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

Acetylcholine in the brain alters neuronal excitability.

“Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates the firing of groups of neurons.”

The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors.

“The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors.”

The diverse effects of acetylcholine depend on the site of release, the receptor subtypes, and the target neuronal population.

“The diverse effects of acetylcholine depend on the site of release, the receptor subtypes, and the 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.”

Acetylcholine in the brain induces synaptic plasticity.

“Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates the firing of groups of neurons.”

Acetylcholine in the brain coordinates the firing of groups of neurons.

“Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates the firing of groups of neurons.”

Acetylcholine in the brain influences synaptic transmission.

“Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity and coordinates the firing of groups of neurons.”

Cholinergic projection neurons project widely and diffusely, innervating neurons throughout the central nervous system.

“These cholinergic neurons project widely and diffusely, innervating neurons throughout the CNS.”

Acetylcholine signals through two classes of receptors: metabotropic muscarinic receptors and ionotropic nicotinic receptors.

“ACh signals through two classes of receptors: metabotropic muscarinic receptors (mAChRs) and ionotropic nicotinic receptors (nAChRs) (reviewed in (Picciotto et al., 2000; Wess, 2003a)).”

• cites Picciotto et al., 2000 sourceNot checked yet

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• cites Wess, 2003aNot checked yet

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Nicotinic receptors function as non-selective, excitatory cation channels.

“Nicotinic receptors function as non-selective, excitatory cation channels (Changeux et al., 1998; Picciotto et al., 2001) 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., 2000)).”

• cites Changeux et al., 1998 sourceNot checked yet

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• cites Picciotto et al., 2001 sourceNot checked yet

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There is some indication from anatomical studies that cholinergic interneurons are present in the rodent and human neocortex, but not the non-human primate cortex.

“there is some indication from anatomical studies that cholinergic interneurons are present in the rodent and human neocortex, but not the non-human primate cortex (Benagiano et al., 2003; Mesulam, 1995; von Engelhardt et al., 2007).”

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• cites Mesulam, 1995Not checked yet

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• cites von Engelhardt et al., 2007 sourceNot checked yet

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Nicotinic acetylcholine receptors are not clustered at postsynaptic membranes apposed to sites of acetylcholine release, but are rather dispersed along the surface and intracellular compartments of neurons, including presynaptic terminals, cell bodies and axons.

“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., 1995; Vidal and Changeux, 1993), cell bodies and even axons (Arroyo-Jimenez et al., 1999; Hill Jr. et al., 1993; Kawai et al., 2007).”

• cites McGehee et al., 1995 sourceNot checked yet

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• cites Vidal and Changeux, 1993Not checked yet

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• cites Arroyo-Jimenez et al., 1999 sourceNot checked yet

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Local infusion of nicotine into the VTA has much greater effects on locomotion and self-administration than local infusion into the NAc.

“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., 2002; Ikemoto et al., 2006).”

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• cites Ikemoto et al., 2006 sourceNot checked yet

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Nicotinic acetylcholine receptors may also be important for synchronizing neuronal activity.

“In addition, nAChRs may also be important for synchronizing neuronal activity.”

Presynaptic effects of nicotinic acetylcholine receptors contribute to synaptic plasticity in the VTA, hippocampus, and prefrontal cortex.

“Presynaptic effects of nAChRs contribute to synaptic plasticity in the VTA (Mansvelder and McGehee, 2000; Wooltorton et al., 2003), hippocampus (Ge and Dani, 2005; Ji et al., 2001; Radcliffe and Dani, 1998), and prefrontal cortex (Couey et al., 2007).”

• cites Mansvelder and McGehee, 2000Not checked yet

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• cites Wooltorton et al., 2003 sourceNot checked yet

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• cites Ge and Dani, 2005Not checked yet

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Stimulation of nicotinic acetylcholine receptors can increase the release of glutamate, GABA, dopamine, acetylcholine, norepinephrine, and serotonin.

“In addition, stimulation of nAChRs can increase the release of glutamate, GABA, dopamine (DA), ACh, norepinephrine, and serotonin (McGehee et al., 1995; Wonnacott, 1997) (Figure 1).”

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• cites Wonnacott, 1997 sourceNot checked yet

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There is evidence that extracellular levels of acetylcholine fluctuate in a manner that is not consistent with localized clearance of a synaptic transmitter.

“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., 1998; Laplante et al., 2004; Mark et al., 1996; Parikh et al., 2004; Reid et al., 1998).”

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• cites Laplante et al., 2004 sourceNot checked yet

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• cites Mark et al., 1996 sourceNot checked yet

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Effects of acetylcholine 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 or auditory discrimination.

“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., 2007a) or auditory discrimination (Letzkus et al., 2011).”

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• cites Letzkus et al., 2011 sourceNot checked yet

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Accumulating evidence indicates that acetylcholine can act through volume transmission in the brain.

“Accumulating evidence indicates that ACh can act through volume transmission in the brain.”

Anatomical studies have identified cortical cholinergic synapses that are structurally similar to those of other point-to-point neurotransmitters, in both rats and humans.

“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., 2001) and humans (Smiley et al., 1997).”

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• cites Smiley et al., 1997 sourceNot checked yet

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Nicotinic acetylcholine receptors 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).

“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., 2010).”

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There is an anatomical mismatch between the sites of acetylcholine release and the location of cholinergic receptors.

