University of California, Department of Psychology, Davis, CA, USA.
California National Primate Research Center, Davis, CA, USA.
Transl Psychiatry. 2024 Mar 15;14(1):148. doi: 10.1038/s41398-024-02858-3.
Anxiety disorders affect millions of people worldwide and impair health, happiness, and productivity on a massive scale. Developmental research points to a connection between early-life behavioral inhibition and the eventual development of these disorders. Our group has previously shown that measures of behavioral inhibition in young rhesus monkeys (Macaca mulatta) predict anxiety-like behavior later in life. In recent years, clinical and basic researchers have implicated the central extended amygdala (EAc)-a neuroanatomical concept that includes the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST)-as a key neural substrate for the expression of anxious and inhibited behavior. An improved understanding of how early-life behavioral inhibition relates to an increased lifetime risk of anxiety disorders-and how this relationship is mediated by alterations in the EAc-could lead to improved treatments and preventive strategies. In this study, we explored the relationships between infant behavioral inhibition and peri-adolescent defensive behavior and brain metabolism in 18 female rhesus monkeys. We coupled a mildly threatening behavioral assay with concurrent multimodal neuroimaging, and related those findings to various measures of infant temperament. To score the behavioral assay, we developed and validated UC-Freeze, a semi-automated machine-learning (ML) tool that uses unsupervised clustering to quantify freezing. Consistent with previous work, we found that heightened Ce metabolism predicted elevated defensive behavior (i.e., more freezing) in the presence of an unfamiliar human intruder. Although we found no link between infant-inhibited temperament and peri-adolescent EAc metabolism or defensive behavior, we did identify infant nervous temperament as a significant predictor of peri-adolescent defensive behavior. Our findings suggest a connection between infant nervous temperament and the eventual development of anxiety and depressive disorders. Moreover, our approach highlights the potential for ML tools to augment existing behavioral neuroscience methods.
焦虑障碍影响着全球数百万人的健康、幸福和生产力。发展研究表明，早期行为抑制与这些障碍的最终发展之间存在联系。我们的研究小组之前曾表明，幼年恒河猴（Macaca mulatta）的行为抑制测量值可预测其日后的焦虑样行为。近年来，临床和基础研究人员认为，中央延伸杏仁核（EAc）——包括杏仁核中央核（Ce）和终纹床核（BST）的神经解剖学概念——是表达焦虑和抑制行为的关键神经基质。更好地理解早期行为抑制如何与焦虑障碍终生风险增加有关，以及这种关系如何通过 EAc 的改变来介导，可能会导致改善治疗和预防策略。在这项研究中，我们探索了 18 只雌性恒河猴婴儿期行为抑制与青春期前防御行为和大脑代谢之间的关系。我们将轻度威胁行为测定与同期多模态神经影像学相结合，并将这些发现与婴儿气质的各种测量方法联系起来。为了对行为测定进行评分，我们开发并验证了 UC-Freeze，这是一种使用无监督聚类来量化冻结的半自动机器学习（ML）工具。与之前的工作一致，我们发现 Ce 代谢升高预测了在陌生人类入侵者面前防御行为（即更多冻结）的增加。虽然我们没有发现婴儿抑制气质与青春期前 EAc 代谢或防御行为之间的联系，但我们确实发现婴儿神经质气质是青春期前防御行为的重要预测指标。我们的研究结果表明，婴儿神经质气质与焦虑和抑郁障碍的最终发展之间存在联系。此外，我们的方法强调了机器学习工具增强现有行为神经科学方法的潜力。
