Neuroimaging Cholinergic Mechanisms of Fear Extinction in PTSD

PTSD 恐惧消退的神经影像学胆碱能机制

• 批准号: 10734244
• 负责人: Ansel Hillmer
• 金额: $ 83.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734244
• 关键词: Acetylcholine; Address; Amygdaloid structure; Anti-Anxiety Agents; Arousal; Basic Science; Behavioral; Brain; Brain region; Chronic Post Traumatic Stress Disorder; Chronic stress; Computer Models; Data; Development; Dimensions; Disease; Evaluation; Exhibits; Extinction; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hippocampus; Human; Image; Impairment; Individual; Learning; Link; Maps; Measures; Mediating; Molecular Target; Neurosciences; Nicotinic Receptors; Participant; Persons; Pharmacological Treatment; Pharmacotherapy; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prefrontal Cortex; Process; Public Health; Receptor Signaling; Reporting; Role; Sampling; Sampling Studies; Scanning; Severities; Symptoms; Therapeutic; Translating; acetylcholine receptor agonist; alpha-bungarotoxin receptor; anxious; cholinergic; clinical development; clinically relevant; diagnostic criteria; human study; improved; learning extinction; meetings; memory process; multidisciplinary; multimodality; neural; neural circuit; neuroimaging; neuronal circuitry; physiologic model; pre-clinical; radioligand; receptor; receptor density; recruit; response; symptom cluster; therapeutic development; trauma exposure

PROJECT SUMMARY Post-traumatic stress disorder (PTSD) is a deeply debilitating disorder with severe public health burden. Yet, current pharmacological treatments are glaringly suboptimal. The α7 nicotinic acetylcholine receptor (nAChR) is a salient molecular target for PTSD therapeutics. Acetylcholine regulates fear learning and memory processes that are impaired in people with PTSD, and α7 nAChR density is reduced by chronic stress in preclinical models. Despite this compelling evidence, the role of α7 nAChRs in the pathophysiology of PTSD in humans is not fully understood. To address this gap, this proposal will characterize α7 nAChR contributions to behavioral and neural markers of fear learning in trauma-exposed participants representing the full spectrum of PTSD severity. Using [18F]ASEM, a positron emission tomography (PET) radioligand specific to α7 nAChRs, we obtained exciting preliminary data indicating lower α7 nAChR availability in people with PTSD that is associated with the severity of PTSD symptom clusters. Further, lower α7 nAChR availability in amygdala corresponded to weakened functional connectivity of the amygdala and ventromedial prefrontal cortex, which is a key circuit that underpins fear learning processes. Motivated by these exciting data, the primary objective of this project is to characterize α7 nAChR contributions to fear extinction learning and circuitry in PTSD. To achieve this goal, we will recruit 80 participants with trauma exposure sampled across the full dimensional spectrum of PTSD symptoms. All participants will be scanned with [18F]ASEM PET and participate in an established fear reversal task with concurrent functional magnetic resonance imaging (fMRI). The acquired data will be used to address three Specific Aims. AIM 1 will determine if people with PTSD have lower α7 nAChR availability than trauma exposed controls, and which PTSD symptom cluster severities correspond to lower α7 nAChR availability. AIM 2 will determine if lower α7 nAChR availability in amygdala predicts impaired learning rates during fear extinction. AIM 3 will determine if lower α7 nAChR availability in amygdala predicts weaker vmPFC-amygdala connectivity during fear extinction. A final analysis will determine if amygdala α7 nAChR availability mediates the relationship of amygdala-vmPFC connectivity with fear extinction learning rates, assessing these receptors a mechanism underlying disrupted fear extinction circuits in PTSD. The findings will determine α7 nAChR roles in the pathophysiology of fear extinction and its brain circuits in living people, informing future therapeutic development to address fear extinction impairments that underlie chronic PTSD symptoms.

项目概要 创伤后应激障碍（PTSD）是一种使人严重衰弱的疾病，给公共健康带来严重负担。然而， 目前的药物治疗显然不是最理想的。 α7 烟碱乙酰胆碱受体 (nAChR) 是 PTSD 治疗的一个重要分子靶点。乙酰胆碱调节恐惧学习和记忆过程 PTSD 患者的 α7 nAChR 密度受到损害，并且临床前模型中的慢性应激会降低 α7 nAChR 密度。 尽管有这些令人信服的证据，α7 nAChR 在人类 PTSD 病理生理学中的作用尚不完全清楚。 明白了。为了解决这一差距，该提案将描述 α7 nAChR 对行为和神经的贡献 遭受创伤的参与者的恐惧学习标记代表了 PTSD 严重程度的全部范围。使用 [18F]ASEM，一种针对 α7 nAChR 的正电子发射断层扫描 (PET) 放射性配体，我们获得了令人兴奋的结果 初步数据表明，PTSD 患者的 α7 nAChR 可用性较低，且与严重程度相关 PTSD 症状群。此外，杏仁核中较低的 α7 nAChR 可用性对应于减弱 杏仁核和腹内侧前额叶皮层的功能连接，这是支撑的关键回路 恐惧学习过程。在这些令人兴奋的数据的推动下，该项目的主要目标是表征 α7 nAChR 对 PTSD 恐惧消退学习和回路的贡献。为实现这一目标，我们将招募80名 经历创伤暴露的参与者在 PTSD 症状的全维度范围内进行采样。全部 参与者将接受 [18F]ASEM PET 扫描，并参与既定的恐惧逆转任务 并发功能磁共振成像（fMRI）。获得的数据将用于解决三个问题 具体目标。 AIM 1 将确定患有 PTSD 的人的 α7 nAChR 可用性是否低于遭受创伤的人 对照，以及哪些 PTSD 症状群严重程度对应于较低的 α7 nAChR 可用性。 AIM 2 将 确定杏仁核中较低的 α7 nAChR 可用性是否预示着恐惧消退期间学习率受损。目的 3 将确定杏仁核中较低的 α7 nAChR 可用性是否预示着 vmPFC-杏仁核连接较弱 恐惧灭绝。最终分析将确定杏仁核 α7 nAChR 可用性是否介导以下关系： 杏仁核-vmPFC 连接与恐惧消退学习率，评估这些受体的机制 PTSD 中潜在的恐惧消退回路被破坏。研究结果将确定 α7 nAChR 在 恐惧消退的病理生理学及其在活人中的大脑回路，为未来的治疗发展提供信息 解决慢性创伤后应激障碍症状背后的恐惧消退障碍。