Interaction of acetylcholine and oxytocin neuromodulation in the hippocampus.

A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different neuromodulators compete or cooperate at various temporal scales remain an open question. We investigated the interaction of acetylcholine (ACh) and oxytocin (OXT) at slow and fast timescales during various brain states. Although these neuromodulators fluctuated in parallel during NREM packets, transitions from NREM to REM were characterized by a surge of ACh but a continued decrease of OXT. OXT signaling lagged behind ACh. High ACh was correlated with population synchrony and gamma oscillations during active waking, whereas minimum ACh predicts sharp-wave ripples (SPW-Rs). Optogenetic control of ACh and OXT neurons confirmed the active role of these neuromodulators in the observed correlations. Synchronous hippocampal activity consistently reduced OXT activity, whereas inactivation of the lateral septum-hypothalamus path attenuated this effect. Our findings demonstrate how cooperative actions of these neuromodulators allow target circuits to perform specific functions. • Hippocampal acetylcholine and oxytocin interact in a brain-state-dependent manner • Acetylcholine and oxytocin distinguish gamma oscillation from sharp-wave ripples • Acetylcholine suppresses ripples, whereas ripples decrease oxytocin levels • Acetylcholine modulates oxytocin through a long-loop hippocampal-lateral septum path Zhang and Karadas et al. use GRAB sensors and electrophysiology to unravel the interaction of acetylcholine and oxytocin at slow and fast timescales across brain states. Perturbation experiments reveal that acetylcholine modulates oxytocin through the hippocampus-lateral septum path, demonstrating how their cooperative actions enable specific functions. [ABSTRACT FROM AUTHOR]