title: Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta-Gamma Coupling during Cue Detection.
abstract: The capacity for using external cues to guide behavior ("cue detection") constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta-gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection.SIGNIFICANCE STATEMENTThe capacity of learned cues to direct attention and guide responding ("cue detection") is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination ofin vivoneurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection.
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109, wmhowe@gmail.com msarter@umich.edu.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215.|Icahn School of Medicine at Mt. Sinai, New York, New York 10029, and.
authors.forename: William M
authors.initials: WM
authors.lastname: Howe
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215.
authors.forename: Howard J
authors.identifier: 0000-0003-3194-3258
authors.initials: HJ
authors.lastname: Gritton
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Nicholas A
authors.identifier: 0000-0001-6346-2083
authors.initials: NA
authors.lastname: Lusk
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215.
authors.forename: Erik A
authors.identifier: 0000-0002-0092-6458
authors.initials: EA
authors.lastname: Roberts
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Vaughn L
authors.initials: VL
authors.lastname: Hetrick
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.|Department of Neurology and Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, California 94143.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Berke
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109, wmhowe@gmail.com msarter@umich.edu.
authors.forename: Martin
authors.identifier: 0000-0003-0441-9936
authors.initials: M
authors.lastname: Sarter
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001683:Biological Clocks / Q000502:physiology; D059329:Cholinergic Neurons / Q000502:physiology*; D003463:Cues; D065818:Gamma Rhythm / Q000502:physiology*; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D012201:Reward; D009435:Synaptic Transmission / Q000502:physiology; D013826:Theta Rhythm / Q000502:physiology*; D014796:Visual Perception / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D000109:Acetylcholine
keywords: acetylcholine; oscillations; prefrontal cortex