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Cited by 733Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchCholinesterase and Neurodegenerative Diseases

Modes and models of forebrain cholinergic neuromodulation of cognition

Open access
Hasselmo, Michael E, Sarter, Martin·2011·Neuropsychopharmacology
DOI 10.1038/npp.2010.104PMC PMC2992803
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Abstract

As indicated by the profound cognitive impairments caused by cholinergic receptor antagonists, cholinergic neurotransmission has a vital role in cognitive function, specifically attention and memory encoding. Abnormally regulated cholinergic neurotransmission has been hypothesized to contribute to the cognitive symptoms of neuropsychiatric disorders. Loss of cholinergic neurons enhances the severity of the symptoms of dementia. Cholinergic receptor agonists and acetylcholinesterase inhibitors have been investigated for the treatment of cognitive dysfunction. Evidence from experiments using new techniques for measuring rapid changes in cholinergic neurotransmission provides a novel perspective on the cholinergic regulation of cognitive processes. This evidence indicates that changes in cholinergic modulation on a timescale of seconds is triggered by sensory input cues and serves to facilitate cue detection and attentional performance. Furthermore, the evidence indicates cholinergic induction of evoked intrinsic, persistent spiking mechanisms for active maintenance of sensory input, and planned responses. Models have been developed to describe the neuronal mechanisms underlying the transient modulation of cortical target circuits by cholinergic activity. These models postulate specific locations and roles of nicotinic and muscarinic acetylcholine receptors and that cholinergic neurotransmission is controlled in part by (cortical) target circuits. The available evidence and these models point to new principles governing the development of the next generation of cholinergic treatments for cognitive disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that forebrain cholinergic modulation operates through fast, second-scale transients that mediate cue detection and attentional orienting, alongside slower tonic modulation and muscarinic-dependent persistent spiking for active maintenance. It integrates lesion, microdialysis, electrochemical, pharmacological, slice, fMRI, and computational evidence into circuit models pointing toward α4β2* nAChR agonists and positive allosteric modulators as new treatment strategies.

Key findings

  • Cortical cholinergic deafferentation selectively and persistently impaired cue detection: intact animals detected over 70–80% of the longest 500 ms cues, whereas lesioned animals detected about 30% of all cues, with no recovery despite months of daily post-surgery practice; blank-trial accuracy was spared.
  • In medial prefrontal cortex, detected cues evoked transient cholinergic increases, while missed cues did not; these transients were absent in motor cortex, and peak amplitude occurred about 1.5 s after cue presentation in animals trained on the shortest cue-reward intervals (2±1 s).
  • Cholinergic transients are hypothesized to mediate attentional orienting and mode switching: transients occurred in hit trials preceded by misses or correct rejections, but not consistently in hits preceded by identical hit trials, suggesting attention remains aligned for a brief period (perhaps 10–20 s during SAT performance; average ITI 9 s).
  • α4β2* nAChR stimulation enhanced attention more efficaciously than nicotine; nicotine alone did not statistically improve performance, but co-administration of nicotine with the α7 nAChR antagonist methyllycaconitine significantly enhanced attention and “sharpened” cholinergic transients.
  • Muscarinic receptor activation induces intrinsic persistent spiking via a calcium-sensitive non-specific cation current I(CAN), proposed to maintain cue or sample representations during delays and trace intervals.

Methods

  • Narrative review and conceptual synthesis, not a primary experimental study; it integrates published and some preliminary/unpublished findings across rodent, non-human primate, and human work.
  • Evidence reviewed includes selective cholinergic lesions, sustained attention tasks, microdialysis, enzyme-coated microelectrode amperometric measures of ACh release, nAChR/mAChR pharmacology, brain slice physiology, human fMRI with AChE inhibitors/nicotine/scopolamine, and computational circuit models.
  • Main analysis is theoretical: the paper builds circuit-based models of prefrontal glutamatergic-cholinergic interactions, nicotinic/muscarinic receptor roles, and cholinergic regulation of attention, encoding, and persistent spiking.

Limitations

  • The paper states that evidence for segregation of cholinergic projections remains limited, that parts of the model are speculative, and that some supporting data are preliminary or unpublished.
  • It states that α7 nAChR agonist evidence remains conflicting, that selective mAChR subtype ligands have been a major obstacle, and that electrochemical ACh measurement cannot be performed with an AChE inhibitor present.
  • Evident from the text: this is a review with no systematic search or meta-analytic method, and several clinical/therapeutic claims are described as limited or requiring future testing.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/npp.2010.104

Cites

310 of 310 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 258 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Cholinergic transients were not observed in trials resulting in a hit if these trials were preceded by identical trials, that is, by cued trials ending with a hit.

    “Cholinergic transients were not observed in trials resulting in a hit if these trials were preceded by identical trials, that is, by cued trials ending with a hit.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Co-administration of nicotine and MLA sharpens the cholinergic transients evoked by nicotine.

    “Corresponding with the behavioral evidence, this combination treatment also “sharpened” the cholinergic transients evoked by nicotine (Howe et al. 2010)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Howe et al. 2010 source

      Not checked in the free run.

  • Premisecitation

    The entire cortex and hippocampus are innervated by cholinergic projections that originate from several regions in the basal forebrain.

    “The entire cortex and hippocampus are innervated by cholinergic projections that originate from several regions in the basal forebrain (Rye et al, 1984; Lysakowski et al, 1989; Mesulam et al, 1992; Kitt et al, 1994).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Rye et al, 1984 source

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    • cites Lysakowski et al, 1989 source

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    • cites Mesulam et al, 1992 source

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  • Interpretationnone given

    Cholinergic activity induces evoked intrinsic, persistent spiking mechanisms for active maintenance of sensory input and planned responses.

    “Furthermore, evidence indicates cholinergic induction of evoked intrinsic, persistent spiking mechanisms for active maintenance of sensory input and planned responses.”
    Quote in the paperNot a substantial claim
  • Interpretationnone given

    Changes in cholinergic modulation on a timescale of seconds are triggered by sensory input cues and serve to facilitate cue detection and attentional performance.

