Silencing basal forebrain cholinergic input to the infralimbic cortex renders fear extinction resistant to renewal

Abstract

The infralimbic cortex (IL) is critical for the extinction of conditioned fear and receives dense cholinergic innervation from the basal forebrain, particularly from the horizontal limb of the diagonal band of Broca (HDB). Acetylcholine release in the IL regulates fear-related processes, but the mechanisms involved remain poorly understood. We investigated whether cholinergic projections from the HDB to the IL regulate the formation, extinction, and renewal of fear memories. Using optogenetics in male and female transgenic rats, we silenced the HDB to IL cholinergic pathway during either fear conditioning or extinction. Silencing during fear conditioning had no effect, whereas silencing during extinction enhanced extinction retrieval and prevented fear renewal. These effects were anatomically specific, as silencing the neighboring HDB to prelimbic cortex pathway had no such consequence. In ex vivo IL slices, stimulation of HDB cholinergic terminals preferentially excited interneurons over pyramidal neurons, consistent with feedforward inhibition of IL output. Finally, blockade of IL nicotinic acetylcholine receptors during extinction fully reproduced the effects of silencing the pathway, whereas muscarinic blockade attenuated renewal without affecting extinction retrieval. These findings indicate that cholinergic input from the HDB to the IL controls the acquisition and contextual specificity of extinction and identify nicotinic signaling in the IL as a potential target for improving extinction-based therapies.