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）：发育性铅暴露可能影响认知发育和晚年认知功能的一个重要方式是通过表观遗传修饰，特别是通过调节 DNA 甲基化。最近的研究表明，成人大脑中的 DNA 甲基化是高度动态的，前额皮质 (PFC) 和海马体甲基化的动态调节共同在记忆形成、巩固和维持中发挥着不可或缺的作用。初步数据表明，PFC和海马体的DNA甲基化在静息条件下以及学习记忆过程中受到发育性铅暴露的影响，干扰学习记忆过程中必需的甲基化和基因转录的正常动态调节，导致认知缺陷。铅的这些影响似乎在男性和女性中表现不同，受到铅暴露的发育时间的影响，并且可能通过品系特异性表观遗传影响而被个体遗传组成所改变。我们的长期目标是了解发育过程中的铅暴露如何对大脑和行为产生长期影响。我们追求这些目标的下一步目标是更好地了解铅对大脑的表观遗传效应以及这些效应如何影响行为。我们的目标是确定低水平的铅暴露如何影响学习和记忆过程中 PFC 和海马中特定基因的动态甲基化，以及这些影响在多大程度上导致雄性和雌性以及不同品系大鼠的认知缺陷。我们的中心假设是，铅暴露将改变 PFC 和海马中关键学习/记忆相关基因 DNA 甲基化的动态调节，并且铅的这种表观遗传影响将因性别和应变而异。本研究的目标将通过追求以下目标来实现：1) 确定低水平铅暴露对学习和记忆过程中 DNA 甲基化动态调节的影响，并研究这些影响如何影响男性和女性的行为和认知相关基因表达。我们鉴定出的雌性菌株对铅的影响高度敏感（Long Evans），而菌株相对具有抵抗力（Sprague Dawley）。我们的假设是，异常的动态 DNA 甲基化会导致学习/记忆相关基因的异常调节以及相关的认知缺陷，并且这些影响将因性别和压力而改变； 2) 确定 DNA 甲基化的药理调节对铅暴露动物认知结果的影响程度以及调节学习/记忆相关基因表达的程度。我们假设异常的 DNA 甲基化可以通过药理学进行操纵，有可能重新设置 Pb 诱导的变化并对认知结果产生积极影响。拟议的研究是在当前拨款的基础上进行的，并将确定铅暴露可能影响行为的表观遗传机制。由于低水平铅暴露带来的广泛危险以及确定可能改善假定为永久性的负面结果的潜在干预措施的可能性，预计结果将产生重要的积极影响。