    “This evidence indicates that changes in cholinergic modulation on a timescale of seconds is triggered by sensory input cues and serves to facilitate cue detection and attentional performance.”
    Quote in the paperSubstantial claim
  • May combine two claims. 63
  • Classified as probably not a substantial claim. 30

  • May combine two claims.

    Findingown data

    Cholinergic transients were observed in cued trials resulting in a hit if preceded by a miss, or if preceded by blank trials resulting in correct rejections.

    “In contrast, transients were observed in cued trials resulting in a hit if preceded by a miss, or if preceded by “blank” trials resulting in correct rejections.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Cue-evoked cholinergic transients were observed in trials yielding hits, but this was not consistently the case.

    “As expected, cue-evoked cholinergic transients were observed in trials yielding hits. However, this was not consistently the case.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Howe et al, 2007

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  • May combine two claims.

    Findingcitation

    Ongoing studies suggest that tonic changes in cholinergic activity are not confounded by phasic cholinergic activity; rather, the direction of changes in tonic cholinergic activity and the amplitudes of cholinergic transients are not necessarily correlated and may in fact be dissociated.

    “Ongoing studies suggest that these tonic changes in cholinergic activity are not confounded by phasic cholinergic activity. Rather, the direction of changes in tonic cholinergic activity (as indicated by microdialysis) and the amplitudes of cholinergic transients (measured electrochemically) are not necessarily correlated and, as evidenced by effects of different nAChR agonists on both measures,”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites G. Paolone, unpublished findings

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    • cites Parikh and Sarter, 2008

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  • May combine two claims.

    Findingreasoning

    Co-administration of nicotine and the α7 nAChR antagonist methyllycaconitine significantly enhances attention, whereas nicotine alone does not statistically improve performance.

    “Indeed, while the administration of nicotine alone did not statistically improve performance, co-administration of nicotine and the α7 nAChR antagonist methyllycaconitine (MLA) resulted in a significant enhancement of attention.”
    • Also stated in: § Nicotinic AChRs · hedged
      “As mentioned above, evidence indicates that, in the presence of an antagonist at the α7 nAChR, nicotine enhanced attentional performance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Administration of the α7 nAChR agonist ABT 107 did not produce beneficial attention effects on basic SAT performance or on recovery from the distractor challenge.

    “Likewise, we were not able to observe beneficial attention effects of the administration of the α7 nAChR agonist ABT 107, neither on basic SAT performance nor on the recovery from the distractor challenge (Paolone et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Paolone et al, 2009

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  • May combine two claims.

    Premisereasoning

    Cholinergic neurotransmission plays a vital role in cognitive function, specifically attention and memory encoding.

    “As indicated by the profound cognitive impairments caused by cholinergic receptor antagonists, cholinergic neurotransmission plays a vital role in cognitive function, specifically attention and memory encoding.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The available evidence and models point to new principles governing the development of the next generation of cholinergic treatments for cognitive disorders.

    “The available evidence and these models point to new principles governing the development of the next generation of cholinergic treatments for cognitive disorders.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Models postulate specific locations and roles of nicotinic and muscarinic acetylcholine receptors and that cholinergic neurotransmission is controlled in part by cortical target circuits.

    “These models postulate specific locations and roles of nicotinic and muscarinic acetylcholine receptors and that cholinergic neurotransmission is controlled in part by (cortical) target circuits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    High levels of ACh excessively stimulate nAChRs, which in turn stimulate the release of several neuromodulators, including ACh itself, thereby robustly modulating the state of local circuitry.

    “Even within the constraints of classic synapses, high levels of ACh are expected to excessively stimulate nAChRs which in turn stimulate the release of several neuromodulators, including ACh itself, thereby robustly modulating the state of local circuitry (e.g., Dani and Bertrand, 2007; Sarter et al, 2009b).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dani and Bertrand, 2007

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    • cites Sarter et al, 2009b

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Specific cognitive operations are mediated by precisely orchestrated and spatially restricted changes in cholinergic neurotransmission.

    “Although recent research indicated that specific cognitive operations are mediated by precisely orchestrated and spatially restricted changes in cholinergic neurotransmission, o u r current model integrates multiple roles and neurotransmission modes of forebrain cholinergic systems”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Sustained, high levels of extracellular ACh cause excessive stimulation of presynaptic M2 receptors, which inhibits the release of ACh and attenuates presynaptic signaling.

    “However, the consequences of sustained, high levels of extracellular ACh levels include the excessive stimulation of presynaptic M2 receptors. Stimulation of these receptors inhibits the release of ACh and thereby attenuates presynaptic signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AChE inhibitors enhance cognitive performance and reduce the impairments caused by mAChR antagonists.

    “AChE inhibitors have been shown to enhance cognitive performance (Aigner and Mishkin, 1986; Aigner et al., 1987) and to reduce the impairments caused by mAChR antagonists (Ghoneim and Mewaldt, 1977).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Aigner and Mishkin, 1986

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    • cites Aigner et al., 1987

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    • cites Ghoneim and Mewaldt, 1977

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  • May combine two claims.

    Interpretationreasoning

    Extremely high extracellular ACh levels stimulate nAChRs, and such effects may interact with the blockade of postsynaptic mAChRs to cause complex behavioral and cognitive effects.

    “As a result, extremely high extracellular ACh levels stimulate nAChRs, and such effects may interact with the blockade of postsynaptic mAChRs to cause rather complex behavioral and cognitive effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    AChE inhibitors do not merely increase cholinergic neurotransmission but uncouple presynaptic from postsynaptic information transmission and produce complex changes in local and efferent circuitry.

    “Thus, AChE inhibitors do not merely increase cholinergic neurotransmission but they uncouple presynaptic from postsynaptic information transmission and produce complex changes in local and efferent circuitry.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Non-selective lesions of the basal forebrain and selective lesions of the basal forebrain cholinergic projections to the cortex indicate that these projections are necessary for performing tasks assessing a range of attentional functions.