“There is an anatomical mismatch between the sites of ACh release (Houser, 1990; Wainer et al., 1984a; Wainer et al., 1984b) and the location of cholinergic receptors (Arroyo-Jimenez et al., 1999; Hill Jr. et al., 1993; Kawai et al., 2007).”

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• cites Wainer et al., 1984aNot checked yet

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• cites Arroyo-Jimenez et al., 1999 sourceNot checked yet

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Cholinergic interneurons and their regulation of muscarinic receptor signaling are critical components in striatum-dependent decision making.

“Additionally, 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., 2012)).”

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Differences in sites of receptor expression, affinity of acetylcholine effects at both muscarinic and nicotinic receptors, as well as rates of synaptic clearance and local concentration of acetylcholine in and outside the synapse, are critical for the control and specificity of cholinergic signaling.

“The data indicate that differences in sites of receptor expression, affinity of ACh effects at both mAChRs and nAChRs, as well as rates of synaptic clearance (mediated through AChE activity) and local concentration of ACh in and outside the synapse, are critical for the control and specificity of cholinergic signaling.”

The ability of acetylcholine to influence synaptic plasticity and dynamics of local circuits can also occur through astrocytic control of synaptic Ca2+ concentration following nicotinic receptor stimulation.

“The ability of ACh to influence synaptic plasticity and dynamics of local circuits can also occur through astrocytic control of synaptic Ca2+ concentration following nAChR stimulation (Takata et al., 2011).”

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An important role for both nicotinic and muscarinic acetylcholine receptors has been defined in hippocampal synaptic plasticity.

“An important role for both nAChRs and mAChRs has been defined in hippocampal synaptic plasticity (reviewed in (Giocomo and Hasselmo, 2007; McKay et al., 2007)) and these effects are mediated through intracellular signaling pathways downstream of mAChRs and nAChRs (reviewed in (Berg and Conroy, 2002; Cancela, 2001; Lanzafame et al., 2003; Rathouz et al., 1996)).”

• cites Giocomo and Hasselmo, 2007Not checked yet

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• cites McKay et al., 2007 sourceNot checked yet

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Nicotinic and muscarinic acetylcholine receptors on both GABAergic and glutamatergic neurons in the hippocampus can alter the subsequent response to excitatory inputs.

“it is clear that nAChRs and mAChRs on both GABAergic and glutamatergic neurons in the hippocampus can alter the subsequent response to excitatory inputs (Drever et al., 2011).”

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Disrupting nicotinic receptor signaling delays the switch from GABA-mediated excitation to inhibition.

“Disrupting nAChR signaling delays the switch from GABA-mediated excitation to inhibition.”

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One fundamental role for acetylcholine signaling through nicotinic receptors is to regulate the timing of expression of the chloride transporter that is necessary for the ability of GABA to hyperpolarize, and therefore inhibit, central neurons.

“For example, one fundamental role for ACh signaling through nAChRs is to regulate the timing of expression of the chloride transporter that is necessary for the ability of GABA to hyperpolarize, and therefore inhibit, central neurons (Liu et al., 2006).”

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Stimulation of nicotinic acetylcholine receptors on glutamatergic terminals in the VTA can induce long-term potentiation of excitatory inputs onto dopamine neurons.

“Similarly, stimulation of nAChRs on glutamatergic terminals in the VTA can induce long-term potentiation (LTP) of excitatory inputs onto DA neurons (Mansvelder and McGehee, 2000), whereas differential effects of nAChRs on glutamatergic and GABAergic terminals in this area appears to be important for changes in dopaminergic firing following prolonged exposure to nicotine (Mansvelder et al., 2002;”

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The timing of acetylcholine release and the subtype of receptor is critical for the type of plasticity induced.

“Recent studies suggest that the timing of ACh release and the subtype of receptor is critical for the type of plasticity induced (Gu and Yakel, 2011); however, it is clear that nAChRs and mAChRs on both GABAergic and glutamatergic neurons in the hippocampus can alter the subsequent response to excitatory inputs (Drever et al., 2011).”

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Nicotinic receptor-mediated facilitation of GABA release reduces calcium levels in prefronto-cortical dendrites.

“In contrast to the ability of nAChR stimulation to promote LTP in a number of brain areas, nAChR-mediated facilitation of GABA release reduces calcium levels in prefronto-cortical dendrites (Couey et al., 2007).”

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Activation of nicotinic acetylcholine receptors can decrease subsequent stimulation of calcium entry into cortical neurons in response to glutamate.

“In addition, activation of nAChRs can also decrease subsequent stimulation of calcium entry into cortical neurons in response to glutamate (Stevens et al., 2003).”

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Nicotinic acetylcholine receptors contribute to the maturation of GABAergic and glutamatergic synapses.

“Recent studies have also shown that nAChRs contribute to the maturation of GABAergic (Kawai et al., 2002; Zago et al., 2006) and glutamatergic (Lozada et al., 2012a, b) synapses, highlighting an important role for ACh signaling in synaptic development, as well as neuronal pathfinding and target selection (reviewed in (Role and Berg, 1996).”

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• cites Zago et al., 2006 sourceNot checked yet

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• cites Lozada et al., 2012a, bNot checked yet

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Cholinergic input from the PPTg and LDTg acting through both muscarinic and nicotinic receptors is critical for modulating the function of the VTA.

“Cholinergic input from the PPTg and LDTg acting through both mAChRs and nAChRs is critical for modulating the function of the VTA.”

