How Fear Learning Alters Sensory Representations of Threat Predictive Stimuli

恐惧学习如何改变威胁预测刺激的感官表征

• 批准号: 10087959
• 负责人: John P McGann
• 金额: $ 50.92万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087959
• 关键词: Acute; American; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Apical; Attention; Aversive Stimulus; Axon; Behavior; Behavioral; Belief; Biological; Brain; Categories; Cells; Clinical; Cues; Dangerousness; Data; Dendrites; Disease; Exhibits; Exposure to; Extinction (Psychology); Feeling; Fright; Funding; Future; Genetic Engineering; Hypersensitivity; Image; Interneurons; Learning; Mental Depression; Mental Health; Modeling; Motivation; Mus; Negative Reinforcements; Neurobiology; Neurons; Odors; Olfactory Nerve; Olfactory Pathways; Output; Patients; Peripheral; Persons; Play; Psychological reinforcement; Reaction; Research; Rest; Role; Science; Sensory; Shock; Signal Transduction; Stimulus; Symptoms; System; Testing; Training; Trauma; anxiety symptoms; attentional bias; base; clinically relevant; conditioning; experience; experimental study; follow-up; insight; mouse model; neural circuit; neurosensory; noradrenergic; novel; novel therapeutics; olfactory bulb; post-traumatic symptoms; protective behavior; relating to nervous system; response; sensory input; sensory stimulus; sensory system; spatiotemporal; traumatic event; treatment of anxiety disorders; vigilance

Threatening or aversive stimuli normally evoke healthy fear, in which the brain’s defensive motivational systems drive protective behaviors. When a person or animal learns that a particular sensory stimulus predicts future harm, that stimulus begins to evoke fearful reactions as well. This is called learned fear. Sensory stimuli that are physically similar or conceptually related to the threat-predictive stimulus normally also evoke fear because of the reasonable belief that they might also predict future harm. This is called generalization of learned fear, and it is a normal part of healthy fear. However, many Americans suffer from disordered fear, in which the feeling of acute threat (fear) or potential threat (anxiety) generalizes to inappropriate stimuli and situations that may resemble or be associated with traumatic events but do not actually indicate an impending threat. Figuring out how to limit generalization so that a patient is only fearful in appropriate situations is a key practical challenge for the treatment of anxiety disorders. Most research on the biological basis of anxiety disorders and learned fear has focused on the mechanisms by which the brain learns the initial fear and extrapolates fearful behavior across situations. However, evidence is accumulating that learned fear also evokes profound changes in the brain’s sensory systems. This includes becoming hyper-sensitive and hyper-responsive to threat-predictive stimuli in ways that may underlie common post-traumatic symptoms like hyper-vigilance and attentional bias toward threat-predictive stimuli. In the previous project period we used a mouse model to observe how the neurobiology of the olfactory system is changed during appropriate fear and observed that fear learning makes the olfactory system selectively hyper-responsive to threat-predictive odor, generating a neural “alarm signal” as early as the sensory input to the brain. In contrast, in this project period we will explore the more clinically- relevant situation of fear generalization, where initial trauma evokes fear of new stimuli that may not actually predict a threat. In preliminary experiments we employed an experimental paradigm in which mice undergo a traumatic experience associated with a particular odor but then generalize their fear across many novel odors. We will test whether this experience causes the olfactory system to become non-selectively hyper-responsive to many dissimilar odors, which might drive downstream responding as if the new odors are dangerous. We will also investigate the neural circuitry by which information about the traumatic event reaches the olfactory system and induces change in the response to many different odors. Finally, we will evaluate multiple candidate approaches to reverse the behavioral and sensory consequences of fear generalization, including comparing conventional exposure (a.k.a. extinction) therapy using the original trauma-associated odor with new therapy paradigms intended to “refine” the generalized fear either through repeated exposure to novel stimuli or through follow-up fear training in which the trauma is explicitly paired with actually predictive stimuli but not with non- threatening stimuli.

威胁性或厌恶性刺激通常会引起健康的恐惧，在这种情况下，大脑的防御性动机系统 驱动保护行为。当一个人或动物学习到一种特定的感官刺激可以预测未来时， 一旦受到伤害，这种刺激也会引起恐惧反应。这就是所谓的学习恐惧。感官刺激， 物理上相似或概念上与威胁预测刺激相关的刺激通常也会引起恐惧，因为 合理地相信他们也可能预测未来的伤害。这被称为习得性恐惧的泛化， 这是正常恐惧的一部分。然而，许多美国人患有混乱的恐惧， 急性威胁（恐惧）或潜在威胁（焦虑）概括为不适当的刺激和情况， 与创伤性事件相似或相关，但实际上并不表示即将发生的威胁。弄清楚 如何限制一般化，使病人只在适当的情况下感到恐惧，是一个关键的实际挑战 用于治疗焦虑症大多数关于焦虑症的生物学基础的研究 恐惧集中在大脑学习最初的恐惧并推断恐惧行为的机制上 在各种情况下。然而，越来越多的证据表明，习得性恐惧也会引起心理上的深刻变化。 大脑的感觉系统。这包括对威胁预测变得高度敏感和高度响应 刺激的方式，可能是常见的创伤后症状，如高度警惕和注意力偏差的基础 威胁预测性刺激在上一个项目期间，我们使用小鼠模型来观察 嗅觉系统的神经生物学在适当的恐惧过程中发生变化，并观察到恐惧学习使 嗅觉系统选择性地对威胁性气味作出高度反应，产生神经“警报信号”， 早在感觉输入到大脑的时候。相反，在这个项目期间，我们将探索更临床- 恐惧泛化的相关情况，其中最初的创伤引起对新刺激的恐惧， 预测威胁。在初步的实验中，我们采用了一种实验范式，其中小鼠经历了一个 一种与特定气味相关的创伤经历，然后将他们的恐惧推广到许多新的气味。 我们将测试这种经历是否会导致嗅觉系统对非选择性的过度反应。 许多不同的气味，这可能会驱使下游做出反应，好像新的气味是危险的。我们将 同时也研究创伤事件的信息到达嗅觉系统的神经回路 并引起对许多不同气味的反应的变化。最后，我们将评估多个候选人 扭转恐惧泛化的行为和感官后果的方法，包括比较 常规暴露（a.k.a.灭绝）疗法使用原始创伤相关气味和新疗法 范式旨在通过反复暴露于新的刺激或通过 后续的恐惧训练，其中创伤与实际预测的刺激明确配对，但不与非 威胁性的刺激