    “A considerable amount of evidence from experiments on the effects of, initially, non-selective lesions of the basal forebrain (Robbins et al, 1989; Dunnett et al, 1991; Muir et al, 1992; Roberts et al, 1992; Voytko et al, 1994) and, subsequently, selective lesions of the basal forebrain cholinergic projections to the cortex (e.g., McGaughy et al, 1996; Turchi and Sarter, 1997; McGaughy and Sarter,”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Robbins et al, 1989

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    • cites Dunnett et al, 1991

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    • cites Muir et al, 1992

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    Premisecitation

    Atropine and scopolamine impair encoding of new memories and impair attention.

    “With respect to the non-selective mAChR antagonists, atropine and scopolamine, these drugs have been shown to impair encoding of new memories (Ghoneim and Mewaldt, 1975, 1977; Kopelman and Corn, 1977; Aigner et al., 1991) and to impair attention (Wesnes and Warburton, 1984; Broks et al., 1988).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ghoneim and Mewaldt, 1975, 1977

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    • cites Kopelman and Corn, 1977

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    • cites Aigner et al., 1991

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  • May combine two claims.

    Premisecitation

    Blockade of nAChRs alone does not affect cognitive performance; when administered together with a mAChR antagonist, substantial or significantly greater cognitive impairments are observed.

    “Consistent with such a potential interaction, several studies demonstrated that blockade of nAChRs alone did not affect cognitive performance; however, when administered together with a mAChR antagonist, substantial or significantly greater cognitive impairments were observed (e.g., Little et al, 1998; Ellis et al, 2006; Erskine et al, 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Little et al, 1998

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    • cites Ellis et al, 2006

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    • cites Erskine et al, 2004

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  • May combine two claims.

    Premisecitation

    Cholinergic lesions cause transient effects or no impairments in the radial arm maze and T-maze alternation.

    “Cholinergic lesions cause transient effects or no impairments in the radial arm maze (Chappell et al., 1997; Galani et al., 2002; Vuckovich et al., 2004) and T-maze alternation (Pang and Nocera, 1999; Galani et al., 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chappell et al., 1997

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    • cites Galani et al., 2002

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    • cites Vuckovich et al., 2004

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  • May combine two claims.

    Premisecitation

    Levels of ACh release in attentional task-performing animals vary as a function of the demands on attention but do not correlate with levels of attentional performance.

    “The results from more recent microdialysis studies indicated that levels of ACh release in attentional task-performing animals vary as a function of the demands on attention (or “attentional effort”) but do not correlate with levels of attentional performance (Passetti et al, 2000; Dalley et al, 2001; Kozak et al, 2006, 2007; Sarter et al, 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Passetti et al, 2000

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    • cites Dalley et al, 2001

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    • cites Kozak et al, 2006, 2007

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  • May combine two claims.

    Premisecitation

    Removal of cortical cholinergic inputs selectively and persistently impaired the animals' detection rate (or number of hits), while response accuracy in blank trials remained completely spared.

    “Removal of cortical cholinergic inputs selectively and persistently impaired the animals’ detection rate (or number of hits). In contrast, response accuracy in blank trials remained completely spared.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites McGaughy et al, 1996 source

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    • cites McGaughy and Sarter, 1998

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  • May combine two claims.

    Premisecitation

    Cortical cholinergic deafferentation did not affect performance in blocks of unimodal trials; under modality uncertainty, the lesion caused a profound speed-accuracy trade-off, with correct responses requiring 700 ms longer in bimodal than in unimodal blocks.

    “Cortical cholinergic deafferentation did not affect the animals’ performance in blocks of unimodal trials in which all cues were either visual or auditory. In contrast, under the condition of modality uncertainty, the lesion caused a profound speed-accuracy trade-off, with correct responses requiring 700 ms longer in bimodal than in unimodal blocks of trials (for additional evidence illustrating”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Turchi and Sarter, 1997

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    A cue may evoke a switch away from the default response mode, to a mode that increases the likelihood that it will be selected for behavioral and cognitive control (that is, detection).

    “Thus, it may be speculated that a cue may evoke a switch away from the default response mode, to a mode that increases the likelihood that it will be selected for behavioral and cognitive control (that is, detection; see above).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Attentional orienting fosters cue detection; however, orienting is neither sufficient nor necessary for detection.

    “Attentional orienting, overtly or covertly, fosters cue detection; however, orienting is neither sufficient nor necessary for detection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Posner, 1980

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  • May combine two claims.

    Premiseown data

    Cholinergic transients were not observed in trials in which cues were missed, and they were not observed in motor cortex.

    “Such transients were not observed in trials in which cues were missed, and they were not observed in motor cortex.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Parikh et al, 2007

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  • May combine two claims.

    Interpretationreasoning

    Misses are attributed to orienting failures, therefore decreasing the likelihood for subsequent detection and increasing the likelihood that the default response (a correct rejection) will be executed.

    “In keeping with this conceptualization, misses are attributed to orienting failures, therefore decreasing the likelihood for subsequent detection and increasing the likelihood that the default response (a correct rejection) will be executed (and counted as a miss in a cued trial).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ACh acts to enhance the glutamatergic representation of thalamic input via stimulation of nAChRs, while suppressing cortico-cortical, or associational input via stimulation of mAChRs.

    “Prior neurophysiological research, recording from brain slices, concluded that ACh acts to enhance the (glutamatergic) representation of thalamic input via stimulation of nAChRs, while suppressing cortico-cortical, or associational input via stimulation of mAChRs (Hasselmo and Bower, 1992; Hasselmo et al, 1992; Hasselmo and Schnell, 1994; Gil et al., 1997; Kimura and Baughman, 1997; Roberts et al.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hasselmo and Bower, 1992

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    • cites Hasselmo et al, 1992

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    • cites Hasselmo and Schnell, 1994

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Via stimulation of mAChR, mechanisms may sustain orienting over longer periods of time, allowing successive detections to occur without generating additional cholinergic transients.