The addictive effects of nicotine are mediated primarily through stimulation of nicotinic acetylcholine receptors in the VTA.

“particularly because the addictive effects of nicotine are mediated primarily through stimulation of nAChRs in the VTA (Drenan et al., 2008; Maskos et al., 2005; McGranahan et al., 2011; Picciotto et al., 1998).”

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• cites Maskos et al., 2005 sourceNot checked yet

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• cites McGranahan et al., 2011 sourceNot checked yet

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It appears likely that acetylcholine release, potentially in response to salient stimuli, potentiates glutamatergic synapses during development through an LTP-like mechanism.

“It appears likely that ACh release, potentially in response to salient stimuli, potentiates glutamatergic synapses during development through an LTP-like mechanism (Aramakis and Metherate, 1998), highlighting another important role for cholinergic signaling in synaptic plasticity.”

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Extracellular acetylcholine levels are increased in the VTA during drug self-administration.

“Extracellular ACh levels are increased in the VTA during drug self-administration (You et al., 2008), that could result from an increase in ACh release from PPTg and LDTg afferents (Futami et al., 1995; Omelchenko and Sesack, 2006).”

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Cholinergic signaling in striatum and NAc is thought to be critical for mediating the association between drugs of abuse and cues in the environment that drive drug craving and relapse to drug use after abstinence.

“Cholinergic signaling in striatum and NAc is also thought to be critical for mediating the association between drugs of abuse and cues in the environment that drive drug craving and relapse to drug use after abstinence (Exley and Cragg, 2008).”

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The effects of striatal acetylcholine are mediated in part through activation of nicotinic receptors on dopaminergic terminals, leading to tonic, low level dopamine release when cholinergic interneurons are firing.

“The effects of striatal ACh are mediated in part through activation of nAChRs on dopaminergic terminals, leading to tonic, low level DA release when cholinergic interneurons are firing.”

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Stimulation of nicotinic receptors and M5-type muscarinic receptors increases the tonic excitability of dopamine neurons.

“Stimulation of nAChR and M5-type mAChRs increases the tonic excitability of these DA neurons (Corrigall et al., 2002; Miller and Blaha, 2005; Yeomans and Baptista, 1997).”

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• cites Miller and Blaha, 2005 sourceNot checked yet

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• cites Yeomans and Baptista, 1997Not checked yet

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The PPTg acts as a gate for salient sensory information associated with reward and/or requiring movement.

“These observations have led to the idea that the PPtg acts as a gate for salient sensory information associated with reward and/or requiring movement (Norton et al., 2011).”

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Striatal cholinergic interneurons can regulate the duration, magnitude, and spatial pattern of activity of striatal neurons, potentially creating an attentional gate that facilitates movement toward salient stimuli.

“These cholinergic interneurons can regulate the duration, magnitude, and spatial pattern of activity of striatal neurons, potentially creating an attentional gate that facilitates movement toward salient stimuli (Oldenburg and Ding, 2011).”

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Tonically active cholinergic interneurons in the striatum pause their firing following exposure to cues associated with reward.

“In contrast to the increased firing rate of cholinergic neurons in the PPTg in response to contextual information related to reward, tonically active cholinergic interneurons in the striatum pause their firing following exposure to cues associated with reward (Goldberg and Reynolds, 2011).”

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The pause in cholinergic interneuron firing would be predicted to enhance the efficacy and summation of glutamatergic inputs arriving during this period.

“Thus, the pause in cholinergic interneuron firing would be predicted to enhance the efficacy and summation of glutamatergic inputs arriving during this period.”

Disruption of PPTg activity decreases the rewarding and locomotor effects of drugs of abuse such as cocaine and nicotine.

“At the behavioral level, this conclusion is consistent with the finding that disruption of PPTg activity decreases the rewarding and locomotor effects of drugs of abuse such as cocaine and nicotine (Champtiaux et al., 2006; Corrigall et al., 1994; Corrigall et al., 2002), while lesion of NAc cholinergic neurons increases cocaine self-administration, as might be expected if a pause in cholinergic”

• cites Champtiaux et al., 2006 sourceNot checked yet

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• cites Corrigall et al., 1994 sourceNot checked yet

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• cites Corrigall et al., 2002 sourceNot checked yet

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Lesion of NAc cholinergic neurons increases cocaine self-administration.

“while lesion of NAc cholinergic neurons increases cocaine self-administration, as might be expected if a pause in cholinergic interneuron firing in NAc signals salience (Smith et al., 2004).”

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Blockade of muscarinic acetylcholine receptors using scopolamine decreases reinstatement of cocaine seeking.

“Less intuitively, blockade of mAChRs using scopolamine decreases reinstatement of cocaine seeking (Yee et al., 2011), but this may be due to increased ACh release through blockade of inhibitory autoreceptors (Douglas et al., 2001).”

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Antagonism of α7-type nicotinic acetylcholine receptors in NAc increases motivation to lever press for nicotine.

“Consistent with a role for the pause in NAc cholinergic neurons in behaviors related to drug reward, antagonism of α7-type nAChRs in NAc increases motivation to lever press for nicotine (Brunzell and McIntosh, 2012).”

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Muscarinic acetylcholine receptors reduce the probability of glutamate release from excitatory afferents to the striatum, negatively regulating the ability of these inputs to drive striatal activity.

