How Fear Learning Alters Sensory Representations of Threat Predictive Stimuli

威胁或厌恶的刺激通常会引起健康的恐惧，在这种情况下，大脑的防御动机系统 推动保护性行为。当一个人或动物了解到一个特定的感官刺激预测未来 伤害，这种刺激也开始引起恐惧的反应。这就是所谓的后天恐惧。感官刺激是 身体上与威胁预测刺激相似或概念上相关的刺激通常也会引起恐惧，因为 他们有理由相信，他们也可以预测未来的伤害。这被称为习得性恐惧的泛化， 这是健康恐惧的一个正常部分。然而，许多美国人患有无序的恐惧，在这种恐惧中， 严重威胁(恐惧)或潜在威胁(焦虑)泛指不适当的刺激和可能 类似于创伤性事件或与创伤性事件有关，但实际上并不表示迫在眉睫的威胁。弄清楚 如何限制泛化，使患者只有在适当的情况下才感到恐惧，这是一个关键的实际挑战。 用于治疗焦虑症。关于焦虑症的生物学基础和习得性研究最多 恐惧主要集中在大脑学习最初恐惧和推断恐惧行为的机制上 在不同情况下。然而，越来越多的证据表明，习得的恐惧也会在 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的基础，如过度警惕和注意偏差 指向威胁预测刺激。在上一个项目期间，我们使用鼠标模型来观察 嗅觉系统的神经生物学在适当的恐惧期间发生了变化，并观察到恐惧学习使 嗅觉系统选择性地对威胁预测气味反应过度，产生神经“警报信号”，如 早在感觉输入到大脑的时候。相比之下，在这个项目期间，我们将探索更临床的- 恐惧泛化的相关情况，其中最初的创伤唤起了对新刺激的恐惧，但实际上可能并不是 预测威胁。在初步实验中，我们采用了一种实验范式，在该范式中，小鼠经历了 与特定气味相关的创伤经历，但随后会在许多新气味中概括他们的恐惧。 我们将测试这种体验是否会导致嗅觉系统非选择性地对 许多不同的气味，这可能会推动下游反应，似乎新的气味是危险的。我们会 还要研究有关创伤事件的信息到达嗅觉系统的神经回路。 并导致对许多不同气味的反应发生变化。最后，我们将对多名候选人进行评估 扭转恐惧泛化的行为和感觉后果的方法，包括比较 常规暴露(也称为利用原始创伤相关气味和新疗法进行治疗 旨在通过反复暴露于新的刺激或通过 在后续恐惧训练中，创伤明确地与实际的预测性刺激配对，而不是与非 威胁性刺激。

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.