COMMENTARY CORTICAL CHOLINERGIC INPUTS ... files...cortical cholinergic input system in either...

COMMENTARY

CORTICAL CHOLINERGIC INPUTS MEDIATING AROUSAL, ATTENTIONALPROCESSING AND DREAMING: DIFFERENTIAL AFFERENT REGULATION OFTHE BASAL FOREBRAIN BY TELENCEPHALIC AND BRAINSTEM AFFERENTS

M. SARTER* and J. P. BRUNODepartment of Psychology, The Ohio State University, 27 Townshend Hall, Columbus, OH 43210, U.S.A.

Abstract—Basal forebrain corticopetal neurons participate in the mediation of arousal, specific attentional functions and rapid eyemovement sleep-associated dreaming. Recent studies on the afferent regulation of basal forebrain neurons by telencephalic andbrainstem inputs have provided the basis for hypotheses which, collectively, propose that the involvement of basal forebraincorticopetal projections in arousal, attention and dreaming can be dissociated on the basis of their regulation via major afferentprojections. While the processing underlying sustained, selective and divided attention performance depends on the integrity of thetelencephalic afferent regulation of basal forebrain corticopetal neurons, arousal-induced attentional processing (i.e. stimulusdetection, selection and processing as a result of a novel, highly salient, aversive or incentive stimuli) is mediated via the abilityof brainstem ascending noradrenergic projections to the basal forebrain to activate or “recruit” these telencephalic afferent circuitsof the basal forebrain. In rapid eye movement sleep, both the basal forebrain and thalamic cortiocopetal projections are stimulatedby cholinergic afferents originating mainly from the pedunculopontine and laterodorsal tegmenta in the brainstem. Rapid eyemovement sleep-associated dreaming is described as a form of hyperattentional processing, mediated by increased activity ofcortical cholinergic inputs and their cortical interactions with activated thalamic efferents. In this context, long-standing specula-tions about the similarities between dreaming and psychotic cognition are substantiated by describing the role of an over(re)activecortical cholinergic input system in either condition.

Finally, while determination of the afferent regulation of basal forebrain corticopetal neurons in different behavioral/cognitivestates assists in defining the general cognitive functions of cortical acetylcholine, this research requires a specification of the preciseanatomical organization of basal forebrain afferents and their interactions in the basal forebrain. Furthermore, the present hypoth-eses remain incomplete because of the paucity of data concerning the regulation and role of basal forebrain non-cholinergic,particularly GABAergic, efferents.q 1999 IBRO. Published by Elsevier Science Ltd.

Key words: basal forebrain, acetylcholine, brainstem, thalamus, attention, dreaming.

CONTENTS

1. INTRODUCTION 9342. BEHAVIORAL AROUSAL AND ATTENTIONAL PERFORMANCE: CONCEPTUAL OVERLAPS AND DIFFERENCES 9343. DISSOCIATIONS AND INTERACTIONS BETWEEN TELENCEPHALIC AND BRAINSTEM PROJECTIONS TO BASAL

FOREBRAIN NEURONS IN AROUSAL AND ATTENTION 9353.1. GABAergic afferents originating from the nucleus accumbens: from motivation to attention to action 9353.2. Glutamatergic afferents: telencephalic stimulation of basal forebrain corticopetal projections in attention 9373.3. Telencephalic afferent regulation of basal forebrain corticopetal neurons in attention: what exactly do telencephalic

afferents “tell” basal forebrain neurons? 9383.4. Arousal-induced attention and the role of basal forebrain noradrenergic afferents for the functional activation of

telencephalic inputs to the basal forebrain 9394. “AUTOSTIMULATION” OF BASAL FOREBRAIN CORTICOPETAL CHOLINERGIC NEURONS BY BRAINSTEM

ASCENDING CHOLINERGIC PROJECTIONS MEDIATES DREAMING 9424.1. Dreaming as hyperattentional processing 9424.2. Increased cortical acetylcholine release and underlying afferent regulation in rapid eye movement sleep 9434.3. Cortical cholinergic hyperactivity and hyperattentional processing 9434.4. Cortical interactions between activated basal forebrain and thalamic projections in rapid eye movement sleep 9454.5. Afferent regulation of basal forebrain and thalamic corticopetal neurons mediating dreaming cognition: implications for

schizophrenia 9455. CONCLUSIONS 946ACKNOWLEDGEMENTS 946REFERENCES 946

Cortical ACh in attention and dreaming 933

933

NeuroscienceVol. 95, No. 4, pp. 933–952, 2000Copyrightq 1999 IBRO. Published by Elsevier Science Ltd

Printed in Great Britain. All rights reserved0306-4522/00 $20.00+0.00PII: S0306-4522(99)00487-X

Pergamon

www.elsevier.com/locate/neuroscience

*To whom correspondence should be addressed. Fax:11-614-688-4733.E-mail address:[email protected] (M. Sarter)Abbreviations: ACh, acetylcholine; AMPA,a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; AP5, 2-amino-5-phosphonopentanoic acid; BZR, benzo-

diazepine receptor; CeA, central nucleus of the amygdala; DA, dopamine; EEG, electroencephalogram; LC, locus coeruleus; LDT, laterodorsal tegmentalnucleus; mPFC, medial prefrontal cortex; NAC, nucleus accumbens; NMDA,N-methyl-d-aspartate; PPT, pedunculopontine tegmental nucleus; REM, rapideye movement.

1. INTRODUCTION

Numerous recent experiments, using a variety of beha-vioral paradigms for the assessment of different aspects ofattention, have concluded that the integrity of cortical cholin-ergic inputs is essential for the detection, selection andprocessing of stimuli and associations.36,52,146,179,216Further-more, basal forebrain neuropharmacological manipulationsknown to increase or decrease the excitability of corticalcholinergic inputs in intact rats bidirectionally alter the atten-tional abilities of rats assessed in tasks designed to measuresustained or divided attention.94,184 Electrophysiologicalstudies demonstrated that the increases in firing rate in medialprefrontal neurons accompanying increases in the demands onsustained attention performance depend on the integrity ofcholinergic inputs to this region.67 These and other datasupport the hypothesis that cortical cholinergic inputs mediatediverse attentional functions, ranging from the ability todetect and select stimuli that occur rarely and unpredictablyand require the subjects’ persistent readiness to detect suchstimuli (as described by the theoretical construct “sustainedattention”), to discriminate significant stimuli from invalidstimuli or “background noise” (“selective attention”), and toallocate processing resources to competing demands on infor-mation processing (“divided attention”). Furthermore, aberra-tions in the integrity or excitability of basal forebraincorticopetal cholinergic neurons have been described to escal-ate into major yet diverse cognitive dysfunctions and thus tocontribute essentially to the manifestation of the core cogni-tive symptoms of major neuropsychiatric disorders.181

This rather recent literature on corticopetal cholinergicprojections as a major component of the neuronal circuitsmediating attentional functions has rarely attempted to inte-grate conceptually the more traditional descriptions of thebasal forebrain efferent system as a rostral extension of theascending arousal system.1,95,136,210Similar to Szymusiak’s210

discussion, the present review stresses the conceptual andempirical overlaps, but also the differences, between themore traditional constructs of arousal and the more recentinterpretation of the functions of cortical cholinergic inputsin terms of cognitive psychology. The neurobehavioralmodels discussed in the present review suggest that theinvolvement of the basal forebrain corticopetal system inarousal, attention and also in rapid eye movement (REM)sleep-associated dreaming can be dissociated on the basis ofits regulation by telencephalic and brainstem afferent projec-tions. In other words, the hypothesis that cortical cholinergicinputs mediate defined attentional abilities is not in conflictwith the more traditional notions about the role of this systemin arousal or dreaming; rather, the specific nature of the infor-mation processing mediated by this system depends on theactivity of the individual components of its afferent networkand the interactions between cortical cholinergic and con-verging sensory or associational inputs.

The present review largely ignores the role of basal fore-brain corticopetal GABAergic projections, as informationabout the afferent regulation of this system and the functionsof GABAergic corticopetal projections is scarce. As will bediscussed last, such information, as well as data about thecortical interactions between basal forebrain GABAergicand cholinergic projections, is key to a more comprehensiveunderstanding of the role of basal forebrain corticopetalprojections in the gating of cortical information processing

and of the psychopathological consequences of aberrations inthe afferent regulation of these cortical input systems.