“In contrast, mAChRs reduce the probability of glutamate release from excitatory afferents to the striatum, negatively regulating the ability of these inputs to drive striatal activity (Barral et al., 1999; Higley et al., 2009; Pakhotin and Bracci, 2007).”

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• cites Higley et al., 2009 sourceNot checked yet

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• cites Pakhotin and Bracci, 2007Not checked yet

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The habenula, particularly the MHb, opposes the behavioral processes mediated through the VTA.

“A number of studies have focused on the ability of the habenula, particularly the MHb to oppose the behavioral processes mediated through the VTA (for reviews, see (Fowler and Kenny, 2012; Hikosaka, 2010)).”

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• cites Hikosaka, 2010 sourceNot checked yet

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Point-to-point acetylcholine signaling could have opposing behavioral consequences, depending on the receptor subtypes, neuronal populations and brain areas stimulated.

“Taken together, these studies suggest that point-to-point ACh signaling could have opposing behavioral consequences, depending on the receptor subtypes, neuronal populations and brain areas stimulated, and that effects of ACh mediated through volume transmission could be distinct from those mediated locally.”

Neocortical acetylcholine function has been linked to control of circuits underlying attention, cue detection, and memory.

“Neocortical ACh function has been linked to control of circuits underlying attention, cue detection, and memory (Hasselmo and Sarter, 2011).”

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Acetylcholine plays an important and diverse role in the regulation of cortical activity over multiple timescales.

“Numerous studies indicate that ACh plays an important and diverse role in the regulation of cortical activity over multiple timescales.”

The fast inhibition is at least partially mediated by the actions of both nicotinic and muscarinic receptors that increase the excitability and firing rates of dendrite-targeting GABAergic interneurons.

“The fast inhibition is at least partially mediated by the actions of both nAChRs and mAChRs that increase the excitability and firing rates of dendrite-targeting GABAergic interneurons (Arroyo et al., 2012; Couey et al., 2007; Fanselow et al., 2008; Ferezou et al., 2002; Gulledge et al., 2007; Kawaguchi and Kubota, 1997).”

• cites Arroyo et al., 2012 sourceNot checked yet

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• cites Couey et al., 2007 sourceNot checked yet

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• cites Fanselow et al., 2008 sourceNot checked yet

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Acetylcholine can produce biphasic changes in the activity of pyramidal neurons, the principal excitatory cells in the neocortex, comprising fast inhibition followed by a slow depolarization.

“Seminal studies revealed that ACh can produce biphasic changes in the activity of pyramidal neurons, the principal excitatory cells in the neocortex, comprising fast inhibition followed by a slow depolarization (McCormick and Prince, 1985, 1986).”

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The precise function of acetylcholine on any given circuit greatly depends on the specific expression patterns of nicotinic and muscarinic receptors, as well as the temporal dynamics of acetylcholine concentration in the extracellular space.

“The precise function of ACh on any given circuit also greatly depends on the specific expression patterns of nAChRs and mAChRs, as well as the temporal dynamics of ACh concentration in the extracellular space.”

Activation of α4β2 nicotinic acetylcholine receptors on thalamocortical terminals enhances glutamate release in both sensory and association cortex.

“Activation of α4β2 nAChRs on thalamocortical terminals enhances glutamate release in both sensory and association cortex (Gil et al., 1997; Lambe et al., 2003; Oldford and Castro-Alamancos, 2003), whereas activation of mAChRs on terminals of parvalbumin-expressing interneurons decreases the probability of GABA release onto the perisynaptic compartment of pyramidal neurons, and therefore reduces”

• cites Gil et al., 1997 sourceNot checked yet

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• cites Lambe et al., 2003 sourceNot checked yet

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• cites Oldford and Castro-Alamancos, 2003Not checked yet

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In the visual system, ACh facilitates ocular dominance plasticity in kittens via M1 mAChRs.

“In the visual system, ACh facilitates ocular dominance plasticity in kittens via M1 mAChRs (Gu and Singer, 1993)”

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In the auditory cortex, pairing sensory stimulation with stimulation of the basal forebrain results in a long-term reorganization of cortical receptive field structure, including a persistent shift in the receptive field towards the paired stimulus.

“In the auditory cortex, pairing sensory stimulation with stimulation of the basal forebrain results in a long-term reorganization of cortical receptive field structure, including a persistent shift in the receptive field towards the paired stimulus (Froemke et al., 2007).”

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Acetylcholine directly inhibits spiny stellate cells in somatosensory cortex receiving thalamic input via M4 muscarinic receptors.

“ACh directly inhibits spiny stellate cells in somatosensory cortex receiving thalamic input via M4 mAChRs (Eggermann and Feldmeyer, 2009).”

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The effect of acetylcholine on the activity of cortical neurons clearly depends critically on the state of the neuron and the timing of acetylcholine release.

“Thus, the effect of ACh on the activity of cortical neurons clearly depends critically on the state of the neuron and the timing of ACh release.”

In the CA1 region of the hippocampus, long-range perforant inputs from the entorhinal cortex are less inhibited by acetylcholine than the Schaeffer collaterals arising from CA3.

“Indeed, in the CA1 region of the hippocampus, long-range perforant inputs from the entorhinal cortex are less inhibited by ACh than the Schaeffer collaterals arising from CA3 (Hasselmo and Schnell, 1994).”

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ACh modulates cortical circuits over longer time scales by influencing the plasticity of cortical circuits.

“ACh also modulates cortical circuits over longer time scales by influencing the plasticity of cortical circuits.”

