Cholinergic Control of Cortical Circuit Activity

Cholinergic neurons of the basal forebrain send extensive projections to all regions of the neocortex and are critically involved in a diverse array of cognitive functions, including sensation, attention and learning. Cholinergic signaling also plays a crucial role in the moment-to-moment control of ongoing cortical state transitions that occur during periods of wakefulness. Yet, the underlying circuit mechanisms of synaptic cholinergic function in the neocortex remain unclear. Moreover, acetylcholine continues to be widely viewed as a slow and diffuse neuromodulator, despite the preponderance of in vivo evidence demonstrating rapid cholinergic function. In this study, we used a combination of optogenetics and in vitro electrophysiology to examine spatiotemporally precise control of cortical network activity by endogenous acetylcholine. We show that even brief activation of cholinergic afferents could powerfully suppress evoked cortical recurrent activity for several seconds. This suppression was reliant on the engagement of both nicotinic and muscarinic acetylcholine receptors. Nicotinic receptors mediated transient suppression by acting in the superficial cortical layers, while muscarinic receptors mediated prolonged suppression in layer 4. In agreement, we found nicotinic-mediated excitation of inhibitory neurons in the supragranular layers, and muscarinic-mediated hyperpolarization of excitatory cells in layer 4. Together, these findings present novel circuit mechanisms for fast and robust cholinergic signaling in neocortex