SYNERGISTIC CONTROL OF AMYGDALA NETWORK DYNAMICS BY NOREPINEPHRINE AND ACETYLCHOLINE

Acetylcholine (ACh) and norepinephrine (NE) are key regulators of internal brain states such as arousal and vigilance. While their effect on ionic and synaptic mechanisms are well established, how their interaction shapes network dynamics and drives brain-state transitions in vivo remains poorly understood. Here, we combined experimental and theoretical approaches to dissect NE–ACh interactions in the amygdala, a central hub for state-dependent processing.
Using simultaneous monitoring of NE and ACh alongside large-scale in vivo electrophysiology in awake mice, we characterize how the joint action of the two neuromodulators influenced neuronal activity. We clustered the neurons according to their latent dynamics and quantified the sensitivity of each subpopulation to independent and joint neuromodulation. Contrary to the general excitatory effects described ex vivo, NE and ACh release triggers heterogeneous responses across neurons in vivo. Notably, a distinct subpopulation of ~30% of the neurons exhibits a supra-additive increase in firing when both NE and ACh are co-released, indicating a synergistic interaction.
To explain the underlying mechanism, we developed a mean-field model incorporating different ACh and NE-dependent modulation of neuronal and synaptic properties. Bifurcation analysis revealed that the combination effect of ACh on presynaptic facilitation and NE on neuronal gain recapitulates the observed population dynamics and explains emergent effects not explicitly imposed in the model, including increased inhibitory neuron firing and suppressed activity in a subset of excitatory neurons.
Together, these results reveal how NE–ACh interactions reorganize amygdala network dynamics during behavior and provide a mechanistic framework for understanding neuromodulator-driven brain-state transitions.