    “Via stimulation of mAChR, we may also begin to speculate about mechanisms that sustain orienting over longer periods of time, allowing successive detections to occur without generating additional cholinergic transients (see below).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    If the next trial is a non-cued trial, the circuit returns to the default state and a subsequent cue is again more likely to be detected if it evokes attentional orienting.

    “If the next trial is a non-cued trial, the circuit returns to the default state and a subsequent cue is again more likely to be detected if it evokes attentional orienting.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Orienting differs from alerting, defined as achieving and maintaining a state of high sensitivity to incoming stimuli, and presumably varies on a longer timescale (minutes and tens of minutes) than orienting (milliseconds and seconds).

    “Orienting differs from “alerting”, defined as “achieving and maintaining a state of high sensitivity to incoming stimuli” (Posner & Rothbart, 2007; p. 7), and presumably varies on a longer timescale (minutes and tens of minutes) than orienting (milliseconds and seconds).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Posner & Rothbart, 2007 source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    If the subsequent trial is cued, detection of this cue would not require attentional (re-)orienting, and therefore, transients are not observed in successive trials ending with hits.

    “If the subsequent trial is cued, detection of this cue therefore would not require attentional (re−) orienting, and therefore, transients are not observed in successive trials ending with hits.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Following a hit, attention was successfully aligned with the source of input and this alignment remains stable for a brief period of time (perhaps 10–20 s during SAT performance; ITI: average of 9 s).

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The MD may be considered as the thalamic exit station for a circuit that involves projections from sensory cortical regions to the thalamic reticular nucleus which, in turn, projects to the MD.

    “The MD may be considered as the thalamic “exit” station for a circuit that involves projections from sensory cortical regions to the thalamic reticular nucleus which, in turn, projects to the MD.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Guillery et al, 1998 source

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    • cites Zikopoulos and Barbas, 2006, 2007a,b

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    • cites Pinault, 2004

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  • May combine two claims.

    Premisecitation

    Cholinergic stimulation of α4β2* nAChRs evokes cholinergic transients via stimulating glutamate release, and the mediodorsal input is required to generate such transients.

    “Furthermore, cholinergic stimulation of α4β2* nAChRs evoked cholinergic transients via stimulating glutamate release, and the mediodorsal input is required to generate such transients.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Parikh et al, 2008, 2010

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    • cites Howe et al, 2010 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Attentional orienting may also involve prospective timing processes, estimating target onset.

    “Attentional orienting may also involve prospective timing processes, estimating target onset.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Preattention-processing thalamic nuclei, including the MD, also receive cholinergic input from the basal forebrain, suggesting an orchestrated cholinergic recruitment of thalamic and cortical circuitries to foster cue detection.

    “It is noteworthy, however, that preattention-processing thalamic nuclei, including the MD, also receive cholinergic input from the basal forebrain (e.g., Hallanger et al, 1987; see Figure 2), suggesting an orchestrated cholinergic recruitment of thalamic and cortical circuitries to foster cue detection.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hallanger et al, 1987

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  • May combine two claims.

    Premisecitation

    The cholinergic receptors situated on GABAergic interneurons likely involve β2 subunit containing nAChRs and also mAChRs.

    “The cholinergic receptors situated on GABAergic interneurons are not clear but likely involve *β2* subunit containing nAChRs and also mAChRs (Bandyopadhyay et al, 2006; Azam et al, 2003; Disney and Aoki, 2008).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bandyopadhyay et al, 2006

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    • cites Azam et al, 2003

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    • cites Disney and Aoki, 2008

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  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationcitation

    Task-unrelated increases in activity in this network prior to the presentation of signals cause attentional interference from GABAergic inhibition of the cholinergic terminals that generate transients.

    “We hypothesize that as a result of, for example, task-unrelated increases in activity in this network prior to the presentation of signals, as demonstrated in Parikh et al (2007), attentional interference results from GABAergic inhibition of the cholinergic terminals that generate transients (Rasmusson et al, 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Parikh et al, 2007

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    • cites Rasmusson et al, 2007

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  • May combine two claims.

    Premisecitation

    Stimulation of α4β2* nAChRs, by administering systemically a full α4β2* nAChR agonist, increased the number of cue detections in SAT performing animals; this effect was seen specifically during performance recovery subsequently to the presentation of a distractor.

    “Furthermore, stimulation of α4β2* nAChRs, by administering systemically a full α4β2* nAChR agonist, increased the number of cue detections in SAT performing animals; this effect was seen specifically during performance recovery subsequently to the presentation of a distractor (“dSAT” performance; Howe et al, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Howe et al, 2010 source

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  • May combine two claims.

    Interpretationreasoning

    The increase in hits occurred specifically in trials that were preceded by misses or blanks, consistent with the hypothesis that α4β2* nAChR agonists facilitate the generation of cholinergic transients that foster attentional orienting and/or the shift into the detection mode.

    “Moreover, this increase in hits occurred specifically in trials that were preceded by misses or blanks, consistent with the hypothesis that α4β2* nAChR agonists facilitate the generation of cholinergic transients that foster attentional orienting and/or the shift into the detection mode.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    This circuit has been proposed to generate preattentionally processed representations of cues.

    “This circuit has been proposed to generate preattentionally processed representations of cues (Guillery et al, 1998; Zikopoulos and Barbas, 2006, 2007a,b; Pinault, 2004; Weese et al, 1999; McAlonan et al, 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Guillery et al, 1998 source

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    • cites Zikopoulos and Barbas, 2006, 2007a,b

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    • cites Pinault, 2004

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    These processes involve top-down control, as the scene and the target that are subject to preattentional processes and attentional orienting are guided by their established significance.

    “Certainly, these processes involve top-down control, as the scene and the target that are subject to preattentional processes and attentional orienting are guided by their established significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Administration of nicotine enhances attentional performance and aspects of memory encoding.

    “A substantial number of studies demonstrated that administration of nicotine enhances attentional performance and aspects of memory encoding (e.g., Wesnes and Warburton, 1984; Rusted and Warburton, 1992; Levin et al, 1998).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Wesnes and Warburton, 1984

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    • cites Rusted and Warburton, 1992

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    • cites Levin et al, 1998

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  • May combine two claims.

