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• W2035946761 abstract "Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. Acetylcholine (ACh) is a fast-acting, point-to-point neurotransmitter at the neuromuscular junction and in the autonomic ganglia; however, there are fewer demonstrations of similar actions in the brain (Changeux, 2010Changeux J.-P. Allosteric receptors: from electric organ to cognition.Annu. Rev. Pharmacol. Toxicol. 2010; 50: 1-38Crossref PubMed Scopus (41) Google Scholar). Instead, central cholinergic neurotransmission predominantly changes neuronal excitability, alters presynaptic release of neurotransmitters, and coordinates the firing of groups of neurons (Kawai et al., 2007Kawai H. Lazar R. Metherate R. Nicotinic control of axon excitability regulates thalamocortical transmission.Nat. Neurosci. 2007; 10: 1168-1175Crossref PubMed Scopus (62) Google Scholar; Rice and Cragg, 2004Rice M.E. Cragg S.J. Nicotine amplifies reward-related dopamine signals in striatum.Nat. Neurosci. 2004; 7: 583-584Crossref PubMed Scopus (193) Google Scholar; Wonnacott, 1997Wonnacott S. Presynaptic nicotinic ACh receptors.Trends Neurosci. 1997; 20: 92-98Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar; Zhang and Sulzer, 2004Zhang H. Sulzer D. Frequency-dependent modulation of dopamine release by nicotine.Nat. Neurosci. 2004; 7: 581-582Crossref PubMed Scopus (122) Google Scholar). As a result, ACh appears to act as a neuromodulator in the brain, despite its role as the primary excitatory neurotransmitter in the periphery. The definition of a neuromodulator is flexible, but has evolved to describe any kind of neurotransmission that is not directly excitatory (mediated through ionotropic glutamate receptors) or inhibitory (mediated through ionotropic gamma-aminobutyric acid [GABA] receptors) (Ito and Schuman, 2008Ito H.T. Schuman E.M. Frequency-dependent signal transmission and modulation by neuromodulators.Front. Neurosci. 2008; 2: 138-144Crossref PubMed Google Scholar; Siggins, 1979Siggins G.R. Neurotransmitters and neuromodulators and their mediation by cyclic nucleotides.Adv. Exp. Med. Biol. 1979; 116: 41-64Crossref PubMed Google Scholar). Neuromodulation can be thought of as a change in the state of a neuron or group of neurons that alters its response to subsequent stimulation. A number of models have been proposed to explain the actions of ACh in the central nervous system (CNS). For example, ACh has been suggested to be critical for the response to uncertainty, such that an increase in cholinergic tone predicts the unreliability of predictive cues in a known context and improves the signal-to-noise ratio in a learning environment (Yu and Dayan, 2005Yu A.J. Dayan P. Uncertainty, neuromodulation, and attention.Neuron. 2005; 46: 681-692Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar). Another model has suggested that ACh reinforces neuronal loops and cortical dynamics during learning by enhancing the influence of feed-forward afferent inputs to the cortex carrying sensory information and decreasing excitatory feedback activity mediating retrieval (Hasselmo, 2006Hasselmo M.E. The role of acetylcholine in learning and memory.Curr. Opin. Neurobiol. 2006; 16: 710-715Crossref PubMed Scopus (312) Google Scholar). ACh can also alter firing of neurons on a rapid time scale, as in fear-conditioning, when foot-shock results in direct cholinergic activation of interneurons in the auditory cortex that contribute to learning (Letzkus et al., 2011Letzkus J.J. Wolff S.B. Meyer E.M. Tovote P. Courtin J. Herry C. Lüthi A. A disinhibitory microcircuit for associative fear learning in the auditory cortex.Nature. 