Acetylcholine engages distinct amygdala microcircuits to gate internal theta rhythm

Abstract

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in basolateral amygdala (BLA) in both humans and rodents have been shown to underlie emotional memory, yet their mechanism remains unclear. Here, using brain slice electrophysiology in male and female mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potentials that depend upon M3 muscarinic receptor activation of cholecystokinin (CCK) interneurons (INs) without the need for external glutamate signaling. Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, providing a functional SOM-CCK IN circuit connection gating BLA theta. Parvalbumin (PV) INs, which can drive BLA oscillations in baseline states, are not involved in the generation of ACh-induced theta, highlighting that ACh induces a cellular switch in the control of BLA oscillatory activity and establishes an internally BLA-driven theta oscillation through CCK INs. Theta activity is more readily evoked in BLA over cortex or hippocampus, suggesting preferential activation of BLA during high ACh states. These data reveal a SOM-CCK IN circuit in BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory.Significance statementWhile ACh plays a critical role in establishing network states enabling emotional behaviors, the mechanisms by which ACh acts on circuits involved in emotional processes remain unclear. The BLA receives dense cholinergic projections and plays a key role in emotional behaviors. Using electrophysiology recordings in mouse brain slices, we show that cholinergic stimuli readily induce theta oscillations in the BLA through CCK, but not PV INs. These oscillations are gated by SOM INs, establishing a CCK-SOM microcircuit in the generation of theta oscillations. Further, oscillatory activity is more readily induced in the BLA compared to hippocampus or cortex. These results reveal a detailed circuit-specific mechanism for ACh modulation of BLA theta oscillations that play a critical role in emotional processing.