Can Affective Resilience be Enhanced? A Developmental and Epigenetic Approach

情感弹性可以增强吗？

• 批准号: 8748818
• 负责人: HUDA AKIL
• 金额: $ 60.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8748818
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Affective; Age; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Binding; Birth; Brain; Breeding; Buffers; Characteristics; Chronic; Depressed mood; Development; Disease; Emotional; Endogenous depression; Environment; Environmental Impact; Enzymes; Epigenetic Process; Exhibits; Exposure to; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptors; Gene Expression; Gene Family; Gene Targeting; Generations; Genes; Genetic Predisposition to Disease; Glucocorticoid Receptor; Hippocampus (Brain); Histones; Human; Individual; Injection of therapeutic agent; Intervention; Lead; Life; Maintenance; Mediating; Mediator of activation protein; Medical; Mental Depression; Modeling; Modification; Molecular; Mood Disorders; Neurobiology; Pattern; Pharmaceutical Preparations; Phenotype; Play; Predisposing Factor; Process; Psychosocial Stress; RNA; Rattus; Regulation; Role; Series; Shapes; Site; Specificity; Stimulus; Stress; System; Techniques; Testing; Time; addiction; base; biological adaptation to stress; cell type; conditioned fear; coping; design; developmental genetics; environmental change; histone modification; indexing; knock-down; member; molecular marker; neurobiological mechanism; novel; postnatal; promoter; protective effect; public health relevance; relating to nervous system; resilience; response; small hairpin RNA; social; social stress; tool

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.

描述（由申请人提供）：我们建议研究对焦虑和压力的情感恢复力的神经生物学机制，并确定特别是在高度脆弱的个体中增强恢复力的策略。我们的一般假设是，表观遗传机制是影响对负价反应并影响慢性焦虑症易感性的关键诱发因素。更具体地说，我们重点关注成纤维细胞生长因子 2 (FGF2)，它作为“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积极塑造情感反应。该提案测试了这样的假设：FGF2 是一种内源性弹性分子，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剂，进而微调情感反应。 拟议的一系列研究依赖于我们根据它们探索轻度压力的新环境的倾向进行基因选择的两种老鼠。我们的育种策略超过 40 代，产生了对比的行为表型，捕获了“负价反应性”与“正价反应性”的稳定偏差。特别是，与繁殖的高反应大鼠 (bHR) 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、更强的恐惧调节能力、对慢性和社交失败压力的更强反应性、更低水平的海马 FGF2 和独特的表观遗传特征。 ）的弹性显着增强。因此，bLR 是消极情感障碍脆弱性的模型，也是增强复原力的目标。 目标 1 使用直接施用 FGF2 来增强生命早期和青春期的恢复能力。它还研究环境复杂性（EC）作为促进青春期复原力的策略。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（可减少焦虑）和糖皮质激素受体 GR（可增强焦虑行为）。 目标 2 描述了与 bHR/bLR 表型相关的基础表观遗传图谱，以及弹性诱导对这些图谱的影响，无论是在全球水平还是与 FGF2 和 GR 启动子相关。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。 目标 3 在机制层面解决 FGF2 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体中的 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，这些研究将为理解和利用表观遗传学作为影响调节的关键因素提供高度针对性的方法。