2. BEHAVIORAL AROUSAL AND ATTENTIONAL PERFORMANCE:CONCEPTUAL OVERLAPS AND DIFFERENCES

The attribution of “arousal” functions to basal forebraincorticopetal neurons has been derived largely from neuro-pharmacological evidence supporting a “cholinergic nature”of cortical arousal, specifically from studies showing relation-ships between electroencephalogram (EEG) desynchroniza-tion, increases in spontaneous alertness and increases incortical acetylcholine (ACh) turnover or cholinergic receptorstimulation.34,166,201,209These studies have further corrobor-ated notions that the basal forebrain corticopetal systemrepresents a rostral extension of the ascending reticular acti-vating system. Such notions have also been substantiated bydescriptions of the “reticular” anatomical and morphologicalcharacteristics of basal forebrain efferent projections, and bythe innervation of the basal forebrain by projections originat-ing in brainstem reticular areas.203 Presently, several inter-related lines of evidence support the role of basal forebraincorticopetal projections in the regulation of “arousal”. Manip-ulations of the excitability of basal forebrain neuronsmodify cortical event-related potentials160 and other EEGmeasures.27,46,224Likewise, neuronal activity in the basal fore-brain correlates with EEG activation.45,150,225 Furthermore,basal forebrain neurons are involved in the diurnal regulationof sleep parameters and associated EEG activity, probablydue to connections with midbrain reticular and pontine struc-tures that represent the primary mediator of sleep–wakerhythm9,107,207,211,212(see below). Thus, the attribution of“arousal”-like functions to basal forebrain corticopetalprojections has remained largely driven by research linkingthe basal forebrain with brainstem ascending systems, and bystudies assessing EEG and global behavioral states.

A wide range of rather generally defined transitions fromsleep or unconscious states to wakefulness, conscious aware-ness or the effective cortical processing of information hasbeen traditionally collapsed into the construct “arousal”.144,203

However, the limitations of such a broad and unitary constructto further assist in the identification and dissociation of speci-fic functions mediated via ascending systems have becomeevident,171 particularly in light of the unexpectedly complexanatomical organization of ascending systems and their impli-cations in a wide range of behavioral functions.29,97,214Thus,in spite of the ubiquitous use of the term “arousal”, a morecircumscribed description of this construct appears timely.

“Arousal” may be more precisely defined on the basis of itssignificance for defined behavioral or cognitive processes,and thus dissociated from the well-defined constructs ofsustained, selective and divided attention. For example,Aston-Joneset al.5,6 describe the arousal associated withemotionally charged stimuli as based on the activation ofthe locus coeruleus (LC), which reflects sympathetic activa-tion, and the consequent modulation of LC target neurons. Inthis context, “emotional arousal” is defined as the activationof the forebrain mediating the biased processing of emotionalinformation and the initiation of adaptive responses.16

Conceivably, related types of arousal, such as those asso-ciated with novel stimuli or stress, also act to enhance gener-ally the gating of forebrain information processing, in part viastimulation of basal forebrain corticopetal cholinergic

M. Sarter and J. P. Bruno934

neurons (see below);1,95,122the effects of different qualities of“arousing” stimuli on forebrain processing may depend onactivation of dissociable components of the “ascending acti-vating system”.136 Furthermore, the involvement of basalforebrain corticopetal projections in “arousal” can be easilyreconciled with the more specific attentional functions of thissystem. For example, the perception of stimuli associatedwith fear and anxiety fosters the search, detection and selec-tion of contextual information, and is associated with theallocation of considerable processing resources toward thatobjective.16,125Importantly, however, attentional performanceand associated cortical activity do not necessarily depend onincreases in arousal and associated activation of forebrainareas by brainstem ascending systems, particularly noradren-ergic projections31,37,132 (see Section 3.4 for illustrations).Thus, “arousal” (as defined above) and attentional functions,while they may interact in particular behavioral contexts,represent distinct constructs. The present discussion is guidedby hypotheses about dissociations and interactions between“arousal”, mediated in part via activation of the basal fore-brain by brainstem ascending systems, and attentional func-tions which depend on the regulation of basal forebraincorticopetal neurons by their telencephalic afferents. Suchhypotheses can be deduced from studies on the interactionsbetween brainstem and telencephalic afferents of basal fore-brain corticopetal projections.

3. DISSOCIATIONS AND INTERACTIONS BETWEEN TELENCEPHALICAND BRAINSTEM PROJECTIONS TO BASAL FOREBRAIN NEURONS IN

AROUSAL AND ATTENTION

As briefly summarized above, cortical cholinergic inputsmediate attentional functions, ranging from aspects ofsustained and selective attention to the regulation of process-ing capacity or the allocation of processing resources (dividedattention). Important tenets of this hypothesis suggest thatchanges in the activity of cortical cholinergic inputs are notdistinctly cortical area specific,87,99,159,179,228and that the selec-tivity of the behavioral effects of cortical ACh is based onclose temporal interactions with converging sensory or asso-ciational cortical inputs.215 We will discuss next the evidencein support of the hypothesis that habitual or routine attentionalperformance, as assessed by an extensively practiced task,depends on the integrity of basal forebrain cholinergicneurons and that, in this case, these neurons are regulatedexclusively by telencephalic afferents to mediate attentionalperformance. Further below, interactions between brainstemafferents and telencephalic afferents to basal forebrainneurons will be described as the main neuronal mechanismsmediating the effects of novel, salient, emotional or stressfulstimuli (i.e. arousal) on cortical information processing.

3.1. GABAergic afferents originating from the nucleusaccumbens: from motivation to attention to action

Telencephalic projections, including afferents from theextended amygdala, converge on basal forebrain neurons32,238

and modulate the excitability of basal forebrain corticopetalneurons in the context of attention-demanding situations70,179

(Fig. 1). Several studies have focused on the regulation ofcortical ACh efflux and associated attentional functions byGABAergic inputs to basal forebrain cholinergic neurons,presumably originating in the nucleus accumbens(NAC).178,179,181,184These studies were based on the facts

that cholinergic neurons in the basal forebrain bear GABAA

receptors and that GABAergic transmission can be bidirec-tionally modulated by administering benzodiazepine receptor(BZR) agonists (which augment the inhibitory effects ofGABA) and inverse agonists (which decrease GABA-gatedchloride flux).178,235,238,241

To investigate the GABAergic modulation of corticopetalcholinergic neurons, the effects of infusions of such positiveand negative modulators of GABAA receptor-mediated chlor-ide flux (i.e. BZR agonists and inverse agonists, respectively)into the basal forebrain on cortical ACh efflux were measuredusing in vivo microdialysis. A test of the effects of BZRligands was preferred over the use of direct GABAA receptoragonists or antagonists, as the former modulate the effects ofendogenously released GABA. These studies revealed thatbasal ACh efflux in animals habituated well to the testingenvironment and to the experimental procedures, remainingunaffected by infusions of BZR ligands. However, activatedACh efflux was blocked and augmented, respectively, byBZR agonists and inverse agonists.178 “Activation” of AChefflux was produced by pre-training the animals to associatesudden exposure to darkness in the test room with the presen-tation of palatable food, yielding a reliable stimulus-inducedincrease in ACh efflux of 100–150% over baseline (see belowfor further analyses on the neuronal and cognitive mediationof the effects of this stimulus on cortical ACh). Collectively,these data indicated that basal forebrain GABAergic afferentsserve to dampen the excitability of basal forebrain cortico-petal cholinergic neurons by other, excitatory, afferents.

These studies did not provide information about the sourceof the GABAergic neurons mediating the effects of BZRligands on cortical ACh efflux. In addition to GABAergicinterneurons in the basal forebrain and the possibility thatGABAergic corticopetal neurons possess recurrent col-laterals,76,241 an extrinsic GABAergic projection arrivesfrom the NAC.140,236GABAergic inputs make direct contactwith cholinergic neurons, and Inghamet al.96 suggested thatGABAergic contacts located more proximally on cholinergicneurons serve to modulate, or even block, the effects of themore distal inputs from reaching the soma. It needs to bestressed, however, that the origin of these inputs is not settled,and may include local interneurons and projections from theNAC and other sites.

Basal forebrain GABAergic and cholinergic neurons maypossess different GABA subunit combinations, witha3b3g2

subunits preferentially located on cholinergic neurons, whileGABAergic cell bodies expressa1b2g2 and a3b2g2 subunitcombinations.64,82,86 The functional implications of suchdifferential receptor subunit distributions are unclear, butsuggest the potential for differential effects of GABA oncholinergic and GABAergic target neurons.108

The GABAergic projections originating in the NAC maycontribute significantly to the regulation of the activity ofbasal forebrain corticopetal cholinergic neurons. Yang andMogenson233 provided evidence in support of the hypothesisthat dopamine (DA) receptor stimulation in the NAC dis-inhibits basal forebrain neurons via a suppression ofGABAergic output neurons.19,208In keeping with this hypoth-esis, infusions of DA receptor antagonists into the NACincreased ventral pallidal GABA extracellular levels.55 Thehypothesis that NAC DA regulates the excitability of basalforebrain cholinergic corticopetal neurons was tested in anexperiment that assessed the effects of infusions of DA


M.

Sarter

andJ.

P.

