Department of Psychology and the California National Primate Research Center, University of California, Davis, Davis, California.
Department of Cell Biology, Downstate Medical Center, State University of New York, Brooklyn, New York.
Biol Psychiatry. 2019 Dec 15;86(12):881-889. doi: 10.1016/j.biopsych.2019.06.022. Epub 2019 Jul 2.
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.
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).
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.
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.
儿童早期焦虑气质（AT）是焦虑、抑郁和共病物质滥用发展的风险因素。我们验证了一种非人类灵长类动物的早期生活 AT 模型，并确定背侧杏仁核是 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、功能脑成像和行为表型分析，揭示 AT 的分子基础。
在 46 只年轻恒河猴中，我们根据潜在威胁评估了 AT 和大脑代谢。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 测序数据来识别与 AT 相关的转录本。基于这些结果，我们使用术中磁共振成像引导手术在背侧杏仁核中过表达神经营养因子 3 基因（NTF3）（每组 5 只）。
这种基于发现的方法确定了与 AT 相关的表达变化的既定和新基因，包括 NTRK3 表达与 AT 之间的反比关系。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，调节细胞内神经可塑性途径。在背侧杏仁核中过表达 NTRK3 的内源性配体 NTF3 的转录本会导致 AT 减少和 AT 神经回路功能改变。
这些数据共同表明，背侧杏仁核中的神经营养因子 3/NTRK3 信号在调节灵长类动物焦虑中起作用。更普遍地说，这种方法为理解早期生活 AT 的分子基础提供了重要的一步，并将有助于指导开发预防应激相关精神病理学的治疗方法。
