Fear extinction induces maladaptive generalization via noradrenergic and GABAergic systems
Abstract
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 β1-adrenergic receptors, engaging a PKA/CREB-dependent signaling cascade that ultimately leads to α4-GABA A R-mediated inhibition of granule cells and impaired threat discrimination. Genetic ablation of α4-GABA A R confirms their essential role. Crucially, this generalization can be prevented by targeting the pathway at distinct points: β1-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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Aiqiu Zheng
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University
Dan Yu
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University
Xin Meng
Shumin Gong
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University
Jiale Ye
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University
Hui Zhou
Department of Chemistry and Materials
Mo Chen
Obstetrics and Gynecology Hospital of Fudan University Shanghai China
Shuming An
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University
Jun Ma
Can Li
State Key Laboratory of Catalysis
Jun-Li Cao
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University
Kunwei Wu
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, National Medical Products Administration Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University