Bruno

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Fig. 1. Afferent regulation of basal forebrain corticopetal cholinergic neurons in attention. This figure does not intend to represent the comprehensive anatomical knowledge of basal forebrain afferent and efferentcircuits, but rather illustrates schematically the main circuits known or hypothesized to affect the activity of cortical cholinergic inputs as they mediate attentional performance (including divided attention;216see text fordefinitions and dissociation from the construct of “arousal”). The present discussion largely ignores basal forebrain GABAergic corticopetal projections because of the paucity of information concerning their afferentregulation and function. Other parallel or direct feedback circuits (such as the cholinergic projection to the basolateral amygdala) are also not shown. Performance in tasks designed to assess sustained, selective ordivided attention depend crucially on the integrity of basal forebrain corticopetal cholinergic neurons and, in these situations, these neurons are hypothesized to be primarily regulated by afferent projections fromtelencephalic regions. As discussed in the text, both glutamatergic stimulation and decreases in GABAergic inhibition (i.e. disinhibition) converge to regulate the excitability of corticopetal neurons, thereby mediating

the detection, selection and processing of stimuli and associations which, consequently, dominate behavioral and cognitive activity. BF, basal forebrain; BLA, basolateral amygdala; GLU, glutamate.

receptor antagonists into the NAC on cortical ACh efflux.142

While infusions of these antagonists did not affect basal corti-cal ACh efflux (which would be predicted from the results ofthe studies on the effects of intra-nucleus basalis administra-tion of BZR ligands; see above), infusions of the D2-likeantagonists sulpiride and haloperidol blocked the increase incortical ACh efflux that was produced by a systemic admin-istration of the BZR partial inverse agonist FG 7142.143 Infu-sions of the DA antagonists into the cortex (through the probeused to collect ACh) remained ineffective. While these dataare consistent with the general hypothesis that the excitabilityof basal forebrain cholinergic neurons is modulated by NACD2 receptors via inhibition of the GABAergic output to thebasal forebrain, more recent experiments from our labora-tories have pointed to a greater complexity in the trans-synap-tic regulation of basal forebrain corticopetal cholinergicneurons by dopaminergic transmission in the NAC. Theseexperiments attempted to determine the contribution ofNAC DA to the increases in cortical ACh produced by thesystemic administration of amphetamine. Arnoldet al.4

demonstrated that infusions of amphetamine into the NAC,while producing the expectedly high increases in NAC DArelease (also see Ref. 42), did not robustly increase corticalACh efflux. Moreover, unlike the case with FG 7142-stimu-lated cortical ACh efflux (see above), intra-nucleus accum-bens administration of D2 receptor antagonists did notattenuate systemic amphetamine-induced increases in corticalACh efflux. Based on these findings, present experimentsassess the possibility that the effective regulation of corticalACh efflux via NAC–basal forebrain links depends neces-sarily on interactions between telencephalic (glutamatergic)and mesencephalic (dopaminergic) afferents in the NAC, andthat such interactions are not modeled by the administrationof amphetamine alone.26,147,219

Several studies have demonstrated that the GABAergicafferents to basal forebrain neurons are involved in the regu-lation of the attentional abilities mediated via basal forebraincorticopetal cholinergic projections. Studies assessing theeffects of infusions of direct GABAA receptor agonists154

are excluded from this discussion, as their effects may bedue to anomalous levels of GABAA receptor stimulationand, as discussed above, do not depend on GABA releaseand thus may be difficult to interpret.47,48 Infusions of BZRligands into the basal forebrain impaired the performance ofrats in tasks designed to assess different aspects of atten-tion.94,184 The specific pattern of these effects supported theassumption that they were due to the modulation of excitabil-ity of corticopetal cholinergic neurons. For example, infu-sions of a BZR agonist selectively reduced the relativenumber of hits, but did not affect the relative number ofcorrect rejections in rats performing a sustained attentiontask.94 Selective decreases in the relative number of hits hasbeen demonstrated by other studies to correlate highly withthe extent of cortical cholinergic deafferentation, produced byintra-nucleus basalis or intracortical infusions of 192immunoglobulin G–saporin.131,133 These data support thehypothesis that the effects of intra-nucleus basalis infusionsof BZR agonists on sustained attention performance were dueto a drug-induced augmentation of the GABAergic inhibitionof cholinergic corticopetal neurons. Likewise, the effects ofintra-nucleus basalis infusions of a BZR agonist on cross-modal divided attention performance184 closely correspond,quantitatively and qualitatively, with the increased divided

attention costs observed following lesions of corticopetalcholinergic projections.216

Intra-nucleus basalis infusions of BZR inverse agonistsproduced a selective increase in the false alarm rate (or adecrease of its inverse, the relative number of correct rejec-tions) in animals performing in a sustained attention task.94

Such an increased frequency in the invalid detection ofsignals has been predicted to result from disinhibition ofcorticopetal cholinergic neurons.177,181 These and otherexperiments on basal forebrain GABA–cholinergic inter-actions, and their role in cognitive functions,145 support thehypothesis that GABAergic afferents regulate the excitabilityof corticopetal cholinergic neurons and thereby mediate atten-tional performance.

Conceptual considerations support the assumption thatNAC GABAergic projections to the basal forebrain representa major source of GABA modulating corticopetal cholinergicneurons in attention. The NAC is traditionally considered amajor site where limbic and telencephalic projectionsconverge to mediate the translation from “motivation toaction” (as coined by Mogensonet al.139). Numerous studieshave refined this hypothesis and, importantly, extended it toaversive motivation.172,175However, for motivation to trans-late into action, the subject is required to detect and separatebehaviorally significant stimuli and contexts from less rele-vant information and, more generally, to allocate processingcapacity to the evaluation of the behavioral situation andavailable response alternatives. In other words, Mogenson’sapothegm requires extension to “from motivation to attentionto action”. Indeed, the NAC has been linked to the ability ofconditioned stimuli to gain control over attentional processesand thereby determine response selection.13,17,170,173,191Thefunctional efficacy of such attentional functions depends onNAC GABAergic projections to the basal forebrain, includingthe GABAergic modulation of the excitability of corticopetalcholinergic neurons.

3.2. Glutamatergic afferents: telencephalic stimulation ofbasal forebrain corticopetal projections in attention

Glutamatergic afferents of the basal forebrain arise primar-ily from cortical and amygdaloid areas32,65,80,240 (Fig. 1).Brainstem regions, including the pedunculopontine tegmentalnucleus (PPT), may also send glutamatergic projections to thebasal forebrain.164 However, the projections from the PPT areless well documented,32,97 and the ability of intra-nucleusbasalis infusions of the non-specific glutamate receptorantagonist kynurenate to block the increases in cortical AChefflux produced by electrical stimulation of the PPT may bedue to polysynaptic, glutamate-mediated effects of PPTstimulation.164

Receptors for botha-amino-3-hydroxy-5-methyl-4-isoxa-zolepropionate (AMPA)/kainate andN-methyl-d-aspartate(NMDA), the two major classes of ionotropic excitatoryamino acid receptors, have been demonstrated within thebasal forebrain.124,152 The greater sensitivity (indicated bycell death or induction of the immediate-early genec-fos) ofbasal forebrain cholinergic neurons to excitotoxins targetingAMPA/kainate as opposed to NMDA receptors has beeninterpreted as indicating a greater prevalence of the formertype of receptor on these neurons.153,222

Although telencephalic glutamatergic projections weresuggested to directly contact basal forebrain cholinergic


neurons,235 the precise localization of glutamate receptors inthe basal forebrain remains unsettled. Furthermore, the major-ity of studies that introduced glutamatergic agonists into thisregion did so solely for the excitotoxic consequences of suchmanipulations, and experiments investigating the modulatoryrole of glutamatergic inputs on corticopetal neurons arescarce. A few studies have demonstrated that basal forebrainadministration of glutamate excites cholinergic neurons inthis area113 and increases cortical high-affinity cholineuptake,223 as well as cortical ACh efflux.112 Conversely,intra-nucleus basalis administration of the competitiveNMDA antagonist 3-(2-carboxy-piperazine-4-yl)propyl-1-phosphonate was shown to decrease cortical ACh efflux inanesthetized rats.69

