Neuromodulation by acetylcholine: examples from schizophrenia and depression

Higley, Michael J.; Picciotto, Marina R.

doi:10.1016/j.conb.2014.06.004

Cited by 154 publications

(102 citation statements)

References 89 publications

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“…Our demonstration of increases in false alarms, resulting from ill-timed cholinergic transients generated during noncued trials, illustrates the potential role of cholinergic dysregulation in the perceptual and cognitive impairments of neuropsychiatric and neurodegenerative disorders (40)(41)(42). Relatively subtle perturbations of the dynamics of cholinergic transients may alter large-scale network operations, such as fronto-parietal oscillatory activity (43), and thereby cause invalid perceptions and cue-oriented behavior (44,45).…”

Section: Discussionmentioning

confidence: 67%

Cortical cholinergic signaling controls the detection of cues

Gritton

Howe

Mallory

et al. 2016

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

186

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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Section: Discussionmentioning

confidence: 67%

Cortical cholinergic signaling controls the detection of cues

Gritton

Howe

Mallory

et al. 2016

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

186

208

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“…Both cholinergic and serotoninergic systems, for example, can activate rapid excitatory postsynaptic potentials in postsynaptic targets through nicotinic and 5HT 3A receptors, respectively [44–46] (see also Higley and Picciotto in this issue [83]). In cortical networks, these receptors are often (but not exclusively) located on particular subpopulations of GABAergic interneurons [47,48] (see also Wester and McBain in this issue [84]) and considerable effort has been recently applied to understand the roles of these pathways (see below).…”

Section: Neurotransmitter Systems Involved In State Controlmentioning

confidence: 99%

Neural control of brain state

Zagha

McCormick

2014

Current Opinion in Neurobiology

158

124

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How the brain takes in information, makes a decision, and acts on this decision is strongly influenced by the ongoing and constant fluctuations of state. Understanding the nature of these brain states and how they are controlled is critical to making sense of how the nervous system operates, both normally and abnormally. While broadly projecting neuromodulatory systems acting through metabotropic pathways have long been appreciated to be critical for determining brain state, more recent investigations have revealed a prominent role for fast acting neurotransmitter pathways for temporally and spatially precise control of neural processing. Corticocortical and thalamocortical glutamatergic projections can rapidly and precisely control brain state by changing both the nature of ongoing activity and by controlling the gain and precision of neural responses.

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“…Anatomical and functional evidence suggests that most of these receptors have a presynaptic and/or preterminal localisation, and modulates the release of almost all neurotransmitters, but some also have a somatodendritic post-synaptic localisation (Albuquerque et al, 2009;Gu and Yakel, 2011). In brain, the nAChRs regulate the release of both excitatory and inhibitory neurotransmitters, as a consequence, the activation of nAChRs can have opposite modulatory effects on the same circuit depending on whether they are expressed on excitatory or inhibitory neurons (Jensen et al, 2005;Albuquerque et al, 2009). nAChRs and nicotinic mechanisms contribute to cognitive function and their decline or dysfunction has been observed in several neuropsychiatric diseases (Lewis and Picciotto, 2013 ; Higley 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 and Picciotto, 2014). In addition, genetic studies have linked nAChRs to epilepsy and schizophrenia, and studies of mutant (knock-out, Ko, or knock-in, Kin) mice have shown that they are involved in pain mechanisms, anxiety depression and nicotine addiction (Picciotto et al, 2001;Champtiaux and Changeux, 2002;Gotti and Clementi, 2004;Changeux, 2010b;Drenan and Lester, 2012;Hurst et al, 2013).…”

Section: Introductionmentioning

confidence: 99%