Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior

Picciotto, Marina R.; Higley, Michael J.; Mineur, Yann S.

doi:10.1016/j.neuron.2012.08.036

Cited by 979 publications

(751 citation statements)

References 220 publications

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“…Recent studies have suggested that individuals with uni-or bipolar illness have increased ACh levels throughout the brain when they are acutely depressed (Saricicek et al, 2012;Hannestad et al, 2013). A number of studies have also addressed the possibility that nAChRs could be involved in depression, because depressed individuals are twice as likely to smoke, have a harder time quitting, and can develop symptoms of depression during withdrawal (for reviews, see Moylan et al, 2012;Picciotto et al, 2012). Despite controversy about the connection that may exist between nAChRs and mood regulation, many studies have shown that decreasing ACh signaling through nAChRs can have antidepressant-like properties in mice (Mineur et al, 2007) and can improve symptoms of depression in some clinical studies (George et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The cholinergic system has been a recent focus for development of novel antidepressant medications (Drevets et al, 2013;Mineur and Picciotto, 2010;Picciotto et al, 2012;Saricicek et al, 2012). Acetylcholine signals through muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs, respectively) and many studies of depression have focused on mAChR signaling (Cannon et al, 2011;Riemann et al, 1994); however, blockade of either mAChRs or nAChRs can reverse the depression-like effects of increased cholinergic signaling in mice (Mineur et al, 2013) and it is likely that multiple receptors can mediate the effects of cholinergic signaling on depression (Drevets et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

Mineur

Fote

Blakeman

et al. 2015

Neuropsychopharmacol

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Electrophysiological and neurochemical studies implicate cholinergic signaling in the basolateral amygdala (BLA) in behaviors related to stress. Both animal studies and human clinical trials suggest that drugs that alter nicotinic acetylcholine receptor (nAChR) activity can affect behaviors related to mood and anxiety. Clinical studies also suggest that abnormalities in cholinergic signaling are associated with major depressive disorder, whereas pre-clinical studies have implicated both β2 subunit-containing (β2*) and α7 nAChRs in the effects of nicotine in models of anxiety-and depression-like behaviors. We therefore investigated whether nAChR signaling in the amygdala contributes to stress-mediated behaviors in mice. Local infusion of the non-competitive non-selective nAChR antagonist mecamylamine or viral-mediated downregulation of the β2 or α7 nAChR subunit in the amygdala all induced robust anxiolytic-and antidepressant-like effects in several mouse behavioral models. Further, whereas α7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only β2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the BLA. In contrast, α7, but not β2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through β2* nAChRs is essential for baseline excitability of the BLA, and a decrease in signaling through β2 nAChRs alters anxiety-and depression-like behaviors even in unstressed animals. In contrast, stimulation of α7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

Mineur

Fote

Blakeman

et al. 2015

Neuropsychopharmacol

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“…Such an anatomical organization favors hypotheses describing the cholinergic mediation of discrete cognitive-behavioral processes. Studies assessing the behavioral effects of cholinergic lesions, recording from or stimulating BF neurons in behaving animals have supported such hypotheses, proposing that cholinergic activity enhances sensory coding and mediates the ability of reward-predicting stimuli to control behavior (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Cortical cholinergic signaling controls the detection of cues

Gritton

Howe

Mallory

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

166

208

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The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.V irtually all cortical regions and layers receive inputs from cholinergic neurons originating in the nucleus basalis of Meynert, the substantia innominata, and the diagonal band of the basal forebrain (BF). Reflecting the seemingly diffuse organization of this projection system, functional conceptualizations traditionally have described acetylcholine (ACh) as a neuromodulator that influences broadly defined behavioral and cognitive processes such as wakefulness, arousal, and gating of input processing (1, 2). However, anatomical studies have revealed a topographic organization of BF cholinergic cell bodies with highly segregated cortical projection patterns (3-7). Such an anatomical organization favors hypotheses describing the cholinergic mediation of discrete cognitive-behavioral processes. Studies assessing the behavioral effects of cholinergic lesions, recording from or stimulating BF neurons in behaving animals have supported such hypotheses, proposing that cholinergic activity enhances sensory coding and mediates the ability of reward-predicting stimuli to control behavior (8-17).In separate experiments using two different tasks, we reported the presence of phasic cholinergic release events (transients) in the medial prefrontal cortex (mPFC) of rodents trained to report the presence of cues (18,19). These studies used choline-sensitive microelectrodes to measure changes in extracellular choline concentrations that reflect the hydrolysis of newly released ACh by endogenous acetylcholinesterase (SI Results and Discussion). Importantly, such cholinergic transients were not observed in trials in which cues were missed and in which the absence of a cue was correctly reported and rewarded. Cho...

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“…In general, acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates firing of groups of neurons [52]. As a result, it changes the state of neuronal networks throughout the brain, and modifies their response to internal and external inputs, which is the classical role of a neuromodulator.…”

Section: (B) Neuronal Control Of Predator-induced Phenotypic Plasticitymentioning

confidence: 99%

Dopamine is a key regulator in the signalling pathway underlying predator-induced defences inDaphnia

Weiss

Leese

Laforsch³

et al. 2015

Proc. R. Soc. B.

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The waterflea Daphnia is a model to investigate the genetic basis of phenotypic plasticity resulting from one differentially expressed genome. Daphnia develops adaptive phenotypes (e.g. morphological defences) thwarting predators, based on chemical predator cue perception. To understand the genomic basis of phenotypic plasticity, the description of the precedent cellular and neuronal mechanisms is fundamental. However, key regulators remain unknown. All neuronal and endocrine stimulants were able to modulate but not induce defences, indicating a pathway of interlinked steps. A candidate able to link neuronal with endocrine responses is the multi-functional amine dopamine. We here tested its involvement in trait formation in Daphnia pulex and Daphnia longicephala using an induction assay composed of predator cues combined with dopaminergic and cholinergic stimulants. The mere application of both stimulants was sufficient to induce morphological defences. We determined dopamine localization in cells found in close association with the defensive trait. These cells serve as centres controlling divergent morphologies. As a mitogen and sclerotization agent, we anticipate that dopamine is involved in proliferation and structural formation of morphological defences. Furthermore, dopamine pathways appear to be interconnected with endocrine pathways, and control juvenile hormone and ecdysone levels. In conclusion, dopamine is suggested as a key regulator of phenotypic plasticity.

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Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior

Cited by 979 publications

References 220 publications

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

Cortical cholinergic signaling controls the detection of cues

Dopamine is a key regulator in the signalling pathway underlying predator-induced defences inDaphnia

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