Can Affective Resilience be Enhanced? A Developmental and Epigenetic Approach

描述（由申请人提供）：我们建议研究焦虑和压力的情感弹性的神经生物学机制，并确定特别是在高度脆弱的个体中增强弹性的策略。我们的一般假设是，表观遗传机制是关键的易感因素，塑造负效价的反应和影响慢性焦虑症的脆弱性。更具体地说，我们专注于成纤维细胞生长因子2（FGF2），它作为一种“主分子组织者”，在发育过程中至关重要，并在整个生命过程中继续积极塑造情感反应。该提案检验了以下假设：FGF2是一种内源性弹性分子，不仅是表观遗传机制的靶点，而且本身是这些机制的修饰剂，进而微调情感反应。 这一系列的研究依赖于两个品系的大鼠，我们根据它们探索轻度压力新环境的倾向进行了基因选择。我们的育种策略超过40代，导致了对比的行为表型，捕获一个稳定的偏见，对“负价反应”与“正价反应”。特别是，繁殖的低反应大鼠（bLR）表现出更大的基础焦虑和抑郁行为，更大的恐惧条件反射，更大的反应慢性和社会失败的压力，海马FGF 2的水平较低和一个独特的表观遗传谱相比，繁殖的高反应（bHR）是显着更有弹性。因此，bLR是一个模型的脆弱性，消极的情感障碍和弹性增强的目标。 目的1使用FGF2的直接管理，以促进生命早期和青春期的恢复力。它还调查了环境复杂性（EC）作为促进青春期恢复力的战略。它研究了这些干预措施对海马体中两个“分子主组织者”基因的影响-FGF2本身，它减少焦虑和糖皮质激素受体GR，它增强焦虑行为。 目的2表征与bHR/bLR表型相关的基础表观遗传特征，以及在全球水平上以及与FGF2和GR启动子相关的弹性诱导对这些特征的影响。这些研究将扩展到使用包括Clarity在内的一系列工具进行解剖分析。 目的3在机械水平上解决了FGF 2和表观遗传机制之间的功能双向关系及其对弹性的影响-无论是基础弹性（在bHR中）还是诱导弹性（在bLR中）。它使用病毒介导的靶向RNA干预策略来敲低海马中的FGF 2或组蛋白修饰酶，并确定它们是否在诱导恢复力中发挥重要作用。 总之，这些研究将提供一种高度针对性的方法来理解和利用表观遗传学作为影响调节的关键因素。

DESCRIPTION (provided by applicant): We propose to study the neurobiological mechanisms of affective resilience to anxiety and stress, and to identify strategies for enhancing resilience specifically in highly vulnerable individuals. Our general hypothesis is that epigenetic mechanisms are critical predisposing factors that shape responsiveness to negative valence and impact vulnerability to chronic anxiety disorders. More specifically, we focus on the Fibroblast Growth Factor 2 (FGF2) which serves as a "master molecular organizer" that is critical during development and continues to be active in shaping affective responsiveness throughout life. This proposal tests the hypothesis that FGF2 is an endogenous resilience molecule that is not only a target of epigenetic mechanisms but is itself a modifier of these mechanisms that, in turn, fine-tune affective responsiveness. The proposed series of studies relies on two lines of rats that we have genetically selected based on their propensity to explore a mildly stressful novel environment. Our breeding strategy over 40 generations has resulted in contrasting behavioral phenotypes that capture a stable bias towards "negative valence responsiveness" versus "positive valence responsiveness". In particular, bred Low-Responder rats (bLRs) exhibit greater basal anxiety and depression behaviors, greater fear conditioning, greater responsiveness to chronic and social defeat stress, lower levels of hippocampal FGF2 and a distinct epigenetic profile when compared to bred High Responders (bHRs) that are significantly more resilient. Thus bLRs are a model of vulnerability to negative affective disorders and a target for resilience enhancement. Aim 1 uses direct administration of FGF2 to promote resilience during early life and in adolescence. It also investigates environmental complexity (EC) as a strategy for promoting resilience during adolescence. It studies the impact of these interventions on two "molecular master organizer" genes in hippocampus- FGF2 itself, which reduces anxiety and the glucocorticoid receptor GR, which enhances anxiety behavior. Aim 2 characterizes the basal epigenetic profiles associated with the bHR/bLR phenotypes and the impact of resilience induction on these profiles both at the global level and in association with FGF2 and GR promoters. These studies will be extended to anatomical analyses using a range of tools including Clarity. Aim 3 addresses at a mechanistic level the functional bidirectional relationship between FGF2 and epigenetic mechanisms and their impact on resilience--- be it basal resilience (in bHRs) or induced (in bLRs). It uses virally-mediated, targeted RNA intervention strategies to knockdown either FGF2 or histone modifying enzymes in the hippocampus and determine whether they play an essential role in the induction of resilience. Together, these studies will provide a highly targeted approach to understanding and harnessing epigenetics as key factors in affect regulation.