Can Affective Resilience be Enhanced? A Developmental and Epigenetic Approach

描述(申请人提供)：我们建议研究情绪对焦虑和压力的复原力的神经生物学机制，并确定特别是在高度脆弱的个人中增强复原力的策略。我们的一般假设是，表观遗传机制是形成对负价反应的关键诱因，并影响慢性焦虑症的易感性。更具体地说，我们关注成纤维细胞生长因子2(FGF2)，它是一种在发育过程中至关重要的“主分子组织者”，在整个生命过程中继续积极地塑造情感反应。这一建议检验了这样一种假设，即FGF2是一种内源性弹性分子，不仅是表观遗传机制的目标，而且本身也是这些机制的修饰者，这些机制反过来又微调情感反应。拟议的一系列研究依赖于两个品系的大鼠，我们根据它们探索温和压力的新环境的倾向从基因上选择了它们。我们的育种策略在40代中产生了不同的行为表型，这些表型捕捉到了对“负价响应”和“正价响应”的稳定偏向。特别是，与更具弹性的饲养高反应鼠(BHR)相比，繁殖的低反应鼠(BLR)表现出更多的基础焦虑和抑郁行为，更强的恐惧条件反射，对慢性和社会失败压力的更大反应，较低的海马FGF2水平和明显的表观遗传学特征。因此，bLRs是易受负面情感障碍影响的模型，也是增强复原力的目标。目标1使用FGF2的直接给药来促进早期生活和青春期的韧性。它还调查了环境复杂性(EC)作为促进青春期适应能力的一种战略。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，它降低了焦虑，以及糖皮质激素受体GR，它增强了焦虑行为。目的2描述与BHR/BLR表型相关的基本表观遗传学特征，以及在全球水平以及与FGF2和GR启动子相关的恢复力诱导对这些表观遗传学特征的影响。这些研究将扩展到使用包括Clarity在内的一系列工具的解剖学分析。目的3在机制水平上探讨FGF2和表观遗传机制之间的功能双向关系及其对复原力的影响-无论是基础复原力(BHRS)还是诱导复原力(BLR)。它使用病毒介导的、有针对性的RNA干预策略来敲除海马体中的FGF2或组蛋白修饰酶，并确定它们是否在诱导弹性方面发挥关键作用。总之，这些研究将为理解和利用表观遗传学作为影响调控的关键因素提供一种高度有针对性的方法。

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.