Spatiotemporal specificity in cholinergic control of neocortical function

•Cholinergic actions with specific spatiotemporal patterns regulate cognition.•Both nicotinic and muscarinic responses can be fast and precise.•Interneuron-specific cholinergic effects contribute to the diversity and specificity of cholinergic actions.•Different activity patterns of cholinergic axons may produce different cellular responses.•It is critical to study when different cellular ACh actions are engaged in physiological conditions.

Cholinergic actions are critical for normal cortical cognitive functions. The release of acetylcholine (ACh) in neocortex and the impact of this neuromodulator on cortical computations exhibit remarkable spatiotemporal precision, as required for the regulation of behavioral processes underlying attention and learning. We discuss how the organization of the cholinergic projections to the cortex and their release properties might contribute to this specificity. We also review recent studies suggesting that the modulatory influences of ACh on the properties of cortical neurons can have the necessary temporal dynamic range, emphasizing evidence of powerful interneuron subtype-specific effects. We discuss areas that require further investigation and point to technical advances in molecular and genetic manipulations that promise to make headway in understanding the neural bases of cholinergic modulation of cortical cognitive operations.