• cites Froemke et al., 2007 sourceNot checked yet

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• cites Gu and Singer, 1993Not checked yet

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• cites Morishita et al., 2010 sourceNot checked yet

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Muscarinic acetylcholine receptors located on pyramidal cell axon terminals suppress cortico-cortical transmission.

“In contrast, mAChRs located on pyramidal cell axon terminals suppress cortico-cortical transmission (Gil et al., 1997; Hsieh et al., 2000; Kimura and Baughman, 1997; Oldford and Castro-Alamancos, 2003).”

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• cites Hsieh et al., 2000 sourceNot checked yet

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• cites Kimura and Baughman, 1997Not checked yet

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Cholinergic agonists enhance LTP of glutamatergic association fibers in the piriform cortex and Schaeffer collaterals in the CA1 region of the hippocampus.

“At the cellular level, cholinergic agonists enhance LTP of glutamatergic association fibers in the piriform cortex and Schaeffer collaterals in the CA1 region of the hippocampus (Huerta and Lisman, 1993).”

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M3 mAChRs facilitate long-term depression (LTD) of synapses in the monocular area of superficial visual cortex.

“In contrast, M3 mAChRs facilitate long term depression (LTD) of synapses in the monocular area of superficial visual cortex (Kirkwood et al., 1999; McCoy and McMahon, 2007).”

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• cites McCoy and McMahon, 2007Not checked yet

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Stimulation of α4β2 nicotinic receptors in the medial prefrontal cortex enhances performance in a visual attention task.

“stimulation of α4β2 nicotinic receptors in the medial prefrontal cortex enhances performance in a visual attention task (Howe et al., 2010)”

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Enhanced LTP is observed in binocular cortex.

“Surprisingly, the same authors observed enhanced LTP in binocular cortex (McCoy et al., 2008).”

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Regional differences in cholinergic effects indicate that cell-specific expression of different receptor subtypes is critical for the varied actions of ACh.

“These regional differences indicate that cell-specific expression of different receptor subtypes is critical for the varied actions of ACh.”

In rodents, lesions of cholinergic inputs to the cortex impair tests of sustained attention, particularly across sensory modalities.

“In rodents, lesions of cholinergic inputs to the cortex impair tests of sustained attention, particularly across sensory modalities (McGaughy et al., 2002; McGaughy et al., 1996; Turchi and Sarter, 1997).”

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• cites McGaughy et al., 1996 sourceNot checked yet

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• cites Turchi and Sarter, 1997Not checked yet

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The pleiotropic effects of ACh on cortical circuits likely underlie its ability to modulate cognitive behaviors.

“The pleiotropic effects of ACh on cortical circuits described above are likely to underlie its ability to modulate cognitive behaviors.”

Genetic deletion of α4β2 nicotinic receptors in the mPFC impairs visual attention.

“while genetic deletion of these receptors in the mPFC impairs visual attention (Guillem et al., 2011)”

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The temporal dynamics of cholinergic signaling are critical for normal behavior.

“suggesting that the temporal dynamics of cholinergic signaling are also critical for normal behavior”

Activity in the PPTg and LDTg adapts quickly to environmental changes.

“Activity in both these areas adapts quickly to environmental changes (Majkutewicz et al., 2010; Woolf, 1991)”

• cites Majkutewicz et al., 2010 sourceNot checked yet

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• cites Woolf, 1991 sourceNot checked yet

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Modulation of hypothalamic function by ACh is likely to be an important component of adaptation to peripheral autonomic signals to the brain.

“The hypothalamus is essential for homeostatic responses regulating metabolism, and consequently, modulation of hypothalamic function by ACh is likely to be an important component of adaptation to peripheral autonomic signals to the brain.”

• AssumptionRests on an assumption: The hypothalamus is essential for homeostatic responses regulating metabolism.

Cholinergic actions across both ionotropic and metabotropic receptors and diverse brain areas contribute to cognitive processing.

“Taken together, these findings suggest that cholinergic actions across both ionotropic and metabotropic receptors and diverse brain areas contribute to cognitive processing.”

Actions of ACh in the brain modulate adaptive responses to environmental and metabolic conditions.

“it is likely that actions of ACh in the brain also modulate adaptive responses to environmental and metabolic conditions.”

• AssumptionRests on an assumption: The role of ACh in control of autonomic functions is well known.

The hypothalamus receives input from the PPTg and LDTg.

“which receives input from the PPTg and LDTg (Hallanger and Wainer, 1988; Jones and Beaudet, 1987).”

• cites Hallanger and Wainer, 1988Not checked yet

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• cites Jones and Beaudet, 1987Not checked yet

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In primates, locally applied ACh enhances the attentional modulation of neuronal activity in the primary visual cortex.

“In primates, locally applied ACh enhances the attentional modulation of neuronal activity in the primary visual cortex, while the muscarinic antagonist scopolamine reduces the effects of attention (Herrero et al., 2008).”

• cites Herrero et al., 2008 sourceNot checked yet

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In primates, the muscarinic antagonist scopolamine reduces the effects of attention.

“while the muscarinic antagonist scopolamine reduces the effects of attention (Herrero et al., 2008).”

• cites Herrero et al., 2008 sourceNot checked yet

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Genetic deletion of α4β2 nicotinic receptors in the mPFC impairs auditory discrimination.

“and auditory discrimination (Horst et al., 2012).”

