Epigenetics, Neurodevelopment, and Emotional Behavior

表观遗传学、神经发育和情绪行为

• 批准号: 9323687
• 负责人: Sarah M Clinton
• 金额: $ 40.25万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323687
• 关键词: Adult; Aggressive behavior; Amygdaloid structure; Anhedonia; Animal Model; Animals; Anxiety; Automobile Driving; Autopsy; Behavior; Behavioral; Biological; Biological Factors; Brain; Candidate Disease Gene; Coupled; DNA; DNA Methylation; Data; Development; Disease; Emotional; Emotional Stress; Environment; Environmental Risk Factor; Epigenetic Process; Exhibits; Exposure to; Fostering; Fright; Functional disorder; Gene Expression; Gene Family; Genes; Genetic; Heritability; Hippocampus (Brain); Human; Impulsivity; Individual; Individual Differences; Lead; Life; Life Experience; Major Depressive Disorder; Maps; Mental disorders; Metabolism; Methylation; Modeling; Modification; Molecular; Molecular Profiling; Mood Disorders; Mothers; Neurobiology; Patients; Pattern; Perinatal; Personality; Pharmacology; Phenotype; Prefrontal Cortex; Preventive treatment; Primary Lesion; Process; Proteins; Rattus; Risk; Risk-Taking; Sampling; Secondary to; Shapes; Stress; Swimming; Synaptic plasticity; Temperament; Testing; Variant; Work; anxiety-like behavior; anxious; base; behavior influence; brain shape; critical developmental period; depressive symptoms; developmental neurobiology; emotional behavior; epigenetic marker; epigenetic profiling; experience; genome-wide; improved; interest; methylation pattern; methylome; neural circuit; neurodevelopment; neuroendocrine phenotype; next generation sequencing; novel; postnatal; public health relevance; pup; relating to nervous system; resilience; tool; trait

DESCRIPTION (provided by applicant): Vulnerability to mental illness and ability to cope with stress are powerfully shaped by individual differences in human temperament and personality. Understanding the mechanisms whereby biological and environmental factors interact to shape brain development, temperament, and vulnerability to stress and emotional dysfunction is crucial for generating improved preventative treatments for a variety of psychiatric disorders, such as major depression and anxiety. To elucidate molecular and neuroanatomical changes in the developing brain that lead to a highly fearful, anxious, and stress-vulnerable phenotype, we developed an advantageous rat model that may permit analysis of biological mechanisms of individual differences in temperament. To do so, we selectively-bred rats for differences in emotional reactivity, and combined this with molecular and epigenetic profiling. Our High-Responder (HR) rats vigorously explore novel environments and exhibit greater impulsivity, aggression, and risk-taking versus Low-Responder (LR) rats, which are very inhibited and show high levels of spontaneous anxiety and depressive-like behavior (i.e. immobility in the Forced Swim Test, diminished sexual interest, and anhedonia). Such HR/LR traits are heritable, but are also sensitive to early-life environmental factors, including naturally-occurring variation in HR v. LR maternal style. Using genome-wide expression profiling, we discovered dramatic gene expression differences in the developing hippocampus, amygdala, and prefrontal cortex of HR vs. LR rats, including changes in genes involved in metabolism and synaptic plasticity. These findings suggest that the distinct HR/LR behavioral phenotypes involve molecular changes that drive differential establishment of hippocampal-limbic circuits. Furthermore, our preliminary data suggest epigenetic differences (in HR/LR DNA methylation patterns) may elicit these differences in gene expression and ultimately behavior. The proposed work will use cutting-edge next-generation sequencing to map DNA methylation patterns (the "methylome") in the developing and adult brain of HR and LR animals to (a) interrogate inborn methylome differences that may drive their distinct behavioral phenotypes; (b) determine how an early-life experience (cross-fostering) reconfigures the developing LR neural methylome to influence behavior; and (c) test whether manipulating DNA methylation in the HR/LR brain suffices to shift their phenotypes. We will thereby test our working hypothesis that HR/LR methylome differences constitute a key phenotype-driving molecular mechanism by testing whether manipulating methylation in the HR/LR brain modifies their behavior. This work will illuminate how epigenetic mechanisms may drive individual differences in emotionality, stress vulnerability, and risk for emotional dysfunction. Unraveling such complicated genetic, epigenetic, neurobiological, and environmental interactions in a model organism of temperamental and stress vulnerability/resilience differences should yield important results relevant to understanding the developmental neurobiology of mood disorders and how to develop improved treatments.

描述（由申请人提供）：对精神疾病的脆弱性和应对压力的能力是由人的气质和人格中的个体差异来有力地塑造的。了解生物学和环境因素相互作用以塑造大脑发育，气质和压力和情绪功能障碍的机制对于为各种精神疾病（例如重大抑郁症和焦虑）产生改善的预防性治疗至关重要。为了阐明发育中的大脑的分子和神经解剖学变化，导致高度恐惧，焦虑和应激性表型，我们开发了一种有利的大鼠模型，可以允许分析气质中个体差异的生物学机制。为此，我们有选择地养育了情绪反应性的差异，并将其与分子和表观遗传分析相结合。我们的高响应者（HR）大鼠大力探索新颖的环境，表现出更大的冲动，侵略性和冒险性和低响应器（LR）大鼠，这些大鼠非常受到抑制，并且表现出高水平的自发性焦虑和抑郁症状的行为（即，在强制游泳测试中固定的固定性（即强制性游泳测试），并减轻了性兴趣，并减轻了性兴趣，并且是性行为的，并且是AnhhedeNonia的）。这种人力资源/LR性状是可遗传的，但对早期生活的环境因素也敏感，包括HR诉LR孕产妇风格的自然变化。使用全基因组表达分析，我们发现了HR与LR大鼠的发展海马，杏仁核和前额叶皮层中的显着基因表达差异，包括涉及代谢和突触可塑性的基因的变化。这些发现表明，独特的HR/LR行为表型涉及分子变化，这些变化驱动了海马 - 边缘电路的差异化。此外，我们的初步数据表明表观遗传差异（在HR/LR DNA甲基化模式中）可能会引起基因表达和最终行为的这些差异。所提出的工作将使用前沿的下一代测序来绘制HR和LR动物的发育中和成年大脑中的DNA甲基化模式（“甲基团”），以（a）询问可能驱动其独特的行为表型的先天甲基差异； （b）确定早期生活体验（交叉培训）如何重新配置​​发展的LR神经甲基化以影响行为； （c）测试在HR/LR大脑中操纵DNA甲基化是否足以改变其表型。因此，我们将通过测试在HR/LR脑中操纵甲基化是否会改变其行为，从而测试我们的工作假设，即HR/LR甲基差异构成了一种关键的表型驱动分子机制。这项工作将阐明表观遗传机制如何推动情绪，压力脆弱性和情绪功能障碍的风险的个体差异。在气质和压力脆弱性/弹性差异的模型生物体中，揭开这种复杂的遗传，表观遗传学，神经生物学和环境相互作用，应产生与了解情绪障碍的发育神经生物学以及如何开发改进的治疗相关的重要结果。