With the exception of rather recent studies from our labora-tory, the behavioral or cognitive significance of basal fore-brain glutamate–ACh interactions has remained largelyunexplored.2,70 Fadelet al.54 demonstrated that increases incortical ACh efflux, which resulted from the presentation of acomplex stimulus (sudden exposure to darkness pre-trained tobe associated with palatable food), were blocked by intra-nucleus basalis infusions of the non-specific ionotropic gluta-mate receptor antagonist kynurenate. This effect of kynure-nate was attributed to blockade of telencephalic, as opposedto brainstem, glutamatergic afferents to the basal forebrain forthe following reasons. The available data do not suggest thatthe projections of the PPT mediate motivational mechanismsor are crucial for the effects of conditioned appetitivestimuli.97 As will be discussed below, ascending projectionsfrom this area play a major role in sleep–wake cycles andarousal168 (as defined above), but they are unlikely to mediatebasal forebrain cholinergic neuronal excitation in response topresentations of an extensively conditioned incentive stimu-lus, such as the one used in our experiments (also see Ref.202). In contrast, glutamatergic afferents, originating fromareas which have been extensively documented to mediatestimulus–reward associations, such as the amygdala51,186,187

and limbic cortical areas,11 probably mediated the increasein cortical ACh associated with the presentation of the condi-tioned stimulus and the effects of kynurenate in the experi-ments of Fadelet al.54

These experiments also demonstrated that infusions ofNMDA did not affect basal ACh efflux, but such infusionsaugmented the increase in cortical ACh efflux produced bythe darkness/palatable food stimulus.54 Similar to the inter-pretation of the effects of kynurenate above, it is hypothesizedthat telencephalic glutamatergic afferents contribute mostly tothe voltage-dependent removal of the magnesium blockade ofNMDA receptors in the infusion area. To exclude possible“arousal” components of this stimulus that may have beenmediated by a noradrenergic stimulation of the basal fore-brain (see below), Fadelet al.54 also assessed the effects ofco-infusions of thea1 antagonist prazosin into the basal fore-brain. The data from this experiment demonstrated thatneither the increases in cortical ACh as a result of the dark-ness/palatable food stimulus nor the augmenting effects ofintra-nucleus basalis NMDA depend on basal forebraina1

receptor stimulation. The repeated presentation of the dark-ness/palatable food stimulus is speculated to have gainedsufficient incentive salience to elicit extensive attentionalprocessing that is mediated via activation of corticopetalcholinergic projections. Collectively, the data of Fadeletal.54 support the hypothesis that, in situations unrelated to

the sleep–wake cycle, or not involving novel or stressfulstimuli, telencephalic glutamatergic afferents represent themajor excitatory input to basal forebrain cholinergic neurons.

Evidence for the assumption that glutamatergic inputs tobasal forebrain neurons are a major source of basal forebrainneuronal stimulation in attentional task-performing animals isbased on recent experiments assessing the attentional effectsof intra-nucleus basalis infusions of the competitive NMDAreceptor antagonist 2-amino-5-phosphonopentanoic acid(AP5). Infusions of AP5 dose-dependently and selectivelydecreased the relative number of hits in animals performinga sustained attention task.217 Importantly, infusions of AP5did not affect the performance of animals assessed in a simplevisual discrimination task that did not explicitly tax atten-tional functions and was not associated with changes in corti-cal ACh efflux.88 For reasons identical to those discussed inthe context of the origin of the glutamatergic activation asso-ciated with the darkness/palatable food stimulus (see above),the effects of AP5 on attentional performance were attributedto the blockade of telencephalic glutamatergic afferents ofbasal forebrain cholinergic neurons. The interpretation ofthe effects of AP5 in terms of specifically blocking the atten-tional performance-associated excitability of basal forebraincholinergic neurons is again based on the similarity betweenthe pattern of the attentional impairments produced by AP5and lesions of cortical cholinergic inputs.131

3.3. Telencephalic afferent regulation of basal forebraincorticopetal neurons in attention: what exactly do telen-cephalic afferents “tell” basal forebrain neurons?

While the available data remain sketchy, it is hypothesizedthat, in situations taxing practiced, routine attentional perfor-mance, the afferent regulation of basal forebrain corticopetalcholinergic neurons is largely restricted to convergingGABAergic afferents from the NAC and glutamatergic affer-ents from telencephalic areas (see Fig. 1). The view thatglutamatergic and GABAergic afferents interact to “recruit”corticopetal cholinergic neurons is further substantiated onthe basis of the functional correlates of amygdala–NAC inter-actions, suggesting parallel circuits within the extendedamygdala that orchestrate the GABAergic fine-tuning ofglutamatergic inputs to the basal forebrain. Specifically, thebasal and basolateral amygdala represents the main, thoughnot exclusive, source of glutamatergic projections to the basalforebrain corticopetal neurons,32,238,242 as well as to theNAC57,62,130,158,231(Fig. 1). The dorsomedial shell of theNAC, in which the GABAergic projections to the basal fore-brain originate,218 also receives input from the basolateralamygdala, yielding a closed parallel circuit via which theamygdala, in addition to its direct projections to the basalforebrain, indirectly regulates the excitability of basal fore-brain corticopetal projections (Fig. 1). A second, closed,parallel circuit involved in the regulation of the excitabilityof basal forebrain neurons via telencephalic afferents consistsof the medial prefrontal cortex (mPFC), with its strongbidirectional connections with the basolateral amygdala,33,185

and direct projections to the shell of the NAC22,77,126and tobasal forebrain corticopetal, mostly non-cholinergic, inhibi-tory neurons.240

As has been discussed previously,179 the anatomical organ-ization of neither the basal forebrain cholinergic perikarya northeir cortical terminals suggests that this projection is


sufficiently topographically organized to mediate a selectiveactivation of specific cortical areas and layers. In other words,the cholinergic corticopetal projections are not “pre-wired”for the processing of selected stimuli (also see Ref. 169). Asdiscussed above, the effects of activation of this system on thecortex are likely to be global, permitting an enhanced infor-mation processing via converging cortical inputs, mainlyfrom thalamic or other cortical areas. What type of informa-tion, therefore, may be processed or “carried” by theGABAergic and glutamatergic afferents to cholinergic basalforebrain neurons?

Assuming that activation of NAC DA receptors inhibits theGABAergic output to the basal forebrain, at least under condi-tions which shift accumbens neurons into the “up state”,151 thefunctional correlate of the disinhibition of basal forebrainneurons via this pathway can be fairly precisely postulated.Recently, Berridge and Robinson17 integrated a vast literatureand provided new evidence in support of the hypothesis thatNAC DA mediates hedonic and aversive processes. Specifi-cally, they propose that activation of NAC DA mediates themotivational salience attributions to the neural representa-tions of stimuli associated with rewarding or aversive experi-ences. In essence, this hypothesis describes attentionalfunctions of NAC DA that convert “an event or stimulusfrom a neutral ‘cold’ representation (mere information) intoan attractive and ‘wanted’ incentive that can ‘grab attention’”(p. 31317). Likewise, stimuli repeatedly associated with aver-sive events may gain “frighteningly salient” properties(p. 34817) and thus dominate the attentional processing.Stimuli or mental representations that gained motivationalsalience increasingly control behavior, at least in part,because such stimuli are more extensively processed andtheir processing consumes substantial processing resources,thereby limiting the processing of behavioral alternatives andthus triggering compulsive responses.17,181

Increases in the excitability of basal forebrain corticopetalcholinergic neurons are likely to represent a crucial com-ponent of the NAC efferent circuits mediating such atten-tional processes. As discussed above, and summarized inFig. 1, increases in the dopaminergic modulation of NACefferents to the basal forebrain may disinhibit basal forebraincholinergic neurons and allow the excitatory afferents to moreeffectively stimulate these neurons, thereby mediating theprevalent processing of stimuli that gained motivationalsalience. Our experiments on the attentional effects of intra-nucleus basalis infusions of BZR inverse agonists, whichaugment activated cortical ACh efflux (see above), supportthe hypothesis that increases in the (re)activity of corticalcholinergic inputs mediate the enhanced or even over-processing of stimuli which, depending on the type of taskand attentional processing requirements, may assist or evenimpair attentional performance.44,94,184Thus, the descriptionof the role of the NAC in a process from “motivation toattention to action” (see above) gains substance by integratingthe basal forebrain as a main target of NAC efferents (also seeRef. 227).

Obviously, the dense interconnections between the areasafferent to the NAC, particularly the amygdala and theprefrontal cortex, and their parallel excitatory projections tothe basal forebrain (Fig. 1), suggest that the NAC efferentdisinhibitory regulation of basal forebrain neurons convergeswith glutamatergic inputs, particularly from the amygdala.Circuits involving the amygdala are traditionally considered

to mediate associations between motivational and emotionalqualities and stimuli and associations.163,185,186 Moreover,Everitt et al.51 provided evidence in support of the hypothesisthat the close interactions between the amygdala and the NACmediate the ability of conditioned incentives to control beha-vior. Thus, it may be speculated that direct stimulation of thebasal forebrain neurons by amygdaloid afferents mediates anincrease in the attentional processing of stimuli associatedwith distinct motivational or emotional qualities. The con-verging, disinhibiting and thus additionally stimulating influ-ence from the NAC may mediate a further elevation of theattentional processing of these stimuli, to the extent that theygain motivational salience.