• cites Horst et al., 2012 sourceNot checked yet

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Transient rises in prefrontal ACh are significantly correlated with cue detection.

“Notably, transient rises in prefrontal ACh are significantly correlated with cue detection, suggesting that the temporal dynamics of cholinergic signaling are also critical for normal behavior (Parikh et al., 2007b).”

• cites Parikh et al., 2007bNot checked yet

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nAChRs in the hypothalamus are critical for feeding behavior.

“and nAChRs in the hypothalamus are critical for feeding behavior (Jo et al., 2002).”

• cites Jo et al., 2002Not checked yet

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Stimulation of nAChRs on lateral hypothalamic neurons increases GABA release.

“stimulation of nAChRs and mAChRs on lateral hypothalamic (LH) neurons increases and decreases GABA release, respectively (Jo and Role, 2002).”

• cites Jo and Role, 2002Not checked yet

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Long-term maintenance on a high-fat/high-sugar diet significantly down-regulated levels of AChE in a number of brain areas, particularly pronounced in the hypothalamus.

“long-term maintenance on a high-fat/high-sugar diet significantly down-regulated levels of ACh-esterase (AChE) in a number of brain areas that was particularly pronounced in the hypothalamus (Kaizer et al., 2004).”

• cites Kaizer et al., 2004 sourceNot checked yet

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In the arcuate nucleus of the hypothalamus, nicotine increases the firing rate of both POMC- and NPY-positive neurons.

“In the arcuate nucleus of the hypothalamus, nicotine increases the firing rate of both POMC- and neuropeptide Y (NPY)-positive neurons”

• cites Huang et al., 2011 sourceNot checked yet

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• cites Mineur et al., 2011 sourceNot checked yet

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The increase in POMC neuron activity predominates in vitro due to more rapid desensitization of nAChR responses in NPY neurons.

“although the increase in POMC neuron activity predominates in vitro due to more rapid desensitization of nAChR responses in NPY neurons”

• cites Huang et al., 2011 sourceNot checked yet

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• cites Mineur et al., 2011 sourceNot checked yet

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There are intrinsic neurons within the hypothalamus that express cholinergic markers.

“There are also intrinsic neurons within the hypothalamus that express cholinergic markers (Tago et al., 1987)”

• cites Tago et al., 1987 sourceNot checked yet

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In non-human primates, neurons in the substantia innominata and LH, most of which express cholinergic markers, were activated in response to presentation of food when the animals were hungry.

“In non-human primates, neurons in the substantia innominata and LH, most of which express cholinergic markers, were activated in response to presentation of food when the animals were hungry (Rolls et al., 1979).”

• cites Rolls et al., 1979 sourceNot checked yet

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Stimulation of mAChRs on lateral hypothalamic neurons decreases GABA release.

“stimulation of nAChRs and mAChRs on lateral hypothalamic (LH) neurons increases and decreases GABA release, respectively (Jo and Role, 2002).”

• cites Jo and Role, 2002Not checked yet

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nAChRs and mAChRs may be localized to different populations of GABAergic terminals.

“The data suggest that the nAChRs and mAChRs may be localized to different populations of GABAergic terminals”

Activity in the PPTg and LDTg is linked to peripheral control of feeding behavior.

“and is linked to peripheral control of feeding behavior (Phillis, 2005).”

• cites Phillis, 2005 sourceNot checked yet

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In vivo, nicotine increases c-fos immunoreactivity predominantly in POMC-positive cells.

“and in vivo, as evidenced by an increase in c-fos immunoreactivity predominantly in POMC-positive cells (Huang et al., 2011; Mineur et al., 2011).”

• cites Huang et al., 2011 sourceNot checked yet

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• cites Mineur et al., 2011 sourceNot checked yet

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β4-containing nAChRs on POMC neurons are critical for the ability of nicotine to reduce food intake in mice.

“β4-containing nAChRs on POMC neurons are critical for the ability of nicotine to reduce food intake in mice (Mineur et al., 2011).”

• cites Mineur et al., 2011 sourceNot checked yet

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In rats, the mAChR competitive antagonist atropine modestly altered the frequency and choice of meals but not their size.

“In rats, the mAChR competitive antagonist atropine modestly altered the frequency and choice of meals but not their size (Nissenbaum and Sclafani, 1988).”

• cites Nissenbaum and Sclafani, 1988Not checked yet

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ACh signaling can be upregulated to compensate for prolonged blockade of glutamatergic signaling in hypothalamic neurons in culture.

“There is also some indication from studies of hypothalamic neurons in culture that ACh signaling can be upregulated to compensate for prolonged blockade of glutamatergic signaling (Belousov et al., 2001).”

• cites Belousov et al., 2001 sourceNot checked yet

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ACh has a potential role in metabolic regulation involving POMC neurons.

“These observations underscore a potential role for ACh in metabolic regulation involving POMC neurons”

Stress increases ACh release in a brain region-specific manner.

“Several studies have shown that stress increases ACh release in a brain region-specific manner (Mark et al., 1996).”

• cites Mark et al., 1996 sourceNot checked yet

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ACh acting through nAChRs may potentiate glutamate signaling in particular neuronal subtypes of the hypothalamus.

“Thus, ACh acting through nAChRs may also potentiate glutamate signaling in particular neuronal subtypes of the hypothalamus”

ACh signaling in a number of brain areas is important for stress responses.

“Increasing evidence suggests that ACh signaling in a number of brain areas is important for stress responses (Figure 4).”