2011; 480: 331-335Crossref PubMed Scopus (67) Google Scholar). All these models are consistent with a primary role of ACh as a neuromodulator that changes the state of an ensemble of neurons in response to changing environmental conditions. In this review, we will provide further support for the idea that cholinergic neurotransmission in the brain is primarily neuromodulatory and is categorically distinct from the actions of ACh at the neuromuscular junction. We propose that the role of ACh as a neuromodulator in the brain is to increase neurotransmitter release in response to other inputs, to promote burst firing, and/or suppress tonic firing, depending upon the system and the neuronal subtypes stimulated. Further, ACh contributes to synaptic plasticity in many brain areas. The two primary sources of ACh in the brain include projection neurons that innervate distal areas and local interneurons that are interspersed among their cellular targets. Cholinergic projection neurons are found in nuclei throughout the brain, such as the pedunculopontine and laterodorsal tegmental areas (PPTg and LDTg), the medial habenula (MHb) (Ren et al., 2011Ren J. Qin C. Hu F. Tan J. Qiu L. Zhao S. Feng G. Luo M. Habenula “cholinergic” neurons co-release glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes.Neuron. 2011; 69: 445-452Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar), and the basal forebrain (BF) complex (Mesulam, 1995Mesulam M.M. Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus of the human brain.in: Bloom F.E. Kupfer D.J. Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, New York1995Google Scholar; Zaborszky, 2002Zaborszky L. The modular organization of brain systems. Basal forebrain: the last frontier.Prog. Brain Res. 2002; 136: 359-372Crossref PubMed Scopus (53) Google Scholar; Zaborszky et al., 2008Zaborszky L. Hoemke L. Mohlberg H. Schleicher A. Amunts K. Zilles K. Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain.Neuroimage. 2008; 42: 1127-1141Crossref PubMed Scopus (34) Google Scholar), including the medial septum. These cholinergic neurons project widely and diffusely, innervating neurons throughout the CNS. Cholinergic interneurons are typified by the tonically active ACh neurons of the striatum and nucleus accumbens, and there is some indication from anatomical studies that cholinergic interneurons are present in the rodent and human neocortex, but not the nonhuman primate cortex (Benagiano et al., 2003Benagiano V. Virgintino D. Flace P. Girolamo F. Errede M. Roncali L. Ambrosi G. Choline acetyltransferase-containing neurons in the human parietal neocortex.Eur. J. Histochem. 2003; 47: 253-256PubMed Google Scholar; Mesulam, 1995Mesulam M.M. Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus of the human brain.in: Bloom F.E. Kupfer D.J. Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, New York1995Google Scholar; von Engelhardt et al., 2007von Engelhardt J. Eliava M. Meyer A.H. Rozov A. Monyer H. Functional characterization of intrinsic cholinergic interneurons in the cortex.J. Neurosci. 2007; 27: 5633-5642Crossref PubMed Scopus (38) Google Scholar). The actions of ACh released from both populations of cholinergic cells are mediated through pre- and postsynaptic receptors on a large variety of neuronal subtypes throughout the brain, and it should be noted that cholinergic inputs contribute to cortical and hippocampal function across phylogeny. ACh signals through two classes of receptors: metabotropic muscarinic receptors (mAChRs) and ionotropic nicotinic receptors (nAChRs) (reviewed in Picciotto et al., 2000Picciotto M.R. Caldarone B.J. King S.L. Zachariou V. Nicotinic receptors in the brain. Links between molecular biology and behavior.Neuropsychopharmacology. 