Dynamic cholinergic signaling differentially desynchronizes cortical microcircuits dependent on modulation rate and network connectivity

Acetylcholine (ACh) affects both the intrinsic properties of individual neurons and the oscillatory tendencies of cortical microcircuits by modulating the muscarinic-receptor gated m-current. ACh concentrations have historically been assumed to vary exclusively over long (supra-second) neuromodulatory timescales, conventionally simplified in silico as a set and constant modulatory tone. However, contemporary experimental studies show cortical ACh concentrations change over sub-second timescales associated with cognitive tasks including attention and sensorimotor coordination. More realistic models reflecting dynamic, sub-second fluctuations in cholinergic tone have yet to be computationally studied. Using a new implementation of a time-varying cholinergic signal in computational excitatory-inhibitory (E-I) spiking neuronal networks, we here delineate how the interaction between dynamic cholinergic modulation and network connectivity influences these systems’ oscillatory tendencies. Synchrony in networks with dominant inter-connectivity (strong E-to-I and I-to-E synapses) is largely unaffected by time-varying cholinergic modulation. In contrast, networks with dominant intra-connectivity (strong E-to-E and I-to-I synapses) desynchronize with increasing cholinergic tone in manners diverging from the predictions of analogous systems with constant ACh levels. The rate and mechanism of this desynchronization is highly sensitive to the modulation’s time course and the E-I connectivity strength. This suggests that traditional in silico simplifications of the temporal profile of cholinergic activity may obscure sub-second neuromodulatory effects, which may be particularly relevant to contemporary efforts to optimize neurostimulation therapies influencing cholinergic pathways.