Layer 6 is a hub for cholinergic modulation in the mouse auditory cortex

TL;DR

The study shows that layer 6 pyramidal neurons in the mouse auditory cortex are a key hub for cholinergic signaling, working alongside layer 1 inhibitory neurons to modulate cortical circuits.

Contribution

The paper identifies layer 6 pyramidal neurons as a novel hub for cholinergic modulation in the auditory cortex, revealing distinct receptor mechanisms and circuit roles.

Findings

Layer 6 pyramidal neurons are enriched in nicotinic and muscarinic ACh receptor transcripts.

BFCN axon activation elicits fast nAChR-mediated excitation and slower mAChR-mediated inhibition in layer 6.

Layer 6 and layer 1 neurons represent two major hubs for cholinergic modulation in the auditory cortex.

Abstract

Basal forebrain cholinergic neurons (BFCNs) densely innervate auditory cortex (ACtx), conveying signals linked to internal brain states and external sensory cues. Acetylcholine (ACh) is known to rapidly modulate cortical circuits through nicotinic ACh receptor (nAChR)-mediated activation of layer 1 inhibitory neurons (L1-INs). However, BFCN terminals are also abundant in deeper layers, where their functional impact has received less attention. Using multi-plex in situ labeling across cortical layers and cell types, we found that layer 6 pyramidal neurons (L6-PNs) are highly enriched in diverse transcripts for nAChR subunits and muscarinic ACh receptors (mAChRs). In vivo optogenetic activation of BFCN axons revealed persistent modulation of regular spiking units in L2-6 but a rapid phasic activation only in L6. In acute slices, optogenetic activation of BFCN axons elicited fast nAChR-mediated excitatory post-synaptic potentials in L6-PNs, comparable to responses in L1-INs, and slower mAChR-mediated inhibitory responses. These findings identify L1-INs and excitatory L6-PNs as two major hubs for BFCN modulation of cortical circuits. By recruiting distinct receptor mechanisms and circuit motifs in L1 and L6, BFCNs may engage parallel pathways of cholinergic control that couple fast, transient modulation with slower, sustained regulation to shape cortical perception and plasticity.

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