Differential Regulation of Prelimbic and Thalamic Transmission to the Basolateral Amygdala by Acetylcholine Receptors

The amygdalar anterior basolateral nucleus (BLa) plays a vital role in emotional behaviors. This region receives dense cholinergic projections from basal forebrain which are critical in regulating neuronal activity in BLa. Cholinergic signaling in BLa has also been shown to modulate afferent glutamatergic inputs to this region. However, these studies, which have used cholinergic agonists or prolonged optogenetic stimulation of cholinergic fibers, may not reflect the effect of physiological acetylcholine release in the BLa. To better understand these effects of acetylcholine, we have used electrophysiology and optogenetics in male and female mouse brain slices to examine cholinergic regulation of afferent BLa input from cortex and midline thalamic nuclei. Phasic ACh release evoked by single pulse stimulation of cholinergic terminals had a biphasic effect on transmission at cortical input, producing rapid nicotinic receptor-mediated facilitation followed by slower mAChR-mediated depression. In contrast, at this same input, sustained ACh elevation through application of the cholinesterase inhibitor physostigmine suppressed glutamatergic transmission through mAChRs only. This suppression was not observed at midline thalamic nuclei inputs to BLa. In agreement with this pathway specificity, the mAChR agonist, muscarine more potently suppressed transmission at inputs from prelimbic cortex than thalamus. Muscarinic inhibition at prelimbic cortex input required presynaptic M4 mAChRs, while at thalamic input it depended on M3 mAChR-mediated stimulation of retrograde endocannabinoid signaling. Muscarinic inhibition at both pathways was frequency-dependent, allowing only high-frequency activity to pass. These findings demonstrate complex cholinergic regulation of afferent input to BLa that is pathway-specific and frequency-dependent.

Automated summary

The amygdalar anterior basolateral nucleus (BLa) plays a crucial role in emotional behaviors, receiving dense cholinergic projections from the basal forebrain and modulating glutamatergic inputs. Electrophysiology and optogenetics experiments in mouse brain slices reveal that cholinergic signaling in BLa has a biphasic effect on cortical inputs, with rapid facilitation followed by slower depression. However, sustained elevation of acetylcholine only suppresses glutamatergic transmission at cortical inputs, not at midline thalamic nuclei inputs. The inhibition at cortex input requires presynaptic M4 mAChRs, while at thalamic input it depends on M3 mAChR-mediated endocannabinoid signaling. The inhibition at both pathways is frequency-dependent, allowing only high-frequency activity to pass.