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: 10312005
• 负责人: John P McGann
• 金额: $ 50.72万
• 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/10312005
• 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.

威胁或厌恶刺激通常会引起健康的恐惧，其中大脑的防御动机系统 驱动保护行为。当一个人或动物得知特定的感官刺激预测未来时 危害，这种刺激也开始引起可怕的反应。这被称为学习的恐惧。感官刺激 与威胁可预测的刺激在物理上相似或概念上相关，通常也引起恐惧 合理的信念，即他们也可以预测未来的伤害。这称为学习恐惧的概括，以及 这是健康恐惧的正常部分。但是，许多美国人遭受恐惧的障碍，其中的感觉 急性威胁（恐惧）或潜在威胁（焦虑）概括为不适当的刺激和可能 类似于或与创伤事件相关，但实际上并不表示即将来临的威胁。弄清楚 如何限制概括，使患者只有在适当情况下害怕是一个关键的实际挑战 治疗焦虑症。大多数关于焦虑症的生物学基础的研究和学会的研究 恐惧集中在大脑学习最初恐惧并推断恐惧行为的机制上 跨境。但是，有证据表明，学到的恐惧也引起了人们的深刻变化 大脑的感觉系统。这包括变得过敏和过度响应对威胁预测性 刺激以可能是普遍的创伤后症状的方式刺激 面向威胁性预测的刺激。在上一个项目期间，我们使用鼠标模型观察 在适当的恐惧中改变了嗅觉系统的神经生物学，并观察到恐惧学习使 嗅觉系统有选择地对威胁可预测性的气味有选择性地产生神经“警报信号” 早在大脑的感觉输入中。相比之下，在这个项目期间，我们将探索临床越多 - 恐惧概括的相关情况，最初的创伤引起了人们对新刺激的恐惧 预测威胁。在初步实验中，我们雇用了一个实验范式，其中小鼠经历了A 与特定气味相关的创伤经历，但随后将其恐惧概括为许多新型气味。 我们将测试这种经验是否会导致嗅觉系统变得非选择性超反应性 许多不同的气味可能会驱动下游的反应，好像新的气味很危险。我们将 还要研究神经回路，有关创伤事件的信息到达嗅觉系统 并影响对许多不同气味的反应变化。最后，我们将评估多个候选人 扭转恐惧概括的行为和感官后果的方法，包括比较 使用原始创伤相关的气味与新疗法的常规暴露（又名扩展）疗法 旨在通过反复接触新型刺激或通过 后续的恐惧训练，其中创伤明确与实际预测性刺激相结合，但没有与非 - 威胁刺激。