The hippocampus, amygdala and PFC are critical nodes in adaptation and responses to stress.

“the amygdala in mediating fear responses and the PFC in attention, these brain areas are critical nodes in adaptation and responses to stress (Belujon and Grace, 2011; Gozzi et al., 2010; McGaugh, 2004; Sapolsky, 2000; Tottenham and Sheridan, 2009).”

• cites Belujon and Grace, 2011Not checked yet

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• cites Gozzi et al., 2010 sourceNot checked yet

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• cites McGaugh, 2004 sourceNot checked yet

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Distinct actions of ACh converge through effects on receptor populations with different electrophysiological properties expressed on distinct subsets of neurons to promote a coordinated output, in this case, activation of POMC neurons.

“Thus, as in the mesolimbic system and the cortex, distinct actions of ACh appear to converge through effects on receptor populations with different electrophysiological properties expressed on distinct subsets of neurons to promote a coordinated output, in this case, activation of POMC neurons.”

Dysfunction in the activity of the hippocampus, amygdala and PFC is strongly implicated in major depressive disorder.

“Dysfunction in the activity of these regions is strongly implicated in major depressive disorder (Sheline et al., 1998; Videbech and Ravnkilde, 2004).”

• cites Sheline et al., 1998 sourceNot checked yet

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• cites Videbech and Ravnkilde, 2004 sourceNot checked yet

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Stimulation of nAChRs on orexin-positive neurons in the LH induces concurrent release of glutamate and ACh.

“Stimulation of nAChRs on orexin-positive neurons in the LH induces concurrent release of glutamate and ACh”

• cites Pasumarthi and Fadel, 2010Not checked yet

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The hippocampus provides inhibitory feedback to the amygdala through inhibition of the HPA axis.

“The hippocampus provides inhibitory feedback to the amygdala through inhibition of the hypothalamic-pituitary-adrenal (HPA) axis (Tasker and Herman, 2011).”

• cites Tasker and Herman, 2011Not checked yet

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Relief from stress leads to an increase in cholinergic signaling in the amygdala and PFC.

“Interestingly, relief from stress leads to an increase in cholinergic signaling in the amygdala and PFC (Mark et al., 1996)”

• cites Mark et al., 1996 sourceNot checked yet

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Acute activation of presynaptic α7 nAChRs in the BLA can favor the release of glutamate from impinging cortical projections.

“Conversely, acute activation of presynaptic α7 nAChRs in the BLA can also favor the release of glutamate from impinging cortical projections”

• cites Klein and Yakel, 2006Not checked yet

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Cholinergic inputs to the hippocampus from the medial septum and the diagonal band of Broca impinge on both glutamatergic and GABAergic neurons throughout the structure.

“Cholinergic inputs to the hippocampus from the medial septum and the diagonal band of Broca impinge on both glutamatergic and GABAergic neurons throughout the structure”

• cites Drever et al., 2011 sourceNot checked yet

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The ability of ACh to induce synaptic plasticity through actions on pre- and post-synaptic nAChRs and mAChRs is likely to modulate learning and memory, including memory of stressful events.

“The ability of ACh to induce synaptic plasticity through actions on pre- and post-synaptic nAChRs and mAChRs is likely to modulate learning and memory, including memory of stressful events (Nijholt et al., 2004)”

• cites Nijholt et al., 2004 sourceNot checked yet

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Stimulation of the α7 nAChR pathway during development blunts paired facilitation due to subsequent stimulation.

“Stimulation of this pathway during development blunts paired facilitation due to subsequent stimulation, however, which would be expected to decrease BLA reactivity (Jiang and Role, 2008)”

• cites Jiang and Role, 2008Not checked yet

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An increase in amygdalar cholinergic tone can reduce BLA activity through activation of mAChRs.

“although an increase in amygdalar cholinergic tone can also reduce BLA activity though activation of mAChRs (Power and Sah, 2008).”

• cites Power and Sah, 2008Not checked yet

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Glutamate release from cortical projections to the BLA is critical for aversive memory and fear.

“which is critical for aversive memory and fear (Klein and Yakel, 2006).”

• cites Klein and Yakel, 2006Not checked yet

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The valence of ACh varies by brain area.

“indicating that the valence of ACh varies by brain area.”

A role for ACh in regulation of hippocampal excitability through presynaptic release of glutamate and GABA has been well-characterized.

“and a role for ACh in regulation of hippocampal excitability through presynaptic release of glutamate and GABA has also been well-characterized (Alkondon et al., 1997; Freund et al., 1988; Radcliffe et al., 1999).”

• cites Alkondon et al., 1997 sourceNot checked yet

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• cites Freund et al., 1988 sourceNot checked yet

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• cites Radcliffe et al., 1999 sourceNot checked yet

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The PFC can normally decrease basolateral amygdala activity through projections to the intercalated nucleus.

“and PFC can normally decrease basolateral amygdala activity through projections to the intercalated nucleus (Manko et al., 2011; Pinard et al., 2012).”

• cites Manko et al., 2011 sourceNot checked yet

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• cites Pinard et al., 2012 sourceNot checked yet

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Stress impairs PFC output.

“but stress impairs PFC output (Arnsten, 2009)”

• cites Arnsten, 2009 sourceNot checked yet

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In rodents, decreasing ACh signaling through nAChRs depresses neuronal activity in the basolateral amygdala as measured by c-fos immunoreactivity.

