BACKGROUND An early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates. METHODS In response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging-guided surgery (n = 5 per group). RESULTS This discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit. CONCLUSIONS Together, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology.

中文翻译：

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背杏仁核神经营养素3降低灵长类动物的焦虑气质

背景技术生命早期的焦虑气质（AT）是发生焦虑、抑郁和共病药物滥用的危险因素。我们验证了早期 AT 的非人类灵长类动物模型，并将背侧杏仁核确定为 AT 神经回路的核心组成部分。在这里，我们结合 RNA 测序、病毒载体基因操作、功能性脑成像和行为表型来揭示 AT 的分子底物。方法 为了应对潜在威胁，我们对 46 只年轻恒河猴的 AT 和脑代谢进行了评估。我们使用来自背侧杏仁核组织（包括杏仁核中央核 [Ce] 和基底核背侧区域）的 RNA 测序数据鉴定了 AT 相关转录本。根据结果​​，我们使用术中磁共振成像引导手术在背侧杏仁核中过度表达神经营养素 3 基因 NTF3（每组 n = 5）。结果这种基于发现的方法确定了已确定的新基因表达中与 AT 相关的改变，包括 NTRK3 表达与 AT 之间的负相关。NTRK3 是一个有趣的靶点，因为它是一种相对未被探索的神经营养因子，可调节细胞内神经可塑性途径。NTRK3 的内源配体 NTF3 转录本在背侧杏仁核中过度表达，导致 AT 减少并改变 AT 神经回路的功能。结论 总之，这些数据表明背侧杏仁核中的神经营养蛋白-3/NTRK3 信号传导介导灵长类动物的焦虑。更一般地说，这种方法为理解生命早期 AT 的分子基础迈出了重要的一步，并将有助于指导治疗方法的开发，以防止与压力相关的精神病理学的发展。