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Taking Action in the Face of Fear: The Neural Substrates of Active Avoidance Learning in Humans.

机译：面对恐惧采取行动：人类主动回避学习的神经基础。

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摘要

Active avoidance (AA) learning is a two-step form of threat learning in which the learner acquires a behavioral strategy to avoid exposure to a threatening stimulus. About eighty percent of wild type rodents evince effective avoidance after adequate training; the other twenty percent continue to display conditioned fear responses and rarely avoid aversive stimuli. Scientists have exploited this natural variation in AA behavior both to illuminate the neurobiology of animal AA, and to model both anxiety and addiction in rodents. The experimental paradigms designed for use in humans, however, have failed to capture individual differences in AA learning or expression. It has been challenging, as a result, in humans both to identify the neural correlates of effective AA and to determine the nature of the relationship between AA and psychological constructs.;In order to meet these objectives, we developed a novel and translational task to investigate AA in humans. In the current manuscript we describe four studies in which we: pilot the task (Study 1); use functional magnetic resonance imaging (fMRI) to document the brain regions that mediate human AA (Study 2); and explore the role of noradrenergic neurotransmission in human AA (Studies 3 and 4). In Study 1, we demonstrate the capacity of our task to elicit variable patterns of AA behavior. We find evidence in Study 2 that the amygdala, striatum, and medial prefrontal cortex (mPFC) are key mediators of this process. Specifically, participants suppressed the right amygdala but activated the right caudate during AA acquisition, while the mPFC influenced avoidance by interacting with both of these subcortical structures. Though beta-adrenergic antagonist propranolol enabled the expression of AA in animals that exhibited robust conditioned fear responses in initial training sessions, we did not document an effect of the drug on human AA in either Study 3 or 4. We review how our data might inform future investigations of avoidance.;Finally we discuss the potential utility of our task as a tool to probe the pathophysiology of psychiatric disease. While we did not detect consistent correlations between AA performance and self-reports of either anxiety or impulsivity, we propose that such associations may only exist in clinical populations. We argue that, even if additional research does not demonstrate that AA behavior is an effective gauge of vulnerability to mental illness, our experimental protocol engages many of the neurocircuits implicated in disorders of emotion regulation and could still advance scientific understanding of mood, anxiety, and substance use disorders.
机译：主动回避（AA）学习是威胁学习的两步形式，学习者获得一种行为策略，以避免接触威胁性刺激。经过充分培训后，约有80％的野生型啮齿动物表明需要有效避免。另外20％的人继续表现出有条件的恐惧反应，很少避免厌恶刺激。科学家们利用AA行为的这种自然变化来阐明动物AA的神经生物学，并为啮齿动物的焦虑和成瘾建模。但是，设计用于人类的实验范式未能捕捉到AA学习或表达的个体差异。结果，对于人类而言，既要确定有效AA的神经相关性，又要确定AA与心理构造之间的关系的性质一直具有挑战性。为了实现这些目标，我们开发了一种新颖的翻译任务调查人类的机管局。在当前的手稿中，我们描述了四项研究：试行任务（研究1）；使用功能磁共振成像（fMRI）记录介导人类AA的大脑区域（研究2）；并探讨去甲肾上腺素能神经传递在人AA中的作用（研究3和4）。在研究1中，我们证明了我们的任务能够引发AA行为的可变模式的能力。在研究2中，我们发现杏仁核，纹状体和内侧前额叶皮层（mPFC）是这一过程的关键介体。具体来说，参与者抑制了右杏仁核，但在AA采集过程中激活了右尾状核，而mPFC通过与这两个皮层下结构相互作用而影响了回避。尽管β-肾上腺素能拮抗剂普萘洛尔在初始训​​练中能表现出强烈的条件恐惧反应的动物表达AA，但我们在研究3或4中均未记录到该药物对人AA的影响。最后，我们将讨论这项任务作为一种工具来探讨精神疾病的病理生理学的潜在效用。虽然我们没有发现AA表现与焦虑或冲动自我报告之间的一致性相关性，但我们建议这种关联可能仅存在于临床人群中。我们认为，即使其他研究未证明AA行为是衡量精神疾病易感性的有效指标，我们的实验方案也能使许多与情绪调节障碍有关的神经回路参与其中，并且仍可以促进对情绪，焦虑和物质使用障碍。

著录项

  • 作者

    Collins, Katherine A.;

  • 作者单位

    Icahn School of Medicine at Mount Sinai.;

  • 授予单位 Icahn School of Medicine at Mount Sinai.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 99 p.
  • 总页数 99
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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