“In rodents, decreasing ACh signaling through nAChRs depresses neuronal activity in the basolateral amygdala as measured by c-fos immunoreactivity (Mineur et al., 2007).”

• cites Mineur et al., 2007 sourceNot checked yet

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The amygdala receives cholinergic inputs from the basal forebrain complex.

“The amygdala also receives cholinergic inputs from the basal forebrain complex (Mesulam, 1995)”

• cites Mesulam, 1995Not checked yet

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Administration of the AChE blocker physostigmine to patients with a history of depression, individuals with Tourette's syndrome and normal volunteers results in increased symptoms of depression.

“This has been observed with administration of the AChE blocker physostigmine to patients with a history of depression, individuals with Tourette’s syndrome and normal volunteers (Risch et al., 1980; Risch et al., 1981; Shytle et al., 2000).”

• cites Risch et al., 1980 sourceNot checked yet

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• cites Risch et al., 1981 sourceNot checked yet

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• cites Shytle et al., 2000 sourceNot checked yet

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Cortico-amygdala glutamatergic connections are strongly and persistently potentiated by nAChR stimulation.

“and cortico-amygdala glutamatergic connections are also strongly and persistently potentiated by nAChR stimulation (Mansvelder et al., 2009).”

• cites Mansvelder et al., 2009 sourceNot checked yet

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Stress induces alternative splicing of the AChE mRNA in the hippocampus leading to altered ACh signaling in this structure.

“Stress also induces alternative splicing of the AChE mRNA in the hippocampus leading to altered ACh signaling in this structure (Nijholt et al., 2004).”

• cites Nijholt et al., 2004 sourceNot checked yet

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Increasing ACh signaling in humans results in increased symptoms of depression.

“There is strong evidence that increasing ACh signaling in humans results in increased symptoms of depression (Janowsky et al., 1972; Risch et al., 1980).”

• cites Janowsky et al., 1972 sourceNot checked yet

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• cites Risch et al., 1980 sourceNot checked yet

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The amygdala is consistently hyperactivated in fMRI studies of patients with mood disorders.

“and is consistently hyperactivated in fMRI studies of patients with mood disorders (Drevets, 2001).”

• cites Drevets, 2001 sourceNot checked yet

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Increasing ACh levels increases symptoms of depression.

“supporting the idea that increasing ACh levels increases symptoms of depression”

Organophosphate inhibitors of AChE produce a similar effect of increased symptoms of depression.

“A similar effect has also been described with organophosphate inhibitors of AChE (Rosenstock et al., 1991).”

• cites Rosenstock et al., 1991 sourceNot checked yet

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Clinical trials have suggested that blockade of either mAChRs or nAChRs can decrease symptoms of depression.

“clinical trials have suggested that blockade of either mAChRs (Furey and Drevets, 2006; Furey et al., 2010) or nAChRs (George et al., 2008; Shytle et al., 2002) can decrease symptoms of depression.”

• cites Furey and Drevets, 2006 sourceNot checked yet

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• cites Furey et al., 2010 sourceNot checked yet

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• cites George et al., 2008 sourceNot checked yet

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ACh can induce heterogeneous effects in different brain areas that appear to have opposite behavioral consequences.

“highlighting the fact that ACh can induce heterogeneous effects in different brain areas that appear to have opposite behavioral consequences.”

Antagonism of mAChRs or nAChRs, or blockade of ACh signaling through nAChRs with partial agonists, can decrease depression-like behavior in rodents.

“Consistent with an increase in ACh leading to symptoms of depression, antagonism of mAChRs or nAChRs, or blockade of ACh signaling through nAChRs with partial agonists, can decrease depression-like behavior in rodents (Caldarone et al., 2004; De Pablo et al., 1991; Mineur et al., 2007; Picciotto et al., 2002; Rabenstein et al., 2006).”

• cites Caldarone et al., 2004 sourceNot checked yet

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• cites De Pablo et al., 1991 sourceNot checked yet

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• cites Mineur et al., 2007 sourceNot checked yet

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In the hypothalamus, despite the ubiquitous expression of nAChRs on multiple neuronal subtypes with reciprocal functions, the kinetics of activation of one set of receptors may bias the output in one direction, based on the starting conditions.

“This organization is echoed in the hypothalamus where, despite the ubiquitous expression of nAChRs on multiple neuronal subtypes with reciprocal functions, the kinetics of activation of one set of receptors may bias the output in one direction, based on the starting conditions.”

Increases in ACh signaling appear to contribute to stress-related illnesses such as major depressive disorder.

“Finally, increases in ACh signaling appear to contribute to stress-related illnesses such as major depressive disorder, although the specific neuronal substrates and cellular mechanisms responsible for these effects are only beginning to be studied.”

State-dependent facilitation of neurotransmission in pathways activated in response to ACh release is likely to be maintained due to facilitated neuronal plasticity.

“this state dependent facilitation of neurotransmission in pathways activated in response to ACh release is likely to be maintained due to facilitated neuronal plasticity.”

The promotion of coordinated firing of adjacent axons and the promotion of rhythmic activity in structures such as the hippocampus when ACh is released and levels are high may provide an increase in the baseline excitability of neurons that are then available for robust responses to glutamate.

“The promotion of coordinated firing of adjacent axons and the promotion of rhythmic activity in structures such as the hippocampus when ACh is released and levels are high may provide an increase in the baseline excitability of neurons that are then available for robust responses to glutamate”