Fear extinction induces maladaptive generalization via noradrenergic and GABAergic systems

• 成果类型: Article
• 署名作者: Zheng, Aiqiu; Yu, Dan; Meng, Xin; Gong, Shumin; Ye, Jiale; Zhou, Hui; Chen, Mo; An, Shuming; Ma, Jun; Li, Can; Cao, Jun - Li; Wu, Kunwei
• 署名单位: Xuzhou Medical University; Xuzhou Medical University; Xuzhou Medical University; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2521767123
• 发表日期: 2026-03-10
• 页码: e2521767123
• 关键词: fear memory; locus coeruleus; GABAA receptors; PTSD; ANXIETY; dentate gyrus; pattern separation; locus-coeruleus; stress; activation; neurogenesis; interneurons; modulation; plasticity; disorder

摘要

Exposure therapy for anxiety disorders relies on fear extinction to reduce pathological fear responses. Here, we show that while effective at diminishing conditioned fear, extinction training paradoxically enhances fear generalization to safe stimuli through activation of the locus coeruleus-dentate gyrus (LC-DG) noradrenergic circuit. Specifically, LC norepinephrine release during extinction stimulates DG GABAergic neurons via beta 1-adrenergic receptors, engaging a PKA/CREB-dependent signaling cascade that ultimately leads to alpha 4-GABAAR-mediated inhibition of granule cells and impaired threat discrimination. Genetic ablation of alpha 4-GABAAR confirms their essential role. Crucially, this generalization can be prevented by targeting the pathway at distinct points: beta 1-AR blockade immediately after extinction or pharmacological inhibition of the PKA/CREB signal during the same postextinction window. These findings reveal that extinction produces competing neural consequences-adaptive fear suppression coupled with LC-DG-mediated maladaptive generalization. The identified molecular targets and their critical timing windows provide a neurobiological framework for improving exposure-based therapies.