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情感弹性的神经生物学机制，并确定提高高度脆弱个体心理弹性的策略。我们的一般假设是，表观遗传机制是形成对负效价的反应和影响慢性焦虑症易感性的关键易感因素。更具体地说，我们关注的是成纤维细胞生长因子2 (FGF2)，它作为一个“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持续活跃地塑造情感反应。这一提议验证了FGF2是一种内源性弹性分子的假设，它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因子，进而微调情感反应。拟议的一系列研究依赖于两种老鼠，我们根据它们探索轻度压力的新环境的倾向，从基因上选择了它们。我们的育种策略超过40代，导致了不同的行为表型，捕获稳定的偏向于“负价反应”和“正价反应”。与高反应大鼠相比，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，对慢性和社会失败压力的更大反应，更低的海马FGF2水平和独特的表观遗传特征。因此，blr是一种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直接管理，以促进早期生活和青春期的恢复能力。它还研究了环境复杂性（EC）作为促进青春期恢复力的一种策略。研究这些干预对海马中两个“分子主组织者”基因FGF2本身的影响，FGF2本身减少焦虑，糖皮质激素受体GR增强焦虑行为。目的2描述了与bHR/bLR表型相关的基本表观遗传谱，以及在全球水平和与FGF2和GR启动子相关的弹性诱导对这些谱的影响。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。Aim 3从机制层面探讨FGF2与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FGF2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，这些研究将提供一个高度有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.