Fear extinction induces maladaptive generalization via noradrenergic and GABAergic systems - PubMed
5 days ago
- #noradrenergic circuit
- #GABAergic system
- #fear extinction
- Fear extinction in exposure therapy reduces conditioned fear but enhances fear generalization to safe stimuli.
- The maladaptive generalization is mediated by the locus coeruleus-dentate gyrus (LC-DG) noradrenergic circuit.
- LC norepinephrine release during extinction activates DG GABAergic neurons via β1-adrenergic receptors.
- This leads to a PKA/CREB-dependent signaling cascade and α4-GABAAR-mediated inhibition of granule cells, impairing threat discrimination.
- Genetic ablation of α4-GABAAR confirms their essential role in this process.
- Generalization can be prevented by targeting β1-AR blockade post-extinction or inhibiting PKA/CREB signaling.
- The findings highlight competing neural consequences of extinction: adaptive fear suppression and maladaptive generalization.
- Identified molecular targets and timing windows offer a framework for improving exposure-based therapies.