from the current grant and will identify epigenetic mechanisms through which Pb exposure may influence behavior. Results are expected to have important positive impact because of the widespread danger from low level Pb exposure and the possibility of identifying potential interventions that may improve negative outcomes assumed to be permanent.

描述（由申请人提供）：发展性PB暴露可能影响认知发展和以后的生活认知功能的一种重要方法是通过表观遗传修饰，特别是通过调节DNA甲基化的。最近的研究表明，成年大脑中的DNA甲基化具有高度动态性，并且在额叶皮层（PFC）和海马中对甲基化的动态调节共同在记忆形成，巩固和维持中起着不可或缺的作用。初步数据表明，PFC和海马中的DNA甲基化受到静止条件下的发育PB暴露的影响，在学习和记忆过程中，在学习和记忆过程中干扰了正常的甲基化和基因转录的动态调节，导致认知缺陷。 PB的这些影响似乎在男性和女性中的表达方式有所不同，受PB暴露的发育时机的影响，并且可以通过菌株特异性表观遗传学影响来修改。我们的长期目标是了解发展性PB暴露如何对大脑和行为产生长期影响。这里的目标是我们追求这些目标的下一步，是更好地了解PB对大脑的表观遗传效应以及这些影响如何影响行为。我们的目标是确定在学习和记忆过程中PFC和海马中特定基因的动态甲基化的低水平PB暴露以及这些作用在多大程度上导致男性和女性以及不同大鼠菌株的认知缺陷的程度。我们的中心假设是，PB暴露会改变PFC和Hippocampus中关键学习/记忆相关基因的DNA甲基化的动态调节，并且PB的表观遗传学影响会因性别和菌株而异。 The objectives of this research will be accomplished by pursuing the following aims: 1) Determine effects of low level Pb exposure on the dynamic modulation of DNA methylation during learning and memory and examine how these effects influence behavior and cognition-related gene expression in males and females in a strain identified by us to be highly susceptible to the effects of Pb (Long Evans) and a strain relatively resistant (Sprague Dawley).我们的假设是，将会存在异常的动态DNA甲基化，从而导致与认知缺陷相关的学习/记忆相关基因的异常调节，并且这些作用将通过性别和菌株来改变； 2）确定DNA甲基化的药理调节影响PB暴露动物的认知结果的程度，并调节学习/与记忆相关的基因表达。我们假设可以在药理上操纵异常的DNA甲基化，并可能重新设置PB诱导的变化并积极影响认知结果。拟议的研究从当前的赠款范围扩展，并将确定PB暴露可能影响行为的表观遗传机制。由于低水平的PB暴露造成了广泛的危险，并且有可能识别可能改善假定是永久性的负面结果的潜在干预措施的可能性，因此结果预计将产生重要的积极影响。