2000; 22: 451-465Crossref PubMed Scopus (206) Google Scholar and Wess, 2003aWess J. Novel insights into muscarinic acetylcholine receptor function using gene targeting technology.Trends Pharmacol. Sci. 2003; 24: 414-420Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Muscarinic receptors are coupled either to Gq proteins (M1, M3, and M5 subtypes) that activate phospholipase C or Gi/o proteins (M2 and M4 subtypes) that negatively couple to adenylate cyclase (reviewed in Wess, 2003aWess J. Novel insights into muscarinic acetylcholine receptor function using gene targeting technology.Trends Pharmacol. Sci. 2003; 24: 414-420Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar), linking ACh activity to a variety of biochemical signaling cascades. Moreover, mAChRs are located both pre- and postsynaptically throughout the brain, producing diverse consequences for brain activity (Figure 1). As examples of the heterogeneous effects of mAChR stimulation, presynaptic M2/M4 mAChRs can act as inhibitory autoreceptors on cholinergic terminals (Douglas et al., 2002Douglas C.L. Baghdoyan H.A. Lydic R. Postsynaptic muscarinic M1 receptors activate prefrontal cortical EEG of C57BL/6J mouse.J. Neurophysiol. 2002; 88: 3003-3009Crossref PubMed Google Scholar; Raiteri et al., 1984Raiteri M. Leardi R. Marchi M. Heterogeneity of presynaptic muscarinic receptors regulating neurotransmitter release in the rat brain.J. Pharmacol. Exp. Ther. 1984; 228: 209-214PubMed Google Scholar) and reduce glutamate release from corticocortical and corticostriatal synapses (Higley et al., 2009Higley M.J. Soler-Llavina G.J. Sabatini B.L. Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration.Nat. Neurosci. 2009; 12: 1121-1128Crossref PubMed Scopus (25) Google Scholar, Gil et al., 1997Gil Z. Connors B.W. Amitai Y. Differential regulation of neocortical synapses by neuromodulators and activity.Neuron. 1997; 19: 679-686Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). In contrast, M1/M5 receptors can stimulate dopamine (DA) release from striatal synaptosomes (Zhang et al., 2002Zhang W. Yamada M. Gomeza J. Basile A.S. Wess J. Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice.J. Neurosci. 2002; 22: 6347-6352PubMed Google Scholar) and postsynaptic M1/M5 receptors can increase excitability of cortical pyramidal neurons (Douglas et al., 2002Douglas C.L. Baghdoyan H.A. Lydic R. Postsynaptic muscarinic M1 receptors activate prefrontal cortical EEG of C57BL/6J mouse.J. Neurophysiol. 2002; 88: 3003-3009Crossref PubMed Google Scholar; McCormick and Prince, 1985McCormick D.A. Prince D.A. Two types of muscarinic response to acetylcholine in mammalian cortical neurons.Proc. Natl. Acad. Sci. USA. 1985; 82: 6344-6348Crossref PubMed Google Scholar). Nicotinic receptors function as nonselective, excitatory cation channels (Changeux et al., 1998Changeux J.P. Bertrand D. Corringer P.J. Dehaene S. Edelstein S. Léna C. Le Novère N. Marubio L. Picciotto M. Zoli M. Brain nicotinic receptors: structure and regulation, role in learning and reinforcement.Brain Res. Brain Res. Rev. 1998; 26: 198-216Crossref PubMed Scopus (207) Google Scholar; Picciotto et al., 2001Picciotto M.R. Caldarone B.J. Brunzell D.H. Zachariou V. Stevens T.R. King S.L. Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications.Pharmacol. Ther. 2001; 92: 89-108Crossref PubMed Scopus (122) Google Scholar) and occur as homomeric or heteromeric assemblies of a large family of α- and β-subunits (α2-α7 and β2-β4; reviewed in Picciotto et al., 2000Picciotto M.R. Caldarone B.J. King S.L. Zachariou V. Nicotinic receptors in the brain. Links between molecular biology and behavior.Neuropsychopharmacology. 2000; 22: 451-465Crossref PubMed Scopus (206) Google Scholar). While neuromodulators are typically associated with metabotropic signaling, the role of the ionotropic nAChRs in the brain appears to be largely modulatory as well (Picciotto, 2003Picciotto M.R. Nicotine as a modulator of behavior: beyond the inverted U.Trends Pharmacol. Sci. 2003; 24: 493-499Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). For example, nAChRs are not clustered at postsynaptic membranes apposed to sites of ACh release, but are rather dispersed along the surface (and intracellular compartments) of neurons, including presynaptic terminals (McGehee et al., 1995McGehee D.S. Heath M.J. Gelber S. Devay P. Role L.W. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors.Science. 