    Premisecitation

    The α7 nAChR has relatively high permeability for Ca2++ and thereby induces vesicular fusion and neurotransmitter release from presynaptic terminals and activates calcium-sensitive protein kinases postsynaptically.

    “The α7 nAChR has a relatively high permeability for Ca2++ and thereby induces vesicular fusion and neurotransmitter release from presynaptic terminals and activates calcium-sensitive protein kinases postsynaptically (Gray et al, 1996; Berg and Conroy, 2002; Bitner et al, 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gray et al, 1996

      Not checked in the free run.

    • cites Berg and Conroy, 2002

      Not checked in the free run.

    • cites Bitner et al, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blocking mAChRs disrupts continuous or sustained attention, the detection of cues in attentional contexts, and the resulting encoding of new information.

    “These studies uniformly indicate that blocking mAChRs disrupts continuous or sustained attention, the detection of cues in attentional contexts, and the resulting encoding of new information (e.g., Dunne & Hartley, 1986; Parrott, 1986; Wesnes et al, 1988).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dunne & Hartley, 1986

      Not checked in the free run.

    • cites Parrott, 1986

      Not checked in the free run.

    • cites Wesnes et al, 1988

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    New M1-selective ligands have become recently available, including a positive allosteric modulator.

    “New M1-selective ligands have become recently available, including, importantly, a positive allosteric modulator (Sheffler et al, 2009; Shirey et al, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sheffler et al, 2009

      Not checked in the free run.

    • cites Shirey et al, 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The lack of selective antagonists and agonists at muscarinic receptor subtypes has remained a major obstacle for research on the functions of mAChRs.

    “As already discussed, the lack of selective antagonists and agonists at muscarinic receptor subtypes has remained a major obstacle for research on the functions of mAChRs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Interpretationcitation

    nAChRs mediate attentional orienting and cue detection while mAChRs recruit circuitry required for attentional performance in situations demanding top-down control, suggesting both cholinergic receptor populations act synergistically to support performance.

    “The hypothesis that nAChRs mediate attentional orienting and cue detection while mAChRs recruit circuitry that is required for attentional performance in situations demanding top-down control suggests that both cholinergic receptor populations act synergistically to support performance (see also Greenwood et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Greenwood et al, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    AChE inhibition facilitates memory-based performance, often associated with reduced activity in prefrontal and even sensory regions.

    “As a result, memory-based performance was facilitated, often associated with reduced activity in prefrontal and even sensory regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    fMRI studies that investigated the effects of scopolamine have focused on memory performance and did not study attention.

    “fMRI studies that investigated the effects of scopolamine have focused on memory performance and, to our knowledge, did not study attention.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Behavioral or cognitive effects of AChE inhibitors in these fMRI studies were not consistently present or were of limited magnitude.

    “Although the behavioral or cognitive effects of AChE inhibitors in these fMRI studies were not consistently present or of limited magnitude”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Studies on scopolamine have produced a range of performance effects in memory tasks and associated changes in blood flow occurring in a diverse set of brain regions.

    “Studies on scopolamine have produced a range of performance effects in memory tasks and associated changes in blood flow occurring in a diverse set of brain regions (Grasby et al, 1995; Bozzali et al, 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Grasby et al, 1995

      Not checked in the free run.

    • cites Bozzali et al, 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cholinergic modulation causes transient inhibition of layer V neocortical neurons, thereby reducing cortical output.

    “Cholinergic modulation also causes transient inhibition of layer V neocortical neurons, thereby reducing cortical output (Gulledge and Stuart, 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gulledge and Stuart, 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscarinic receptor activation causes heterosynaptic presynaptic inhibition of glutamatergic synaptic transmission at excitatory recurrent synapses between neurons within the cortex, thereby reducing the spread of neural activity and enhancing the relative influence of external input on cortical activity.

    “Muscarinic receptor activation also causes heterosynaptic presynaptic inhibition of glutamatergic synaptic transmission at excitatory recurrent synapses between neurons within the cortex (Hasselmo and Bower, 1992; Hasselmo and Schnell, 1994; Hasselmo and Cekic, 1996; Kimura, 2000; Kimura and Baughman, 1997) thereby reducing the spread of neural activity and enhancing the relative influence of”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hasselmo and Bower, 1992

      Not checked in the free run.

    • cites Hasselmo and Schnell, 1994

      Not checked in the free run.

    • cites Hasselmo and Cekic, 1996

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Computational modeling of cortical circuitry indicates that cholinergic effects on inhibitory neurons can enhance the response to sensory input while reducing background activity in cortical circuits.

    “Computational modeling of cortical circuitry indicates that these effects of cholinergic modulation on inhibitory neurons can enhance the response to sensory input while reducing background activity in cortical circuits (Patil and Hasselmo, 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Patil and Hasselmo, 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stimulation of nAChRs enhances glutamatergic transmission at thalamocortical synapses, thereby enhancing thalamic activation of subsets of cortical neurons.

    “Previous studies have shown that stimulation of nAChRs enhances the glutamatergic transmission at thalamocortical synapses (Gil et al., 1997; Gioanni et al., 1999; Hsieh et al., 2000), thereby enhancing the thalamic activation of subsets of cortical neurons.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gil et al., 1997 source

      Not checked in the free run.

    • cites Gioanni et al., 1999

      Not checked in the free run.

    • cites Hsieh et al., 2000 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Cellular effects of cholinergic modulation are consistent with unit recording and fMRI data showing that cholinergic modulation reduces the spatial spread of activity in visual cortex and underlies the enhancement of unit responses with attention.

    “These cellular effects are consistent with unit recording and fMRI data showing that cholinergic modulation reduces the spatial spread of activity in visual cortex (Roberts et al., 2005; Roberts and Thiele, 2008; Silver et al., 2008) and showing that cholinergic mechanisms underlie the enhancement of unit responses with attention (Herrero et al., 2008; Roberts and Thiele, 2008).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Roberts et al., 2005

      Not checked in the free run.