Although these suggestions may appear highly speculative,they correspond with the interpretation of results of aningenious experiment by Everittet al.50 In their study, lesionsof the basolateral amygdala did not affect instrumentalresponses elicited by a primary reinforcer (an estrous female),but suppressed responding under a second-order schedulemaintained by a conditioned reinforcer (a previously neutralstimulus that gained incentive salience by repeatedly beingassociated with the female). Importantly, infusions ofamphetamine into the NAC ameliorated the lesion-induceddecrease in conditioned reinforcer-maintained responding.This finding supports the speculations about the synergisticinteractions between the NAC and the amygdala in theprocessing of motivationally salient stimuli (see above).Collectively, these data demonstrate that the amygdala’sinvolvement in the ability of previously neutral stimuli togain behavioral control (also see Refs 63, 84 and 174),presumably as a result of gaining motivational salience,17

depends on the route via the NAC, and thus the presentmodel adds on the converging stimulation and disinhibitionof basal forebrain corticopetal projections.

The functional contributions of direct and indirect connec-tions between the mPFC (Fig. 1), the basal forebrain, the NACand the basolateral amygdala are less well understood,although some data allow the speculation that cortical inputsto the NAC gate amygdaloid inputs,147,213 thereby possiblyallowing cognitive variables to influence the NAC-mediatedincentive salience attribution to stimuli.25

In summary, the afferent regulation of basal forebraincholinergic neurons as they mediate attentional performanceis largely restricted to inputs from telencephalic areas. Amongthese afferent projections, the projections originating specifi-cally in the NAC and the basolateral amygdala are hypothe-sized to mediate, via their effects on cortical cholinergicinputs, the increases in detection, discrimination and process-ing of previously neutral stimuli that thereby gain motiva-tional salience and increasingly control behavior.

3.4. Arousal-induced attention and the role of basal forebrainnoradrenergic afferents for the functional activation oftelencephalic inputs to the basal forebrain

“Arousal” is defined in the present context as the activationof the forebrain in order to mediate the biased processing ofemotional, novel and/or stress-related information, and theinitiation of adaptive responses (see above). Cognitively,the early steps of arousal-induced attentional processes differfundamentally from the processing that underlies the morehabitual, well-practiced attentional performance assessed bystandardized tasks. Arousal-induced attention is typically


initiated by a very salient external stimulus (novelty, threat),triggering “low-level” pre-attentional responses, includingorientation responses, defensive reflexes and globalsearch,16,155that are followed by the more controlled, effortfulattentional processes of stimulus detection, discriminationand extended stimulus processing.56,162,190It should be notedthat sustained attention performance has often been suggestedto rely on adequate levels of arousal; therefore, it should bereiterated that, based on the more refined definition of“arousal” to maintain its usefulness as a construct, sustainedattention performance and arousal represent separate

constructs (see Section 2). As will be discussed next, arousal-induced attentional processing is hypothesized to be mediatedvia the ability of ascending noradrenergic projections to thebasal forebrain to activate (or even “recruit”) the telence-phalic afferent inputs to basal forebrain neurons (Fig. 2).Obviously, this specific perspective ignores the functions ofother telencephalic, particularly cortical, noradrenergicprojections which may directly contribute to the modulationof cortical information processing. As will be discussedbelow, however, evidence supports the assumption thatbasal forebrain noradrenergic–cholinergic interactions


Fig. 2. Afferent regulation of basal forebrain corticopetal cholinergic neurons mediating arousal-induced attentional processing. Novel, salient or “emotionallycharged” stimuli activate ascending noradrenergic systems, possibly via afferents of the LC originating in the nucleus paragigantocellularis (PGi), asympathoexcitatory structure.5,6 Noradrenergic stimulation of the basal forebrain cholinergic neurons may allow telencephalic glutamatergic inputs to thebasal forebrain to recruit the cholinergic neurons via NMDA receptors,54 thereby mediating the initiation of attentional processes triggered by crucial stimuli(for details and discussion of the additional, parallel circuits shown in this figure, see text). Abbreviations not listed above or in the legend to Fig. 1: AC, nucleus

accumbens; Na, noradrenaline.

represent a crucial link in arousal-induced attentionalprocessing.

Noradrenergic projections to basal forebrain cholinergicneurons originate in the LC and the A5 group in the ventro-lateral tegmentum.103,118The cholinergic neurons of the basalforebrain receive a particularly dense noradrenergic input andthe distal segments of their dendrites are repeatedly contactedby noradrenergic fibers.200,235,237,239Basal forebrain cholin-ergic neurons are predominantly depolarized viaa1 receptors,driving cholinergic cells into a tonic mode of firing andincreasing their rate of repetitive spike discharge.30,60 Inaddition to direct noradrenergic inputs to basal forebraincholinergic neurons, other evidence suggests polysynapticpathways, including the possibility that projections from theamygdala (see above) receive terminal input from ascendingnoradrenergic systems.35

While the performance of rats in a sustained attention taskfirmly depends on the integrity of basal forebrain corticopetalcholinergic neurons and on the GABAergic and glutamatergicinnervation of these neurons from telencephalic areas (asdiscussed above), lesions of the dorsal noradrenergic bundle,which decreased forebrain noradrenaline contents by morethan 90%, did not affect performance in this task.132 Thisfinding closely corresponds with the lack of effects of similarlesions on the performance of rats in the five-choice serialreaction time task, even under conditions of decreased stimulusdiscriminability.31,37,111 However, Robbins and co-workers31

also demonstrated that brief bursts of white noise presentedjust prior to the presentation of the stimulus in the five-choicereaction time task resulted in a decreased response accuracyand increased omissions in lesioned animals. These effectsmay be interpreted as reflecting the ascending noradrenergicsystem’s mediation of arousal-induced biasing of attentionalprocessing.171,176,193Although the significance of conclusionsderived from studies on the effects of lesions of the noradren-ergic system may generally be limited by the well-docu-mented plasticity in this system, even following extensivedeafferentation (see the discussion in Ref. 132), the arousal-mediating functions of the ascending noradrenergic systemare supported by studies showing that novel, salient or aver-sive stimuli, capable of eliciting orienting and defensiveresponses, evoke phasic discharges in LC activity.58,72,120

Aston-Joneset al.5 hypothesized that the projections of thenucleus paragigantocellularis, a sympathoexcitatory nucleus,to the LC import information about the sympathetic activationproduced by novel, “emotionally charged” or stress-likestimuli to the LC (see their Fig. 11). The ascending projec-tions of the LC mediate the biasing of forebrain informationprocessing toward the processing of such stimuli andcontexts. This abbreviated discussion of their hypothesiswould predict that lesions of the noradrenergic bundle maynot affect habitual attentional performance (as assessed byusing a well-practiced task such as our operant sustainedattention task132), as such performance does not involve suffi-ciently provocative stimuli (see above). In contrast, theperformance effects of a stressor (bursts of white noise)observed in the experiments by Robbins and co-workers31

(see above) may be associated with the necessary sympatheticactivation to affect LC activity which, in lesioned animals,reveals the consequences of a dysfunctional ascending nor-adrenergic system.

Thus, the functional significance of basal forebrainnoradrenergic–cholinergic interactions can be, at least

hypothetically, described as follows: sustained attentionalperformance necessarily requires the integrity of basal fore-brain corticopetal cholinergic projections, but not of theirnoradrenergic afferents (or of the dorsal noradrenergic bundlein general). Optimization of the subjects’ attentional process-ing in response to urgent (e.g., aversive) stimuli is mediatedvia noradrenergic mechanisms that facilitate the ability oftelencephalic afferent circuits to regulate the excitability ofbasal forebrain corticopetal neurons (Fig. 2).

The noradrenergic projections to the basal forebrain andto other telencephalic structures, including the shell of theNAC and the central nucleus of the amygdala (CeA;Fig. 2)5,6,43,59,104,114may collectively mediate such salientstimuli-induced attentional processing. The hypothesis thatnoradrenergic inputs to the basal forebrain are an essentialcomponent of these functions of the ascending noradrenergicsystem gains support from studies on the effects of infusionsof noradrenergic drugs into the basal forebrain on corticalACh efflux,54 and from the recent suggestion that basal fore-brain noradrenergic–cholinergic interactions are particularlycrucial in the processing of anxiogenic stimuli and contexts.16

The data of Fadelet al.54 allow the speculation that nor-adrenergic stimulation of basal forebrain neurons is sufficientto permit telencephalic glutamatergic afferents to stimulatebasal forebrain neurons via NMDA receptors. Furthermore,Fadelet al. demonstrated that, in animals in which corticalACh efflux is already activated by the presentation of a condi-tioned stimulus for palatable food,53 or in which NMDAaugmented the increase in cortical ACh efflux produced bysuch a conditioned stimulus,54 infusion of thea1 antagonistprazosin into the basal forebrain did not affect cortical AChefflux. These data suggest that, while noradrenergic stimula-tion of basal forebrain cholinergic neurons may facilitate theability of telencephalic inputs to stimulate the basal forebraincorticopetal system, noradrenergic inputs do not furthermodulate the excitability of this system once it is functionallyinnervated by telencephalic inputs and via their postsynapticNMDA receptors. In other words, these data may be specu-lated to reflect the ability of noradrenergic inputs to initiateattentional processing, but they are not capable of furtherinfluencing this processing once initiated.

