Epigenetics, neurodevelopment, and emotional behavior

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受到人类气质和个性的个体差异的强烈影响。了解生物和环境因素相互作用形成大脑发育、气质以及对压力和情绪功能障碍的脆弱性的机制，对于改善各种精神疾病（如重度抑郁症和焦虑症）的预防性治疗至关重要。为了阐明发育中的大脑中导致高度恐惧、焦虑和压力易感表型的分子和神经解剖学变化，我们开发了一个有利的大鼠模型，可以分析个体气质差异的生物学机制。为了做到这一点，我们选择性地培育了情绪反应差异的大鼠，并将其与分子和表观遗传分析相结合。与低反应（LR）大鼠相比，高反应（HR）大鼠积极探索新环境，表现出更大的冲动、攻击性和冒险精神，低反应（LR）大鼠非常受抑制，表现出高水平的自发焦虑和抑郁样行为（即在强迫游泳测试中不动、性兴趣减弱和快感缺乏）。这种HR/LR特征是可遗传的，但也对早期环境因素敏感，包括HR和LR母系风格的自然变异。通过全基因组表达谱分析，我们发现HR大鼠与LR大鼠在发育中的海马、杏仁核和前额叶皮层中存在显著的基因表达差异，包括代谢和突触可塑性相关基因的变化。这些发现表明，不同的HR/LR行为表型涉及驱动海马体-边缘回路差异建立的分子变化。此外，我们的初步数据表明，表观遗传差异（HR/LR DNA甲基化模式）可能导致这些基因表达和最终行为的差异。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先天甲基组差异；(b)确定早期生活经历（交叉培养）如何重新配置发育中的LR神经甲基组，从而影响行为；(c)测试操纵HR/LR脑中的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大脑中操纵甲基化是否会改变他们的行为，来验证我们的工作假设，即HR/LR甲基组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驱动情绪、压力脆弱性和情绪功能障碍风险的个体差异。揭示这种复杂的遗传、表观遗传、神经生物学和环境相互作用在气质和应激脆弱性/恢复力差异的模式生物中应该产生重要的结果，这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有关。

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.