1995; 269: 1692-1696Crossref PubMed Google Scholar; Vidal and Changeux, 1993Vidal C. Changeux J.P. Nicotinic and muscarinic modulations of excitatory synaptic transmission in the rat prefrontal cortex in vitro.Neuroscience. 1993; 56: 23-32Crossref PubMed Scopus (139) Google Scholar), cell bodies, and even axons (Arroyo-Jiménez et al., 1999Arroyo-Jiménez M.M. Bourgeois J.P. Marubio L.M. Le Sourd A.M. Ottersen O.P. Rinvik E. Fairén A. Changeux J.P. Ultrastructural localization of the alpha4-subunit of the neuronal acetylcholine nicotinic receptor in the rat substantia nigra.J. Neurosci. 1999; 19: 6475-6487PubMed Google Scholar; Hill et al., 1993Hill Jr., J.A. Zoli M. Bourgeois J.-P. Changeux J.-P. Immunocytochemical localization of a neuronal nicotinic receptor: the β 2-subunit.J. Neurosci. 1993; 13: 1551-1568Crossref PubMed Google Scholar; Kawai et al., 2007Kawai H. Lazar R. Metherate R. Nicotinic control of axon excitability regulates thalamocortical transmission.Nat. Neurosci. 2007; 10: 1168-1175Crossref PubMed Scopus (62) Google Scholar). In addition, stimulation of nAChRs can increase the release of glutamate, GABA, DA, ACh, norepinephrine, and serotonin (McGehee et al., 1995McGehee D.S. Heath M.J. Gelber S. Devay P. Role L.W. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors.Science. 1995; 269: 1692-1696Crossref PubMed Google Scholar; Wonnacott, 1997Wonnacott S. Presynaptic nicotinic ACh receptors.Trends Neurosci. 1997; 20: 92-98Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar) (Figure 1). Nicotinic modulation of neurotransmitter release is often subtype-specific, and this specificity can vary across brain areas, with distinct nAChRs coupling to release of glutamate (α7) versus GABA (α4β2) (Mansvelder et al., 2002Mansvelder H.D. Keath J.R. McGehee D.S. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.Neuron. 2002; 33: 905-919Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar) in the ventral tegmental area (VTA), while β2-containing nAChRs can modulate the release of glutamate from thalamocortical projections (Parikh et al., 2010Parikh V. Ji J. Decker M.W. Sarter M. Prefrontal beta2 subunit-containing and alpha7 nicotinic acetylcholine receptors differentially control glutamatergic and cholinergic signaling.J. Neurosci. 2010; 30: 3518-3530Crossref PubMed Scopus (31) Google Scholar). Similarly, different nAChR subtypes mediate the release of DA (α4/α6β2) versus ACh (α3β4) (Grady et al., 2001Grady S.R. Meinerz N.M. Cao J. Reynolds A.M. Picciotto M.R. Changeux J.-P. McIntosh J.M. Marks M.J. Collins A.C. Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus: a function mediated by a different nAChR than dopamine release from striatum.J. Neurochem. 2001; 76: 258-268Crossref PubMed Scopus (102) Google Scholar). Presynaptic effects of nAChRs contribute to synaptic plasticity in the VTA (Mansvelder and McGehee, 2000Mansvelder H.D. McGehee D.S. Long-term potentiation of excitatory inputs to brain reward areas by nicotine.Neuron. 2000; 27: 349-357Abstract Full Text Full Text PDF PubMed Google Scholar; Wooltorton et al., 2003Wooltorton J.R.A. Pidoplichko V.I. Broide R.S. Dani J.A. Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas.J. Neurosci. 2003; 23: 3176-3185PubMed Google Scholar), hippocampus (Ge and Dani, 2005Ge S. Dani J.A. Nicotinic acetylcholine receptors at glutamate synapses facilitate long-term depression or potentiation.J. Neurosci. 2005; 25: 6084-6091Crossref PubMed Scopus (60) Google Scholar; Ji et al., 2001Ji D. Lape R. Dani J.A. Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity.Neuron. 2001; 31: 131-141Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar; Radcliffe and Dani, 1998Radcliffe K.A. Dani J.A. Nicotinic stimulation produces multiple forms of increased glutamatergic synaptic transmission.J. Neurosci. 1998; 18: 7075-7083Crossref PubMed Google Scholar), and prefrontal cortex (Couey et al., 2007Couey J.J. Meredith R.M. Spijker S. Poorthuis R.B. Smit A.B. Brussaard A.B. Mansvelder H.D. Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex.Neuron. 2007; 54: 73-87Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). In addition, nAChRs may also be important for synchronizing neuronal activity. For example, nicotine is reported to coordinate firing of thalamocortical fibers through effects on nAChRs in white matter (Bucher and Goaillard, 2011Bucher D. Goaillard J.M. Beyond faithful conduction: short-term dynamics, neuromodulation, and long-term regulation of spike propagation in the axon.Prog. Neurobiol. 2011; 94: 307-346Crossref PubMed Scopus (15) Google Scholar; Kawai et al., 2007Kawai H. Lazar R. Metherate R. Nicotinic control of axon excitability regulates thalamocortical transmission.Nat. Neurosci. 2007; 10: 1168-1175Crossref PubMed Scopus (62) Google Scholar). Despite the clear effects of presynaptic nAChRs in electrophysiological studies, their relationship to the behavioral consequences of nicotine administration is not completely understood. For example, nicotine stimulates the firing of DA neurons through actions in the VTA and increases release of DA from the midbrain projections to the nucleus accumbens (NAc) through actions on terminal nAChRs, but local infusion of nicotine into the VTA has much greater effects on locomotion and self-administration than local infusion into the NAc (Ferrari et al., 2002Ferrari R. Le Novère N. Picciotto M.R. Changeux J.P. Zoli M. Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections.Eur. J. Neurosci. 2002; 15: 1810-1818Crossref PubMed Scopus (88) Google Scholar; Ikemoto et al., 2006Ikemoto S. Qin M. Liu Z.-H. Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area.J. Neurosci. 2006; 26: 723-730Crossref PubMed Scopus (66) Google Scholar). Recent studies have, however, suggested that nAChRs in the NAc are important for the motivational effects of nicotine (association between stimulus and drug intake), rather than the primary reinforcing effects of the drug (desire for drug) (Brunzell et al., 2010Brunzell D.H. Boschen K.E. Hendrick E.S. Beardsley P.M. McIntosh J.M. Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors in the nucleus accumbens shell regulate progressive ratio responding maintained by nicotine.Neuropsychopharmacology. 2010; 35: 665-673Crossref PubMed Scopus (36) Google Scholar). In addition, it is clear that cholinergic interneurons and their regulation of muscarinic receptor signaling are also critical components in striatum-dependent decision making (see, e.g., Goldberg et al., 2012Goldberg J.A. Ding J.B. Surmeier D.J. Muscarinic modulation of striatal function and circuitry.Handb. Exp. Pharmacol. 2012; 208: 223-241Crossref PubMed Scopus (9) Google Scholar). While presynaptic effects of nAChRs have been the focus of a great deal of work, effects of nicotinic stimulation are clearly not exclusively presynaptic (Figure 1). Exogenous application of nicotine can induce significant inward currents in neurons in a number of brain areas (Léna and Changeux, 1999Léna C. Changeux J.P. The role of beta 2-subunit-containing nicotinic acetylcholine receptors in the brain explored with a mutant mouse.Ann. N Y Acad. Sci. 1999; 868: 611-616Crossref PubMed Scopus (24) Google Scholar; Picciotto et al., 1995Picciotto M.R. Zoli M. Léna C. Bessis A. Lallemand Y. Le Novère N. Vincent P. Pich E.M. Brûlet P. Changeux J.-P. Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain.Nature. 1995; 374: 65-67Crossref PubMed Scopus (432) Google Scholar, Picciotto et al., 1998Picciotto M.R. Zoli M. Rimondini R. Léna C. Marubio L.M. Pich E.M. Fuxe K. Changeux J.P. Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.Nature. 1998; 391: 173-177Crossref PubMed Scopus (788) Google Scholar), and there have been several examples of direct postsynaptic effects of ACh in the brain (Alkondon et al., 1998Alkondon M. Pereira E.F. 