These speculations can be further substantiated by datafrom experiments designed to determine the forebrain areasinvolved in the processing of anxiogenic stimuli and contexts,and the role of sympathetic activation elicited by such stimuliin the processing of anxiogenic information by forebraincircuits. Berntson and co-workers15,16,81 demonstrated thatif anxiogenic situations are associated with demands onelaborate processing of stimuli or contexts (as opposed tothe effects of unconditioned stimuli and classically condi-tioned stimuli for aversive events), such stimuli elicitspecified increases in cardiac reactivity, reflecting sympa-thetic activation (as well as parasympathetic withdrawal).Furthermore, this psychophysiological response, as well asthe ability of animals to process contextual information in aconditioned suppression paradigm, depend on the integrity ofbasal forebrain cholinergic neurons, specifically on theprojections to the mPFC. These findings correspond with amodel outlined by Berntsonet al.,16 which suggests that thepresentation of anxiogenic stimuli initiates the effectiveevaluation of relevant contextual information, and that theinitiation of this attentional processing depends both onsympathetic activation (indexed by increased cardiac


reactivity) and on the integrity of basal forebrain corticopetalcholinergic function. As would be predicted from the work byAston-Joneset al. (see above), ascending noradrenergicprojections are hypothesized to mediate the attentional effectsof an “emotionally charged” (e.g., anxiogenic) stimulus, andthe data of Berntsonet al. demonstrate that this processdepends on the integrity of basal forebrain cholinergic projec-tions to the mPFC, thus conceptually linking ascending nor-adrenergic projections with basal forebrain cholinergicefferents to the cortex (Fig. 2).

Basal forebrain noradrenergic–glutamatergic–cholinergicinteractions are not likely to represent an exclusive mechan-ism mediating the effects of alerting stimuli on attentionalprocesses. For example, the failure of rats with lesions ofthe CeA to acquire conditioned orienting responses may beattributed to the disruption of a circuit consisting of noradren-ergic inputs to the CeA and their effects on projections to thebasal forebrain.36,93 This circuit may also be involved in themediation of the processing of anxiogenic stimuli discussedabove (see the effects of CeA lesions on conditioned suppres-sion demonstrated by Killcrosset al.110). Likewise, noradren-ergic inputs to the NAC modulate NAC DA release114 andthus may, via the NAC efferents to the basal forebraindiscussed above, also disinhibit basal forebrain cholinergicneurons, thereby mediating the initiation of attentionalprocessing by alerting stimuli.28,31 Furthermore, similar tothe effects of noradrenaline in the basal forebrain, noradren-ergic inputs to the NAC may sufficiently stimulate theseneurons to open NMDA receptors, thus allowing telence-phalic glutamatergic inputs to the NAC to regulate NACefferent processing (see Fig. 2). Taken together, thesescenarios suggest multiple parallel pathways, all of whicheventually converge on basal forebrain neurons, and all ofwhich allow noradrenergic ascending projections to stimulateand disinhibit the corticopetal projections of the basal fore-brain, thereby allowing the subject to engage in the evaluationof novel or emotionally significant stimuli and contextualinformation.

4. “AUTOSTIMULATION” OF BASAL FOREBRAIN CORTICOPETALCHOLINERGIC NEURONS BY BRAINSTEM ASCENDING CHOLINERGIC

PROJECTIONS MEDIATES DREAMING

4.1. Dreaming as hyperattentional processing

Hobson90 described dreaming as characterized by visualimagery, inconstancy of place, time and person, a scenario-like knitting of disparate elements, and amnesia about dream-ing contents (recall of dreams is usually restricted to those“rehearsed” when the subject awakes from REM sleep).While the extent to which dreaming differs from wakingcognition has remained a matter of debate,105 the amnesia,the predominant processing of internal data (as opposed tosensory stimuli) and the hyperassociated processing ofunrelated information represent distinct cognitive character-istics of dreaming.106,117Kahnet al.106 further conceptualizedthe bizarreness of dreaming cognition as a result of “defectivebinding over time”, i.e. the inability of the self-activated brainto move from one stimulus to the processing of related stimulior associations. This contrasts with the processing in the wakestate that is typically dominated by the multiple features of astimulus that are perceived in some temporally synchronizedway (and thus are “bound”). To illustrate the point, in theawake state, a red dragon may spur associations about

mystical animals or fairy tales, while in dreams it may befollowed by a lawn mower, and these two items are forgedinto a chain of events in dreams. The resulting dissociated orincongruous contents of dreams are typically characterized asbizarre.3 Thus, dreaming cognition can be described to behyperassociational, as unrelated fragments of informationare fused into a bizarre scene.

Dreaming cognition can be described in terms of atten-tional processing. Dreaming cognition is characterized bythe random selection of representational stimuli (or associa-tions), the lack of discrimination between relevant (or“bound”) features of such stimuli and the activation ofunrelated information, and the immediate, extensive process-ing of such information (as opposed to the normally effortfulsteps through multiple attentional “bottlenecks” to assignprocessing resources to a particular stimulus39,156). Tocontinue with the illustrative example used above, the factthat the lawn mower follows the red dragon in the chain ofevents does not result in the rejection or filtering of the lawnmover as an unlikely association, as would be the case in theawake state. Furthermore, in dreams, the processing of thelawn mower next to the dragon will be as extensive as itwould be in the wake state as a valid contextual association,such as elicited by thoughts about Saturday’s chores. Indreams, there is no division of attention that would allowthe maintenance of parallel or competing streams of imagery,and there is no capacity for prioritizing one content over theother. In contrast, all the available processing capacityappears to be allocated to the single sequence of dissociateditems and the construction of a scene into which those itemsare fused. If dreaming is disrupted and thus may be recalled,the perceived intensity of dreaming sequences which con-textualize emotions, however bizarre they may be,83 particu-larly well illustrates the “single mindedness” of dreamingcognition.106

Cognitive theory predicts two major consequences result-ing from such an exhaustion of processing capacity, both ofwhich are highly characteristic of dreaming cognition. First,the suppression or filtering of irrelevant stimuli normallyrequires processing resources; conversely, the exhaustion ofsuch resources diminishes the ability to prevent irrelevantstimuli from being selected and processed.115,157,167 Asdiscussed above, this ability is completely absent in dreams;thus, the sequential, incongruous selection of stimuli indreams represents an expected consequence of the depletionof processing resources.

Second, as a result of the depletion of processing resourcesand/or limitations in the allocation of resources to activitiesother than the processing of a particular representationalstimulus, there is no processing capacity left to “network”or integrate a particular stimulus with stored information,thereby preventing a later recall of this stimulus40 (similarimplications apply to Baddeley’s “central executive”;7 alsosee Ref. 162). (Once again, dreams that are seeminglyrecalled are those immediately rehearsed once awakenedduring REM sleep. This issue is beyond this discussion.) Tocontinue with our example, in the awake state, a picture of ared dragon may initiate the processing of related associations,ranging from phonological features to mnemonic information(e.g., “curious that dragons are part of fairy tales as well asmedieval epics”), and this associational processing representsthe basis for subsequent recall of having seen the picture. Indreams, however, such associational networking does not take


place, probably because of the lack of processing resourcesfor this task, thereby limiting subsequent recall. Moreover,the random and usually incoherent sequence of events indreams would require particularly extensive associationalprocessing to allow later recall of those contents (similar to,for example, recalling the contents of an illogical movie).However, in dreams, extremely limited residual processingresources allow little, if any, such integration of contentsinto mnemonic contexts.

