Modes of Acetylcholine Signaling in the Prefrontal Cortex: Implications for Cholinergic Dysfunction and Disorders

Abstract

The forebrain cholinergic system is an important mediator of arousal, attention, memory, and other cognitive processes. Cholinergic signaling is typically divided into two patterns, tonic signaling, which involves sustained changes in ambient acetylcholine (ACh) tone over seconds to minutes, and phasic signaling, which involves fast changing, spatially specific release of ACh on a millisecond timescale. There is evidence to suggest unique functional roles for both types of signaling in the prefrontal cortex: phasic release of ACh is thought to be necessary for attentional processes, as well as cue detection, while tonic signaling is thought to be involved in regulating global arousal states and has been shown to increase with general cognitive demand. The differences between these two types of signaling may originate from electrophysiological properties of cholinergic cell types, distinct muscarinic and nicotinic receptor utilization and/or expression, and/or differential hydrolysis of ACh by acetylcholinesterase. This review will summarize the current views on the functional role of each type of signaling, while the contributions of ACh receptors, hydrolysis, and basal forebrain anatomy are examined. Additionally, the implications of these factors in ACh signaling will be examined in terms of cholinergic circuit dysfunction that occurs in neurodegenerative diseases.