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.

项目摘要 创伤后应激障碍（PTSD）是一种严重的公共卫生伯恩（Burnen）严重的使人衰弱的疾病。然而， α7烟碱乙酰胆碱受体（NACHR）为 PTSD疗法的显着分子靶标。乙酰胆碱调节恐惧学习和记忆过程 临床前模型中的慢性应激会降低PTSD患者的损害，而α7NACHR密度会降低。 尽管有这些令人信服的证据，但α7NACHR在人类PTSD的病理生理学中的作用并不完全 理解。为了解决这一差距，该提案将表征α7NACHR对行为和中性的贡献 暴露创伤的参与者中恐惧学习的标记代表了PTSD的全部严重程度。使用 [18F] ASEM，正电子发射断层扫描（PET）rADILIGAND特定于α7NACHR，我们获得了令人兴奋的 初步数据，表明与严重程度相关的PTSD患者的α7NACHR可用性较低 PTSD符号群集。此外，杏仁核中较低的α7NACHR可用性对应于弱 杏仁核和腹侧前额叶皮层的功能连通性，这是基础的关键电路 害怕学习过程。由这些令人兴奋的数据激发，该项目的主要目的是表征 α7NACHR对PTSD中恐惧扩展学习和电路的贡献。为了实现这一目标，我们将招募80 在PTSD符号的完整维度范围内取样了创伤暴露的参与者。全部 参与者将被[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 具体目标。 AIM 1将确定PTSD患者的α7NACHR可用性是否低于暴露的创伤 对照，哪些PTSD符号簇严重程度对应于较低的α7NACHR可用性。 AIM 2意志 确定杏仁核中较低的α7NACHR的可用性是否可以预测恐惧扩展期间学习率受损。目的 3将确定杏仁核中较低的α7NACHR的可用性是否会预测较弱的VMPFC-Amygdala连接性。 恐惧延伸。最终分析将确定杏仁核α7NACHR的可用性是否介导 杏仁核-VMPFC连接性，恐惧扩展学习率，评估这些受体一种机制 基本的破坏了PTSD中的恐惧延伸电路。这些发现将确定α7NACHR在 恐惧扩展的病理生理及其在活人中的大脑回路，告知未来的治疗发展 解决恐惧的扩展障碍，这是慢性PTSD症状的基础。