4.2. Increased cortical acetylcholine release and underlyingafferent regulation in rapid eye movement sleep

Similar to the increases in cortical ACh release associatedwith the arousing events or manipulations, REM sleep hasbeen documented to be associated with increases in corticalACh release for almost 30 years.98,123The available evidenceconsistently suggests that the levels of cortical ACh effluxduring REM sleep are similar to those during waking andtwice or more the levels observed during slow-wave sleep.Correspondingly, high discharge rates of basal forebrainneurons during REM sleep have been reported.212 The impor-tance of cholinergic mechanisms for REM sleep has also beensuggested by results showing that the systemic administrationof physostigmine, a cholinesterase inhibitor, in sleepinghumans induced REM sleep and dreaming, without alteringmentation during non-REM sleep.14,61,199

A substantial body of evidence indicates that muscarinicreceptor stimulation in the medial pontine reticular formationis sufficient and necessary for the induction of REMsleep.8,66,68,89,92,101,196,220The cholinergic cell bodies in thebrainstem releasing ACh in the medial pontine reticularformation and thereby mediating the production of REMsleep originate mainly from the PPT and laterodorsal teg-mental nucleus (LDT) region (Mesulam’s Ch5 and Ch6).75,137

Cholinergic neurons in these areas increase their firing ratessubstantially during REM sleep and, possibly via polysynap-tic reciprocal connections with the LC, depress LC neuronalactivity during REM sleep.101,119,127

The ability of the tegmental cholinergic neurons to mediatecortical desynchronization has traditionally been assumed todepend on connections via the thalamus, specifically becauseACh release in the thalamus is highest during REMsleep.41,102,128,203,204,226However, the PPT and LDT alsoproject to the basal forebrain,79,103,189,195,200,229suggestingthat the increased cortical ACh efflux during REM sleep isdue mainly to stimulation of basal forebrain corticopetalcholinergic neurons by these ascending cholinergic projec-tions. The basal forebrain area of humans shows notableincreases in metabolic activity in REM sleep,20,149 and it ishypothesized that this activity reflects cholinergic receptorstimulation-mediated excitation of corticopetal neurons.113

The cholinergic innervation of the basal forebrain by thetegmental projections was supported by demonstrating, inanimals, that lesions of the PPT resulted in a decreasedcholinergic innervation of the basal forebrain.38 Moreover,increases in ACh release in the basal forebrain followingthe systemic administration of scopolamine were not blockedby excitotoxic lesions of the basal forebrain, suggesting thatrecurrent collaterals of corticopetal cholinergic neurons donot significantly contribute to the cholinergic, afferent regula-tion of basal forebrain neurons.38 Finally, electrical stimula-tion of the PPT appears to be sufficient to produce an increase

in cortical ACh release via projections terminating in thebasal forebrain.164 To the extent that this effect may be attrib-uted to stimulation of PPT cholinergic efferents to the basalforebrain, it may be mediated indirectly via presynapticcholinergic stimulation of glutamatergic inputs to the basalforebrain.164 While the exact distribution of cholinergic ter-minals in the basal forebrain remains unsettled and mayinclude direct contacts of cholinergic terminals with basalforebrain corticopetal cholinergic neurons,243 it seems morelikely that the majority of cholinergic inputs does not synapsedirectly onto basal forebrain cholinergic neurons (also seeRefs 195 and 236). The origin of the glutamatergic inputsmediating these effects is unknown (but see above). It is notclear, in this context, whether PPT glutamatergic/aspartat-ergic projections reach the area of basal forebrain cholinergicneurons.32

Collectively, the available data provide the basis for thehypothesis that the increases in cortical ACh efflux duringREM sleep are due to increases in the cholinergic stimulationof the basal forebrain which, possibly via a glutamatergictrans-synaptic mediator, activate basal forebrain corticopetalcholinergic neurons. An extension of this hypothesis suggeststhat the hyperattentional processing during REM sleep, i.e.dreaming, depends on such basal forebrain interactions,possibly in interaction with the activation of the thalamic–cortical projection system via parallel and even collateralizedcholinergic projections from the LDT/PPT to the thala-mus78,129,194,226,229(see Fig. 3). The discussion below willfocus on this hypothesis and further detail the hyperatten-tional characteristics of dreaming cognition as mediated viacortical interactions between activated cholinergic and thala-mic projections. It should be noted that the determination ofneuronal circuits, including the basal forebrain, that may benecessary and sufficient to initiate or maintain REM sleep orto mediate somnogenic effects is not within the scope of thistopic.12,107,161

4.3. Cortical cholinergic hyperactivity and hyperattentionalprocessing

As stated at the beginning of this article, the mediation ofattentional functions (sustained, selective, divided) by corticalACh has been extensively characterized in recent years.While this literature has mostly focused on the effects ofloss of cortical cholinergic inputs in different aspects of atten-tion, and on intact cortical cholinergic input-mediated aspectsof attention,24,67,88some evidence has supported the hypoth-eses that an increased (re)activity of cortical cholinergicinputs mediates hyperattentional impairments (discussedabove). It should be noted that significant increases in corticalACh efflux or cholinergic receptor stimulation (the latter asproduced, for example, by the application of a muscarinic ornicotinic receptor agonist) cannot reflexively be assumed tobenefit or facilitate cholinergically mediated functions; rather,increased tonic levels of cholinergic transmission are morelikely to interfere with the normal, phasic ACh efflux andassociated receptor stimulation, and thus produce detrimentalfunctional effects.182,232 The attentional effects of manipula-tions known to stimulate cortical cholinergic inputs (above)support the assumption that increases in cortical cholinergictransmission mediate the lowering of threshold for the selec-tion of signals and the overprocessing of stimuli, and thus


support the proposed crucial role of cortical cholinergichyperactivity in the generation of dreams.

Such hyperattentional consequences of increases in corticalACh can also be extrapolated from studies on the effects

of ACh on neuronal activity in sensory cortical areas. Forexample, in the visual cortex, iontophoretically applied AChgenerally enhances stimulus-driven neuronal activity which,importantly, is accompanied by a decrease in directional


Fig. 3. Schematic illustrations of the main ascending circuits hypothesized to mediate REM sleep-associated cognition, or dreaming. Note that thishypothesisdoes not necessarily address the neuronal mechanisms of REM sleep induction or termination that appear to include collateral projections from the LDT/PPT tothe medial pontine reticular formation (mPRF; see text for references). Likewise, other contributions of basal forebrain circuits to the regulation of the sleep–wake cycle are beyond the present focus on circuits mediating the hyperattentional processing characteristic for dreaming (see text). Dreaming is hypothesizedto depend on the activation of basal forebrain corticopetal cholinergic projections and therefore the increases in cortical ACh, and the intracortical interactionsbetween the increased cholinergic receptor stimulation and the converging, stimulated inputs from the thalamus (TH). In REM sleep, both structuresareactivated via ascending cholinergic projections from the LDT/PPT. At least some tegmental cholinergic neurons may be collateralized and innervateboth thethalamus and the basal forebrain. The exact interaction between tegmental cholinergic inputs and basal forebrain corticopetal cholinergic projections isunsettled, but may be mediated via glutamatergic neurons. Basal forebrain cholinergic neurons also project to the reticular thalamic nucleus, thereby possibly

disinhibiting and thus further stimulating thalamocortical projections (see text for references). For further abbreviations, see the legends to Figs 1 and 2.

selectivity of visual cortical units.148,188 Similarly, in theauditory cortex, application of muscarinic agonists facili-tates the responses of neurons to frequencies which areoutside the band that optimally drives these neurons (“bestfrequency”).134 Likewise, stimulation of the cholinergic basalforebrain enhances the responses of neurons in the somato-sensory cortex to stimulation of the skin.221 Moreover, Bakinand Weinberger10 demonstrated that pairing auditory stimuliwith basal forebrain stimulation changed auditory corticalreceptive fields so that they then become receptive for thefrequency of the stimuli as the new “best frequency” (foranalogous findings in the somatosensory cortex, seeRasmusson and Dykes165). Importantly, cortical muscarinicreceptor stimulation enhances the excitability of individualcortical units, but does not appear to enhance the processingvia corticocortical connections within the auditory cortex.197

Although some of these data may be interpreted as reflectingadaptive consequences of cortical ACh on informationprocessing, particularly the receptive field changes followingpaired basal forebrain and sensory stimulation, ACh stimula-tion-mediated decreases in direction selectivity of visualcortical units, or the response of auditory neurons to stimulithat were not previously “best frequencies”, indicate thatsufficiently high levels of cortical ACh release may mediatean overprocessing of “noise” or of irrelevant stimuli. As tele-ncephalic ACh efflux is highest during REM sleep, these data,as well as the attentional effects of treatments which increasecortical ACh efflux (above), support the hypothesis that thehyperattentional characteristics of dreaming cognition areprimarily mediated via the increases in cortical ACh efflux.