    • cites Roberts and Thiele, 2008

      Not checked in the free run.

    • cites Silver et al., 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lesions of the entorhinal cortex impair trace conditioning, and local infusions of the M1 antagonist pirenzepine during conditioning impair learning of a fear response when a stimulus is separated from a shock by a trace interval, but do not impair expression of a previously learned trace fear response.

    “Consistent with the evidence for persistent spiking in entorhinal cortex, lesions of the entorhinal cortex were shown to impair trace conditioning, and local infusions of the M1 antagonist pirenzepine during conditioning impaired learning of a fear response when a stimulus was separated from a shock by a trace interval, but did not impair expression of a previously learned trace fear response (Es”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Esclassan et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selective lesions of the cholinergic innervation of rhinal cortex impaired delayed recognition in rats and monkeys, but cholinergic lesions of inferotemporal cortex in monkeys did not.

    “Selective lesions of the cholinergic innervation of rhinal cortex impaired delayed recognition in rats (McGaughy et al., 2005) and monkeys (Turchi et al., 2005), but cholinergic lesions of inferotemporal cortex in monkeys did not (Browning et al., 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites McGaughy et al., 2005

      Not checked in the free run.

    • cites Turchi et al., 2005

      Not checked in the free run.

    • cites Browning et al., 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Persistent spiking has been demonstrated in the perirhinal cortex and infusion of scopolamine into the perirhinal cortex impairs trace conditioning without impairing delay conditioning.

    “Persistent spiking has also been demonstrated in the perirhinal cortex (Leung et al., 2006) and infusion of scopolamine into the perirhinal cortex was shown to impair trace conditioning without impairing delay conditioning (Bang and Brown, 2009).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Leung et al., 2006

      Not checked in the free run.

    • cites Bang and Brown, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Persistent spiking occurs even when glutamatergic and GABAergic synaptic connections have been blocked pharmacologically, indicating that it arises from intrinsic mechanisms for self-sustained persistent spiking activity.

    “This persistent spiking occurs even when glutamatergic and GABAergic synaptic connections have been blocked pharmacologically, indicating that it arises from intrinsic mechanisms for self-sustained persistent spiking activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In working memory tasks, scopolamine does not impair tasks using the articulatory loop such as digit span, but does cause impairments in tasks that include interfering stimuli such as the n-back task.

    “In working memory tasks, scopolamine does not impair tasks using the articulatory loop such as digit span (Kopelman and Corn, 1988), but does cause impairments in tasks that include interfering stimuli such as the n-back task (Green et al., 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kopelman and Corn, 1988

      Not checked in the free run.

    • cites Green et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lesions of the fornix or medial septum cause profound impairments in memory guided tasks such as spatial alternation and reversal in rats, and lesions including fornix and basal forebrain impair scene learning in monkeys.

    “Lesions of the fornix or medial septum which are the source of most of the cholinergic fibers innervating the hippocampus cause profound impairments in memory guided tasks such as spatial alternation and reversal in rats (M'Harzi et al., 1987; Givens and Olton, 1990; Ennaceur et al., 1996; Aggleton and Brown, 1999; Bussey et al., 2000), and lesions including fornix and basal forebrain impair scene”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites M'Harzi et al., 1987

      Not checked in the free run.

    • cites Givens and Olton, 1990

      Not checked in the free run.

    • cites Ennaceur et al., 1996

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This transient increase activates postsynaptic muscarinic receptors that activate calcium-sensitive non-specific cation currents in cortical pyramidal cells, allowing them to show sustained depolarization and persistent spiking activity even after the stimulus input has terminated.

    “This transient increase activates postsynaptic muscarinic receptors that activate calcium-sensitive non-specific cation currents in cortical pyramidal cells (Fransen et al., 2002), allowing them to show sustained depolarization and persistent spiking activity even after the stimulus input has terminated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fransen et al., 2002

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The framework described above indicates how cholinergic modulation of persistent spiking could allow encoding of information into working memory for performance of tasks ranging from delayed match to sample to trace conditioning to cue detection.

    “The framework described above indicates how cholinergic modulation of persistent spiking could allow encoding of information into working memory for performance of tasks ranging from delayed match to sample to trace conditioning to cue detection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In non-human primates, systemic scopolamine impairs encoding for subsequent recognition, an effect that can be replicated by selective muscarinic blockade in the perirhinal cortex or by cholinergic lesions of the perirhinal cortex, though Browning et al. did not see impaired recognition memory after cholinergic lesions of inferotemporal cortex that include perirhinal cortex.

    “In non-human primates, systemic scopolamine impairs encoding for subsequent recognition (Aigner and Mishkin, 1986), an effect that can be replicated by selective muscarinic blockade in the perirhinal cortex (Tang et al., 1997) or by cholinergic lesions of the perirhinal cortex (Turchi et al., 2005) though Browning et al. (2010) did not see impaired recognition memory after cholinergic lesions of”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Aigner and Mishkin, 1986

      Not checked in the free run.

    • cites Tang et al., 1997

      Not checked in the free run.

    • cites Turchi et al., 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, infusion of muscarinic blockers impairs encoding of stimuli for subsequent free recall and cued recall, while sparing procedural memory.

    “Evidence in humans demonstrates that infusion of muscarinic blockers impairs encoding of stimuli for subsequent free recall (Ghoneim and Mewaldt, 1975, 1977; Petersen, 1977), and cued recall (Atri et al., 2004), while sparing procedural memory (Nissen et al., 1987).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ghoneim and Mewaldt, 1975, 1977

      Not checked in the free run.

    • cites Petersen, 1977

      Not checked in the free run.

    • cites Atri et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Stable intrinsic mechanisms for persistent spiking do not appear in hippocampal slice recordings, consistent with the lower spontaneous background firing rate of hippocampal neurons, suggesting that the hippocampus is less engaged with active maintenance for working memory and more engaged with encoding into long-term episodic memory.

