Localizing and modulating competing memories of fear and safety in the human brain

定位和调节人脑中关于恐惧和安全的竞争记忆

• 批准号: 10329994
• 负责人: Joseph Edward Dunsmoor
• 金额: $ 56.05万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10329994
• 关键词: Adult; Affect; American; Amygdaloid structure; Animal Experimentation; Animal Model; Animals; Anxiety; Anxiety Disorders; Arousal; Award; Behavior; Behavioral; Brain; Brain region; Categories; Clinical; Clinical Research; Clinical Treatment; Code; Data; Dorsal; Emotional; Episodic memory; Event; Exposure to; Extinction (Psychology); Failure; Feeling; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Gold; Hippocampus (Brain); Hour; Human; Hybrids; Image; Individual; Information Retrieval; Knowledge; Learning; Link; Measurable; Memory; Mental Health; Mental disorders; Modeling; Motivation; Neurosciences; Outcome; Pathogenesis; Pathological anxiety; Pathology; Patients; Pattern; Phase; Physiological; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevalence; Psychiatric therapeutic procedure; Recovery; Relapse; Research; Retrieval; Risk; Rodent; Safety; Semantics; Series; Site; Stress; Symptoms; Techniques; Testing; Time; Training; Translating; Visual; Work; anxiety treatment; base; classical conditioning; conditioned fear; conditioning; diagnostic criteria; endophenotype; fear memory; human model; improved; innovation; insight; learning extinction; memory encoding; memory recognition; memory retrieval; neuroimaging; neurophysiology; novel; relating to nervous system; resilience; response; standard care; stress disorder; stress related disorder

PROJECT SUMMARY. Pathologies characterized by excessive fear and anxiety are the most common mental illness with a 12-month prevalence estimate of about 40 million American adults. The primary treatment for anxiety and stress-related disorders is exposure therapy, which is informed by theoretical and technical aspects of Pavlovian extinction. However, extinguished behaviors are prone to relapse under a variety of circumstances. Further, clinical research reveals serious deficits across a host of psychiatric conditions in the ability to form and retrieve extinction memories, which likely contributes to relapse following extinction-based therapies. Accordingly, there is strong motivation to better understand how extinction memories are encoded, stored, and expressed so as to bolster the strength and generalization of clinical treatment. Pioneering research in rodents reveals that fear conditioning and extinction generate separate and measurable memory traces within and across discrete brain regions. Whether such an organization exists in the human brain is unknown. More precise knowledge on how threat and safety memories are represented and interact in the human brain will advance innovative treatments for pathological anxiety that are built on the neuroscience of learning and memory. The goal of this research is to better understand how competing memories of fear and safety are formed, stored, and retrieved in the human brain. To build directly on mechanistic insights from animal models, we utilize Pavlovian fear conditioning and extinction in adult humans during functional magnetic resonance imaging (fMRI). The research leverages advances in multivariate pattern analysis techniques, and integrates theoretical and technical advancements of fear extinction research from animal models with computational approaches developed to study human memory. Each study includes healthy adults and individuals with posttraumatic stress disorder (PTSD), as linking advances in fear extinction research to the pathophysiology of PTSD can have direct benefit to exposure therapy—the gold-standard treatment based on the principles of extinction. We also evaluate extinction memory at 24-hours and again at 1 month. Assessing long-term extinction retrieval in humans is extremely rare, but consistent with diagnostic criteria for assessing PTSD, and thus furthers the bridge to translational relevance. Aim 1 attempts to identify separate and stable memory traces of fear and extinction in by identifying the correspondence (overlap) between neural activity related to the formation and retrieval of fear and extinction over time. Aim 2 decodes a multivariate neural signature selective to the contextual encoding of extinction memories. Aim 3 uses a non-pharmacological behavioral strategy to modulate the strength of extinction to determine how enhanced fear extinction affects multivariate neural signature of extinction memory retrieval over time. These findings have the potential to establish new risk and resilience factors for anxiety and stress-related pathologies, and may ultimately contribute to innovative neuroscience-based treatments for psychiatric conditions marked by excessive fear and the inability to regulate unwanted emotional responses.

项目摘要。以过量恐惧和动画为特征的病理是最常见的心理 大约4000万美国成年人的12个月患病率估计疾病。主要治疗 焦虑和与压力相关的疾病是暴露疗法，这是由理论和技术方面告知的 Pavlovian扩展。但是，在各种情况下，熄灭的行为易于中继。 此外，临床研究还揭示了在形成能力和形成能力方面的许多精神病条件下的严重防御能力 检索扩展记忆，这可能有助于基于扩展的疗法后继电器。 彼此之间，有强大的动力可以更好地了解扩展记忆的编码，存储以及 表达了促进临床治疗的强度和概括。啮齿动物的开创性研究 揭示恐惧调节和扩展会在内部和跨越可测量的记忆痕迹 离散的大脑区域。这种组织是否存在于人脑中是未知的。更精确 关于如何代表威胁和安全记忆的知识，并在人脑中互动会发展 建立在学习和记忆的神经科学上的病理焦虑的创新治疗方法。 这项研究的目标是更好地了解如何形成，存储恐惧和安全的回忆以及 在人脑中检索。为了直接建立在动物模型的机械见解的基础上，我们利用了Pavlovian 在功能磁共振成像（fMRI）期间，成年人的恐惧调节和扩展。 研究利用多元模式分析技术的进步，并整合理论和技术 恐惧扩展研究的进步来自动物模型，其开发的计算方法 研究人类记忆。每项研究包括健康的成年人和创伤后应激障碍的人 （PTSD），因为将恐惧扩展研究的进步与PTSD的病理生理联系起来可以直接利益 暴露疗法 - 基于扩展原理的金色标准疗法。我们还评估 在24小时内延长内存，并在1个月再次进行。评估人类的长期扩展检索是 极为罕见，但与评估PTSD的诊断标准一致，从而进一步促进了桥梁 翻译相关性。 AIM 1尝试识别恐惧和扩展的单独稳定记忆痕迹 通过确定与形成和检索有关的神经活动之间的对应关系（重叠） 和随着时间的推移。 AIM 2将多元神经签名选择性解码为上下文编码 扩展记忆。 AIM 3使用非药理行为策略来调节 扩展以确定增强的恐惧扩展如何影响扩展记忆的多元神经标志 随着时间的流逝检索。这些发现有可能建立动画的新风险和弹性因素， 与压力相关的病理，并最终可能有助于基于创新的神经科学治疗 过度恐惧和无法调节不必要的情绪反应的精神病条件。