4.4. Cortical interactions between activated basal forebrainand thalamic projections in rapid eye movement sleep

As was discussed previously,179 basal forebrain cortico-petal cholinergic inputs are likely to be regulated in acortex-wide manner rather than showing changes in AChefflux that are area or modality specific.87 Accordingly, atten-tional abilities were attributed to the ACh-mediated changesin the processing of information in the aggregate cortex. Thishypothesis is supported by evidence demonstrating that lossof cholinergic inputs to an individual area, such as to themPFC,67 did not affect sustained attention performance,while a generally modest yet more widespread loss of corticalcholinergic inputs did.133 As cortical ACh gates informationprocessing across the entire cortex,135,179an important tenet ofthis hypothesis suggests that, at the level of individual corticalunits, the selectivity of the amplifying effects of ACh is due tothe selectivity of the thalamic afferents activated as a result ofsensory stimulation (studies referenced above; also see Refs138, 206 and 215). However, in REM sleep, such a selective,modality-specific activation of thalamic efferents appears tobe replaced by a more global activation of the thalamus viathe ascending afferents from the tegmenta (see above; Fig. 3).It is noteworthy in this context that the reticular nucleus of thethalamus receives cholinergic inputs from both the PPT andthe basal forebrain.78,116,230The effects of ACh on reticularthalamic activity have been suggested to disinhibit thalamo-cortical projections.204,205 As both cholinergic inputs to thereticular thalamus can be assumed to be highly active duringREM sleep (Fig. 3), the synergistic convergence of directcholinergic stimulation of the thalamus and the reticularnucleus-mediated disinhibition of thalamocortical projections

may represent a major contributor to the hyperattentionalcharacteristics of dreaming described above. A highly activethalamus in REM sleep may be speculated to contribute to themediation of impairments in stimulus selection and discrimi-nation, i.e. the above-described impaired “binding” of dream-ing cognition.

While, with respect to cortical activity, REM sleep andwakefulness appear to represent equivalent states,117 thisdiscussion stresses that the afferent regulation of the basalforebrain and the thalamus differ fundamentally betweenthe two stages. Attentional performance-associated activationof cortical activity is based on the telencephalic regulation ofthe activity of basal forebrain corticopetal neurons (Fig. 1),and their cortical interactions with modality- and corticalarea-specific thalamic inputs. In contrast, dreaming cognitionis largely based on the extensive stimulation of basal fore-brain and thalamic corticopetal projections by ascending,primarily cholinergic, projections from the tegmenta (Fig.3). This hypothesis does not exclude the possibility thatdreaming cognition would be influenced by telencephalicafferent regulation of the basal forebrain, as the strongemotional context of some dreams may be mediated viaamygdaloid influences.91,121,149,186,187Moreover, such influ-ences may gain strength or become sensitized in certainpsychopathological disorders or following trauma to mediatedreaming cognition that is predominated by particularemotional concerns.83

4.5. Afferent regulation of basal forebrain and thalamiccorticopetal neurons mediating dreaming cognition:implications for schizophrenia

The persisting idea that hallucinations in schizophrenia aredue to intrusions of REM sleep into waking168 has not beenconvincingly substantiated. However, the present hypothesisabout the hyperattentional characteristics of dreamingmediated via cortical cholinergic hyperactivity relates topsychopathological concepts that describe disinhibition ofbasal forebrain corticopetal cholinergic projections as aneuronal mechanism contributing to the development andescalation of delusions and hallucinations.177,180,181Thus, thesimilarities between the regulation of cortical informationprocessing in REM sleep and schizophrenia may arise fromthe functional consequences of cortical cholinergic hyper-activity in either case.

The degree to which the hyperattentional mechanisms andthe associated depletion of processing capacity have beendescribed as characteristic for psychotic and dreaming cogni-tion is intriguing. In both cases, the inability to filter irrelevantor unrelated information from being extensively processed,and the related inability to allocate processing resources forsource and reality monitoring,100 characterize the attentionalprocessing.74,177,192

As discussed above, the attentional functions of corticalACh have been extrapolated to mediate such hyperattentionaldysfunctions in situations in which cortical cholinergicinputs are hyper(re)active. Increases in cortical ACh effluxobviously occur during REM sleep. Based on the evidenceand related theories about the role of abnormally regulated,overactive mesolimbic dopaminergic projections in schizo-phrenia,21,71,73and on the possibility that increases in meso-limbic DA disinhibit basal forebrain corticopetal cholinergicprojections142 (see above), over(re)active cortical cholinergic


inputs have been proposed to represent an integral componentof the neuronal circuit mediating psychotic cognition (for adiscussion of evidence and further aspects of this hypothesis,including a discussion of the reasons why muscarinic receptorantagonists are not expected to benefit psychotic symptoms,see Ref. 181). This extremely brief summary of this hypoth-esis suggests that increased activity in cortical cholinergicinputs may represent a common final pathway contributingto the mediation of dreaming and psychotic cognition. Impor-tantly, however, the increases in the activity in cortical cholin-ergic inputs in REM sleep and schizophrenia are hypothesizedto result from fundamentally different patterns of afferentregulation of basal forebrain cholinergic corticopetal neurons(PPT/LDT stimulated in REM sleep versus loss of GABA-ergic inhibition due to mesolimbic DA receptor overstimula-tion in schizophrenia). Although it is also intriguing thathallucinating patients show increased activity in the thalamusin addition to telencephalic structures,198 and that someschizophrenics show decreased REM latency and early-onset REM as well as a possible increase in the number ofcholinergic cells in the tegmenta,234 the available and largelycircumstantial evidence remains insufficient to proclaim arelationship between psychotic cognition and potentiallyabnormal neuronal circuits mediating dreaming. However,the present hypothesis suggests that the similarities betweendreaming and psychotic cognition reflect a cortical hyper-cholinergic component that may be involved in the attentionalprocessing characteristic for both states.

5. CONCLUSIONS

The present review extends previous attempts to reconcilethe role of cortical ACh in different cognitive and behavioralstates.210 Such a reconciliation does not readily arise fromsimply increasing or detailing the list of states to which corti-cal ACh contributes, but from an understanding of the funda-mental cognitive processing mediated via cortical ACh, andfrom hypotheses about the role of such processes in differentbehavioral or cognitive states. The crucial early steps of infor-mation processing, i.e. the detection, selection, discriminationand processing of stimuli and associations, depend on theintegrity of cortical cholinergic inputs. These cortical cholin-ergic inputs may be activated in different conditions as aresult of stimulation by dissociable afferent projections ofthe basal forebrain. Thus, while previous discussions stressedthe fundamental similarities between waking and REM sleepwith respect to cortical activation,117 and while cortical AChrelease appears activated in either state, the functionsmediated via cortical ACh can be dissociated on the basisof the different afferent regulation of the basal forebrain.

As briefly mentioned above, the discussion and the modelsthat are summarized schematically in Figs 1–3 remain pre-mature for several reasons. Most importantly, the lack of dataon the regulation and role of basal forebrain GABAergicefferents renders any of these models incomplete, specificallyin conjunction with the possibility that tegmental ascending

projections may preferably contact non-cholinergic cortico-petal neurons of the basal forebrain (see above). Likewise,information about the distribution of inputs within the basalforebrain is desperately needed, particularly with respect toinputs that have been largely ignored in the discussion above,including the distribution of terminals of mesencephalicdopaminergic inputs85,141 and of the brainstem inputs ingeneral. Although recent work has started to determine theinteractions between different inputs to the basal forebrainwith respect to the regulation of cortical ACh efflux (seeabove), and while these experiments have generated usefulexperimental paradigms and defined conditions under whichsuch interactions can be meaningfully studied,24,183our under-standing of the fundamental interactions between the maininputs remains limited. Our experiments have also demon-strated the importance of systematically varying the state ofbehavioral or cognitive activity in the analysis of such inter-actions,23,24 suggesting that data from animals in one state30

may not be generalizable to the role of an input or the inter-action between multiple inputs in the basal forebrain inanother state of activity. This issue may be of particularimportance with respect to inputs, such as dopaminergicinputs, that are likely merely to modulate other afferentsrather than produce main effects on the excitability of basalforebrain corticopetal neurons.

Finally, cortical ACh release, when paired with sensorystimulation, has long-lasting effects on the sensory field prop-erties that have been interpreted in terms of neuronal plasti-city.18,49,109,215Although the adaptive significance of changesin cortical sensory processing that depend on paired basalforebrain stimulation (or cortical application of ACh) andsensory input stimulation remains a subject of debate, thispossibility has yet to be integrated into the investigation ofthe role of cortical ACh in normal attentional processing,dreaming and models suggesting that abnormal excitabilityof cortical cholinergic afferents mediate the manifestation ofpsychiatric disorders.181 If endogenously released corticalACh indeed induces lasting modifications in cortical informa-tion processing, the impact of persistent aberrant regulation ofcortical ACh release on the development of such disorderscould be described in even more dramatic terms. Moreover, itwould be important to clarify whether such changes alsooccur during REM sleep, where corticopetal cholinergic andthalamic projections are activated, and to suggest their func-tional implications. Clearly, the incorporation of persistentchanges in cortical information processing as a result ofpaired stimulation of cholinergic and sensory inputs intocurrent theories about the cognitive functions of corticalACh awaits more information, particularly with reference tothe temporal dynamic properties of the effects of endo-genously released ACh on cortical information processing.

Acknowledgements—Our research was supported by NIH GrantsNS32938, MH57436, NS37026 and AG10173. We are grateful toAnne Marie Himmelheber and Janita Turchi for their comments onthe final draft of this manuscript.

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(Accepted27 September1999)


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