    “However, stable intrinsic mechanisms for persistent spiking do not appear in hippocampal slice recordings, consistent with the lower spontaneous background firing rate of hippocampal neurons, suggesting that the hippocampus is less engaged with active maintenance for working memory and more engaged with encoding into long-term episodic memory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Muscarinic receptor activation causes presynaptic inhibition of recurrent excitatory connections in hippocampal region CA3 and suppresses connections from CA3 to CA1, similar to effects shown in piriform cortex and neocortex.

    “Muscarinic receptor activation causes presynaptic inhibition of recurrent excitatory connections in hippocampal region CA3 (Hasselmo et al., 1995; Vogt and Regehr, 2001; Kremin and Hasselmo, 2007) and suppresses connections from CA3 to CA1 (Hounsgaard, 1978; Valentino and Dingledine, 1981; Hasselmo and Schnell, 1994), similar to effects shown in piriform cortex (Hasselmo and Bower, 1993) and neoc”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hasselmo et al., 1995

      Not checked in the free run.

    • cites Vogt and Regehr, 2001

      Not checked in the free run.

    • cites Kremin and Hasselmo, 2007

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    With the exception of persistent spiking, cellular effects within the hippocampal formation resemble those observed in neocortical structures, and could change the dynamics of hippocampal function to enhance the encoding of new information.

    “With the exception of persistent spiking, cellular effects within the hippocampal formation resemble those observed in neocortical structures, and could change the dynamics of hippocampal function to enhance the encoding of new information.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The AChE inhibitor physostigmine reduces behavioral retrieval of previous learning, and physostigmine impairs consolidation while scopolamine enhances consolidation, consistent with the theory that lower levels of ACh during slow wave sleep might allow enhanced feedback appropriate for consolidation.

    “Consistent with this, the AChE inhibitor physostigmine reduces behavioral retrieval of previous learning (Rogers and Kesner, 2003, 2004), suggesting that cholinergic modulation reduces the influence of retrieval. Physostigmine also impairs consolidation (Gais and Born, 2004) and scopolamine enhances consolidation (Rasch et al., 2006), consistent with the theory that lower levels of ACh during slow”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Rogers and Kesner, 2003, 2004

      Not checked in the free run.

    • cites Gais and Born, 2004

      Not checked in the free run.

    • cites Rasch et al., 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Cellular effects of acetylcholine are similar within the hippocampal formation and the neocortex.

    “In summary, cellular effects of acetylcholine are similar within the hippocampal formation and the neocortex.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The lack of impairment with selective ACh lesions could be due to GABAergic modulation playing a redundant role with cholinergic modulation, because combined lesions of both cholinergic and GABAergic input from the medial septum impair spatial memory.

    “The lack of impairment with selective ACh lesions could be due to GABAergic modulation playing a redundant role with cholinergic modulation, because combined lesions of both cholinergic and GABAergic input from the medial septum impair spatial memory (Pang and Nocera, 1999; Pang et al., 2001).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pang and Nocera, 1999

      Not checked in the free run.

    • cites Pang et al., 2001

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In this framework, cholinergic modulation may enhance persistent spiking in the entorhinal cortex and perirhinal cortex as a short-term buffer for new information, while also enhancing the responsiveness of hippocampus to afferent input for encoding via enhanced induction of long-term potentiation.

    “In this framework, cholinergic modulation may enhance persistent spiking in the entorhinal cortex and perirhinal cortex as a short-term buffer for new information (Hasselmo and Stern, 2006), while also enhancing the responsiveness of hippocampus to afferent input for encoding via enhanced induction of long-term potentiation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hasselmo and Stern, 2006

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Cholinergic modulation of cellular properties in the neocortex might switch dynamics from a default state to a state fostering cue detection.

    “Cholinergic modulation of cellular properties in the neocortex might switch dynamics from a default state to a state fostering cue detection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cholinergic modulation of the medial septum induces theta rhythm oscillations and theta rhythm is correlated with higher levels of acetylcholine in the hippocampus, while lesions of the cholinergic innervation reduce the magnitude of theta rhythm.

    “On a network level, cholinergic modulation of the medial septum induces theta rhythm oscillations (Lawson and Bland, 1993) and theta rhythm is correlated with higher levels of acetylcholine in the hippocampus (Marrosu et al., 1995; Monmaur et al., 1997), while lesions of the cholinergic innervation reduce the magnitude of theta rhythm (Lee et al., 1994).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Lawson and Bland, 1993

      Not checked in the free run.

    • cites Marrosu et al., 1995 source

      Not checked in the free run.

    • cites Monmaur et al., 1997

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Within a major branch of the brain's cholinergic systems there is substantially greater topographic differentiation than originally assumed.

    “it seems that within a major branch of the brain’s cholinergic systems there is substantially greater topographic differentiation than originally assumed”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other nAChR subunits are likely to modulate the gain in other aspects of cortical circuitry.

    “Other nAChR subunits are likely to modulate the gain in other aspects of cortical circuitry (e.g., Dickenson et al, 2008)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dickenson et al, 2008

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Enhancement of afferent input to the hippocampus might enhance encoding into long-term episodic memory.

    “The enhancement of afferent input to the hippocampus might enhance encoding into longterm episodic memory”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Stimulation of α4β2* nAChRs amplifies cholinergic transients and enhances attentional performance.

    “Most obviously, we can stimulate α4β2* nAChRs to amplify cholinergic transients and enhance attentional performance (e.g., Howe et al, 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Howe et al, 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Different yet complementary functions are likely mediated by cholinergic signaling mechanisms that occur on different time scales (seconds versus minutes).

    “It is likely that different yet complementary functions are mediated by cholinergic signaling mechanisms that occur on different time scales (seconds versus minutes).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    PAMs acting at AChRs are expected to afford a level of modulatory selectivity and temporal precision that will assist in revealing the precise role of cholinergic systems in a particular behavioral or cognitive context and may allow the manifestation of effect sizes that are of clinical relevance.

