Epigenetics, neurodevelopment, and emotional behavior

描述(由申请人提供)：精神疾病的脆弱性和应对压力的能力在很大程度上是由人类气质和个性的个体差异决定的。了解生物和环境因素相互作用塑造大脑发育、气质以及对压力和情绪功能障碍的脆弱性的机制，对于改进对各种精神疾病的预防性治疗至关重要，如严重的抑郁和焦虑。为了阐明大脑发育中导致高度恐惧、焦虑和易受压力影响的表型的分子和神经解剖学变化，我们开发了一种有利的大鼠模型，该模型可能允许分析个体气质差异的生物学机制。为了做到这一点，我们有选择地培育了情绪反应性不同的大鼠，并将其与分子和表观遗传学特征相结合。我们的高响应性(HR)大鼠积极探索新环境，表现出比低响应性(LR)大鼠更强的冲动、攻击性和冒险行为，低响应性(LR)大鼠非常受抑制，并表现出高度的自发焦虑和抑郁样行为(即强迫游泳测试中的静止不动、性兴趣减弱和快感丧失)。这种HR/LR性状是可遗传的，但对早期环境因素也很敏感，包括HR与LR母体风格的自然变异。利用全基因组表达谱，我们发现HR和LR大鼠在发育中的海马区、杏仁体和前额叶皮质的基因表达存在显著差异，包括与新陈代谢和突触可塑性有关的基因的变化。这些发现表明，不同的HR/LR行为表型涉及驱动海马-边缘回路的不同建立的分子变化。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)可能导致这些基因表达和最终行为的差异。这项拟议的工作将使用尖端的下一代测序来绘制HR和LR动物发育和成年大脑中的DNA甲基化模式(“甲基组”)，以(A)询问可能驱动其不同行为表型的天生甲基组差异；(B)确定早期生活经验(交叉培养)如何重新配置正在发育的LR神经甲基组以影响行为；以及(C)测试在HR/LR脑中操纵DNA甲基化是否足以改变它们的表型。因此，我们将通过测试HR/LR大脑中的甲基化是否改变他们的行为来检验我们的工作假设，即HR/LR甲基组的差异构成了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个体在情绪性、应激脆弱性和情绪障碍风险方面的差异。在气质和压力易损性/恢复力差异的模式生物体中解开这种复杂的遗传、表观遗传、神经生物学和环境相互作用，应该会产生与理解情绪障碍的发育神经生物学和如何开发改进的治疗方法相关的重要结果。

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.