Brain Mechanisms Mediating Genetic Risk For Anxiety And Depression

项目总结/摘要 神经可塑性的改变与压力相关的精神病理学密切相关。该提案将使用 非人灵长类动物（NHP），以调查在多大程度上改变了中枢神经可塑性系统， 杏仁核（Ce）是焦虑气质（AT）的基础，AT是焦虑的早期风险表型， 抑郁症我们还将通过一个未充分研究的， 直接前额皮质到Ce通路，这将为通路特异性治疗的发展提供信息 专注于调节Ce功能。焦虑症（AD）通常出现在儿童时期， 流行，导致严重残疾，儿童期发病预示着更严重和更长时间的 医学。尽管目前的治疗，许多人与广告仍然是高度症状， 针对儿童期AD发病机制的干预措施将是理想的。来深入了解 儿童AD的潜在机制，并概念化更有效的干预措施，我们开发了一个 AT的NHP模型，可直接转化为人类。我们的研究显示出 人类和猴子AT之间的关系，阐述了AT的神经回路，并使用RNA测序（RNA-Seq） 已经表征了Ce中的分子变化。为了促进分子机制研究，我们开发了 术中实时MRI方法可靠地递送病毒载体以选择神经靶点，包括Ce。 我们的工作使我们得出了一个神经发育假说， Ce中的机制用于维持高水平的AT及其最终转化为焦虑， 抑郁症虽然从啮齿动物的研究中了解了很多关于BDNF（脑源性神经营养因子）的信息， 因子）-TrkB系统介导恐惧，抑郁行为和抗抑郁作用，我们的RNA-Seq和 来自年轻灵长类动物的病毒载体过表达数据也指出NT 3（神经营养因子3）-TrkC的改变 Ce内的信号传导是导致病理性焦虑的途径。进一步探讨行政首长协调会的作用 NT 3/TrkC和BDNF/TrkB系统在早期病理性焦虑中的作用，我们将使用病毒载体来调节 神经可塑性系统在Ce和直接调节Ce的前额叶通路。为了评估影响，我们 将使用独特的措施组合，包括：行为，神经成像，死后分析， RNA测序。除了体内实验，我们将使用来自恒河猴的Ce样神经元诱导 多能干细胞（iPSC），以研究细胞水平的机制。该提案中的实验 将提供证据表明，在灵长类动物中，Ce神经可塑性的改变参与了早期生活的焦虑 并将为探索焦虑患者的新治疗方法建立一个翻译理论基础， 萧条

PROJECT SUMMARY/ABSTRACT Alterations in neuroplasticity are strongly implicated in stress-related psychopathology. This proposal will use nonhuman primates (NHP) to investigate the extent to which altered neuroplasticity systems in the central nucleus of the amygdala (Ce) underlie anxious temperament (AT), the early risk phenotype for anxiety and depressive disorders. We will also investigate the effects of increasing neuroplasticity via an understudied, direct prefrontal cortex to Ce pathway, which will inform the development of pathway specific treatments focused on modulating Ce function. Anxiety disorders (ADs) commonly emerge during childhood, are highly prevalent, result in significant disability, and childhood onset predicts more severe and prolonged symptomatology. Despite current treatments, many individuals with ADs continue to be highly symptomatic and interventions aimed at mechanisms mediating the childhood onset of ADs would be ideal. To gain insights into the mechanisms underlying childhood ADs, and to conceptualize more effective interventions, we developed a NHP model of AT that is directly translatable to humans. Our studies demonstrate remarkable similarities between human and monkey AT, have elaborated AT’s neural circuit, and using RNA sequencing (RNA-Seq) have characterized molecular alterations in the Ce. To facilitate molecular, mechanistic studies, we developed intraoperative real-time MRI methods to reliably deliver viral vectors to select neural targets, including the Ce. Our work led us to posit a neurodevelopmental hypothesis suggesting that reduced neuroplasticity mechanisms in the Ce serve to maintain high levels of AT and its ultimate conversion to anxiety and depressive disorders. While much is known from rodent studies about the BDNF (brain-derived neurotrophic factor)-TrkB system in mediating fear, depressive behaviors, and antidepressant effects, our RNA-Seq and viral vector overexpression data from young primates also points to alterations in NT3 (neurotrophin 3)-TrkC signaling within the Ce as a pathway that contributes to pathological anxiety. To further explore the role of Ce NT3/TrkC and BDNF/TrkB systems in early-life pathological anxiety, we will use viral vectors to modulate neuroplasticity systems in the Ce and in a prefrontal pathway that directly regulates Ce. To assess effects we will use a unique combination of measures including: behavioral, neuroimaging, postmortem analyses, and RNA-Seq. Paralleling the in vivo experiments, we will use Ce-like neurons derived from rhesus induced pluripotent stem cells (iPSCs), to investigate mechanisms at a cellular level. The experiments in this proposal will provide evidence in primates for the involvement of altered Ce neuroplasticity in mediating early-life anxiety and will establish a translational rationale for exploring new therapeutic approaches in patients with anxiety and depression.