    “PAMs acting at AChRs are expected to afford a level of modulatory selectivity and temporal precision that will not only assist in revealing the precise role of cholinergic systems in a particular behavioral or cognitive context but also may allow the manifestation of effect sizes that are of clinical relevance.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Modification of an endogenous signal represents a superior approach to cognitive enhancement when contrasted against introducing a pharmacological signal to influence circuit functions.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Enhancement of persistent spiking might gate sensory information into working memory for the active maintenance of future responses.

    “Enhancement of persistent spiking might gate sensory information into working memory for the active maintenance of future responses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Treating heart disease is commonly expected to consist of combinations of pharmacological and behavioral therapies.

    “As previously discussed (Sarter & Bruno 1997), treating, for example, heart disease is commonly expected to consist of combinations of pharmacological and behavioral therapies (see also Keefe et al, 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sarter & Bruno 1997

      Not checked in the free run.

    • cites Keefe et al, 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Treatments of cognitive disorders often are expected to consist solely of the administration of a pharmacological "magic bullet".

    “In contrast, treatments of cognitive disorders often are expected to consist solely of the administration of a pharmacological “magic bullet”.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The potentially highly specific functions of ACh within a particular target region are based in part on highly topographic projection systems.

    “the potentially highly specific functions of ACh within a particular target region are based in part on highly topographic projection systems”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The cognitive selectivity of the effects of cholinergic modulation may be largely determined by the target circuit, based on local microcircuitry controlling cholinergic presynaptic activity, via heteroreceptors expressed on cholinergic terminals.

    “Moreover, the cognitive selectivity of the effects of cholinergic modulation may be largely determined by the target circuit, based on local microcircuitry controlling cholinergic presynaptic activity, via heteroreceptors expressed on cholinergic terminals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PAMs targeted at M4 receptors may allow selective suppression of glutamatergic excitatory transmission.

    “For example, PAMs targeted at M4 receptors may allow selective suppression of glutamatergic excitatory transmission (Shirey et al., 2008)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shirey et al., 2008

      Not checked in the free run.

86 of 86

  • The authors state this as an assumption.

    Following a hit, attention was successfully aligned with the source of input and this alignment remains stable for a brief period of time (perhaps 10–20 s during SAT performance; ITI: average of 9 s).

    “This conceptualization further requires the assumption that following a hit, attention was successfully aligned with the source of input and that this alignment remains stable for a brief period of time (perhaps 10–20 s during SAT performance; ITI: average of 9 s).”

  • The authors state this as an assumption.

    Separate populations of cholinergic neurons influence the release of glutamate from MD inputs and are targeted by such inputs, respectively.

    “The model speculates that separate populations of cholinergic neurons influence the release of glutamate from MD inputs and are targeted by such inputs, respectively (Figure 2).”

  • The authors state this as an assumption.

    A separate group of cholinergic neurons contacts MD glutamatergic terminals in the PFC, allowing relatively slowly changing levels of ACh released by these neurons to modulate the gain of glutamatergic-cholinergic interactions via stimulation of α4β2* nAChRs.

    “The model illustrated in Figure 2 implies that a separate group of cholinergic neurons contacts MD glutamatergic terminals in the PFC, allowing for relatively slowly changing levels of ACh released by these neurons to modulate the gain of glutamatergic-cholinergic interactions via stimulation of α4β2* nAChRs.”

  • The paper relies on this without support.

    In most cases, glutamatergic input during the non-signal period or during distractor stimuli is not associated with a transient increase of acetylcholine levels.

    “However, in most cases this glutamatergic input will not be associated with a transient increase of acetylcholine levels.”

  • The paper relies on this without support.

    Sensory information during the non-signal period or during distractor stimuli activates glutamatergic thalamic input to cortical structures such as the prefrontal cortex.

    “Sensory information during the non-signal period or during distractor stimuli will activate glutamatergic thalamic input to cortical structures such as the prefrontal cortex.”

  • The authors state this as an assumption.

    Modification of an endogenous signal represents a superior approach to cognitive enhancement when contrasted against introducing a pharmacological signal to influence circuit functions.

    “The promise for such ligands is based on the general assumption that modification of an endogenous signal represents a superior approach to cognitive enhancement when contrasted against introducing a pharmacological signal to influence circuit functions (Sarter & Bruno 1997).”
6 of 6

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Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Martin citation year differs from the reference list

    Minor

    The text cites Martin et al. as a 2004 study, while the corresponding reference lists its year as 1994.

  • Lambe citation year differs from the reference list

    Minor

    The text cites Lambe et al. as a 2006 study, but the Lambe study listed in the references is dated 2003.

2 of 2

Cites

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Research works printed but not linked: 1

  1. Leung VL, Zhao Y, Brown TH (2006). Graded persistent firing in neurons of rat perirhinal cortex. Soc Neurosci Abstr 32: 636.618.

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Related

Authors
Hasselmo, M. E., & Sarter, M.
Affiliations
  • Boston University (US)
  • University of Michigan (US)
Corresponding author
Hasselmo, Michael E
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2010-07-28
Volume
36
Issue
1
Pages
52-73
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2010.104
PMC
PMC2992803
OpenAlex
W2036322060
Semantic Scholar
465d8d9323b166452a2bb44a92d3f548f0ae7dc6
Cited by
733
References
310
Citations by year
2026: 40 · 2025: 32 · 2024: 45 · 2023: 45 · 2022: 46 · 2021: 53 · 2020: 38 · 2019: 35 · 2018: 50 · 2017: 50 · 2016: 52 · 2015: 52 · 2014: 54 · 2013: 52 · 2012: 48
FWCI
3.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Mental Health (R01 MH 61492, MH-71702, R01 MH60013, R01MH080332, R01MH060013, R01MH061492, P50MH071702, R01MH086530, R21MH080426)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
cholinergic neurotransmission, forebrain, neuromodulation, cognition, attention, memory encoding, acetylcholinesterase inhibitors, nicotinic acetylcholine receptors, muscarinic receptors, dementia, cognitive impairment
MeSH terms
Acetylcholine, Action Potentials, Animals, Attention, Cholinergic Fibers, Cognition, Humans, Models, Neurological, Neural Pathways, Neurons, Perception, Prosencephalon

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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