**1. Introduction**

While the role of acetylcholine (ACh) as a neuromodulatory regulator of REM sleep, global arousal states, and consciousness in the prefrontal cortex has been known for quite some time [1–3], the evidence that ACh also functions as a fast-acting neurotransmitter on a precise spatial and temporal scale to carry out specific cognitive operations has only begun to be explored within the past two decades, with progress accelerating significantly in recent years [4–6]. Studies elucidating short-duration phasic cholinergic signaling in the cortex have been made possible by the use of techniques for collecting temporally precise data on ACh *in vivo*, beginning with electrochemical detection [7], and more recently including optogenetics and fiber photometry [8–11]. Such techniques open exciting new possibilities to advance our understanding of cholinergic neurotransmission in the brain, and importantly, our understanding and treatment of brain disorders such as Alzheimer's disease (AD) and alcohol use disorder (AUD).

ACh functions in the prefrontal cortex are based on a variety of factors such as cortical cytoarchitecture, receptor utilization, cholinesterase activity, and basal forebrain anatomy. It is therefore necessary to reevaluate our understanding of the literature on disorders of the basal forebrain through the lens of the tonic/phasic ACh signaling distinction. The goal of this review is to define what is currently known about tonic and phasic ACh signaling in the prefrontal cortex, how the heterogeneity between these two types of signaling may arise, review the differences in receptor utilization these two types of transmission require, evaluate the role of acetylcholinesterase activity in this distinction, and review some of the deficits to each type of transmission that occur in both AD and AUD.