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The debate has focused on whether cholinergic signaling occurs via traditional synapses (cellular specializations comprising closely apposed pre- and postsynaptic membranes with associated release/receptor machinery) or via volume transmission (actions of a neurotransmitter that occur at a distance from its site of release, mediated by diffusion through the extracellular space (Zoli et al., 1999Zoli M. Jansson A. Syková E. Agnati L.F. Fuxe K. Volume transmission in the CNS and its relevance for neuropsychopharmacology.Trends Pharmacol. Sci. 1999; 20: 142-150Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Accumulating evidence indicates that ACh can act through volume transmission in the brain. The relatively diffuse nature of brain cholinergic innervation further reinforces this idea. There is an anatomical mismatch between the sites of ACh release (Houser, 1990Houser C.R. Cholinergic synapses in the central nervous system: studies of the immunocytochemical localization of choline acetyltransferase.J. Electron Microsc. Tech. 1990; 15: 2-19Crossref PubMed Google Scholar; Wainer et al., 1984aWainer B.H. Bolam J.P. Freund T.F. Henderson Z. Totterdell S. Smith A.D. Cholinergic synapses in the rat brain: a correlated light and electron microscopic immunohistochemical study employing a monoclonal antibody against choline acetyltransferase.Brain Res. 1984; 308: 69-76Crossref PubMed Google Scholar, Wainer et al., 1984bWainer B.H. Levey A.I. Mufson E.J. Mesulam M.M. Cholinergic systems in mammalian brain identified with antibodies against choline acetyltransferase.Neurochem. Int. 1984; 6: 163-182Crossref PubMed Scopus (38) Google Scholar) and the location of cholinergic receptors (Arroyo-Jiménez et al., 1999Arroyo-Jiménez M.M. Bourgeois J.P. Marubio L.M. Le Sourd A.M. Ottersen O.P. Rinvik E. Fairén A. Changeux J.P. Ultrastructural localization of the alpha4-subunit of the neuronal acetylcholine nicotinic receptor in the rat substantia nigra.J. Neurosci. 1999; 19: 6475-6487PubMed Google Scholar; Hill et al., 1993Hill Jr., J.A. Zoli M. Bourgeois J.-P. Changeux J.-P. Immunocytochemical localization of a neuronal nicotinic receptor: the β 2-subunit.J. Neurosci. 1993; 13: 1551-1568Crossref PubMed Google Scholar; Kawai et al., 2007Kawai H. Lazar R. Metherate R. Nicotinic control of axon excitability regulates thalamocortical transmission.Nat. Neurosci. 2007; 10: 1168-1175Crossref PubMed Scopus (62) Google Scholar). There is also evidence that extracellular levels of ACh fluctuate in a manner that is not consistent with localized clearance of a synaptic transmitter (Hajnal et al., 1998Hajnal A. Pothos E.N. Lénárd L. Hoebel B.G. 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Anatomical studies have identified cortical cholinergic synapses that are structurally similar to those of other point-to-point neurotransmitters in both rats (Turrini et al., 2001Turrini P. Casu M.A. Wong T.P. De Koninck Y. Ribeiro-da-Silva A. Cuello A.C. Cholinergic nerve terminals establish classical synapses in the rat cerebral cortex: synaptic pattern and age-related atrophy.Neuroscience. 2001; 105: 277-285Crossref PubMed Scopus (73) Google Scholar) and humans (Smiley et al., 1997Smiley J.F. Morrell F. Mesulam M.M. Cholinergic synapses in human cerebral cortex: an ultrastructural study in serial sections.Exp. Neurol. 1997; 144: 361-368Crossref PubMed Scopus (45) Google Scholar). Effects of ACh on a rapid time-scale likely underlie its role in stimulus-response tasks in which subsecond reactivity is required for appropriate behavioral responses, as in prefrontal cortex-dependent cue detection (Parikh et al., 2007aParikh V. Kozak R. Martinez V. Sarter M. Prefron" @default.
• W2035946761 created "2016-06-24" @default.
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• W2035946761 date "2012-10-01" @default.
• W2035946761 modified "2023-10-14" @default.
• W2035946761 title "Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior" @default.
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