Noradrenergic neuromodulation of cholecystokinin interneurons in the basolateral amygdala alters rhythmic activity and restrains fear memory

Norepinephrine (NE) release in the basolateral amygdala (BLA) during emotional arousal plays an essential role in the processing of fear. However, the cell type-specific NE neuromodulation of the fear circuit in the BLA has not been fully resolved. We reported previously a facilitation of fear memory by Gq-coupled receptor induction of repetitive bursting in parvalbumin-expressing interneurons and suppression of gamma oscillations in the BLA. Here, using patch clamp recordings, Cre-dependent DLX-driven intersectional targeting, and genetic manipulations, we demonstrate that NE also activates cholecystokinin (CCK)-expressing interneurons to generate synchronized trains of rhythmic CB1-sensitive IPSCs in BLA principal neurons via Gq-coupled 1A adrenoreceptor activation. The Gq-dependent mechanism in CCK interneurons is generalizable to chemogenetic Gq manipulation and Gq-coupled 5-HT2C serotoninergic receptor activation. We next tested the role of Gq neuromodulation of CCK interneurons in the regulation of BLA network activity associated with the behavioral expression of fear learning by rescued expression of 1A adrenoreceptors or chemogenetic Gq activation selectively in BLA CCK interneurons in a global 1A adrenoreceptor knockout mouse. Restoration of the rhythmic inhibitory synaptic activity via rescue of Gq-coupled receptor signaling in CCK interneurons enhanced LFP theta power in the BLA in vivo and decreased fear memory acquisition and recall. These data indicate an inhibitory role for CCK interneuron Gq signaling in fear learning via activation of patterned inhibitory synaptic input to principal neurons and enhanced theta oscillations in the BLA, and reveal a G protein-dependent, receptor-nonselective neuromodulatory mechanism in the BLA that regulates network and behavioral states.