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

The infralimbic cortex (IL) is critical for the extinction of conditioned fear and receives dense cholinergic innervation from the basal forebrain, notably 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 transgenic rats, we silenced the HDB to IL cholinergic pathway during fear conditioning or extinction. Silencing during fear conditioning had no effect, while doing so during extinction enhanced extinction retrieval and prevented fear renewal. This effect was anatomically specific, as silencing the neighboring HDB to prelimbic cortex pathway had no effect. In ex vivo IL slices, stimulation of HDB cholinergic terminals preferentially excited superficial layer interneurons, consistent with feedforward inhibition of IL pyramidal neurons. Finally, blockade of IL nicotinic, but not muscarinic, acetylcholine receptors during extinction fully reproduced the effects of silencing the pathway. These findings indicate that cholinergic input from the HDB to the IL controls the durability and contextual specificity of extinction and identify nicotinic signaling in the IL as a potential target for improving extinction-based therapies.