Cortical ACh in attention and dreaming Neuroscience Vol. 95, No. 4, pp. 933–952, 2000933 Copyright ᭧ 1999 IBRO. Published by Elsevier Science Ltd Pergamon Printed in Great Britain. All rights reserved PII: S0306-4522(99)00487-X 0306-4522/00 $20.00+0.00 www.elsevier.com/locate/neuroscience

COMMENTARY

CORTICAL CHOLINERGIC INPUTS MEDIATING AROUSAL, ATTENTIONAL PROCESSING AND DREAMING: DIFFERENTIAL AFFERENT REGULATION OF THE BASAL FOREBRAIN BY TELENCEPHALIC AND BRAINSTEM AFFERENTS

M. SARTER* and J. P. BRUNO Department 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 eye movement sleep-associated dreaming. Recent studies on the afferent regulation of basal forebrain neurons by telencephalic and brainstem inputs have provided the basis for hypotheses which, collectively, propose that the involvement of basal forebrain corticopetal projections in arousal, attention and dreaming can be dissociated on the basis of their regulation via major afferent projections. While the processing underlying sustained, selective and divided attention performance depends on the integrity of the telencephalic afferent regulation of basal forebrain corticopetal neurons, arousal-induced attentional processing (i.e. stimulus detection, selection and processing as a result of a novel, highly salient, aversive or incentive stimuli) is mediated via the ability of brainstem ascending noradrenergic projections to the basal forebrain to activate or “recruit” these telencephalic afferent circuits of the basal forebrain. In rapid eye movement sleep, both the basal forebrain and thalamic cortiocopetal projections are stimulated by cholinergic afferents originating mainly from the pedunculopontine and laterodorsal tegmenta in the brainstem. Rapid eye movement sleep-associated dreaming is described as a form of hyperattentional processing, mediated by increased activity of cortical 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)active cortical cholinergic input system in either condition. Finally, while determination of the afferent regulation of basal forebrain corticopetal neurons in different behavioral/cognitive states assists in defining the general cognitive functions of cortical acetylcholine, this research requires a specification of the precise anatomical 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. ᭧ 1999 IBRO. Published by Elsevier Science Ltd.

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

CONTENTS 1. INTRODUCTION 934 2. BEHAVIORAL AROUSAL AND ATTENTIONAL PERFORMANCE: CONCEPTUAL OVERLAPS AND DIFFERENCES 934 3. DISSOCIATIONS AND INTERACTIONS BETWEEN TELENCEPHALIC AND BRAINSTEM PROJECTIONS TO BASAL FOREBRAIN NEURONS IN AROUSAL AND ATTENTION 935 3.1. GABAergic afferents originating from the nucleus accumbens: from motivation to attention to action 935 3.2. Glutamatergic afferents: telencephalic stimulation of basal forebrain corticopetal projections in attention 937 3.3. Telencephalic afferent regulation of basal forebrain corticopetal neurons in attention: what exactly do telencephalic afferents “tell” basal forebrain neurons? 938 3.4. Arousal-induced attention and the role of basal forebrain noradrenergic afferents for the functional activation of telencephalic inputs to the basal forebrain 939 4. “AUTOSTIMULATION” OF BASAL FOREBRAIN CORTICOPETAL CHOLINERGIC NEURONS BY BRAINSTEM ASCENDING CHOLINERGIC PROJECTIONS MEDIATES DREAMING 942 4.1. Dreaming as hyperattentional processing 942 4.2. Increased cortical acetylcholine release and underlying afferent regulation in rapid eye movement sleep 943 4.3. Cortical cholinergic hyperactivity and hyperattentional processing 943 4.4. Cortical interactions between activated basal forebrain and thalamic projections in rapid eye movement sleep 945 4.5. Afferent regulation of basal forebrain and thalamic corticopetal neurons mediating dreaming cognition: implications for schizophrenia 945 5. CONCLUSIONS 946 ACKNOWLEDGEMENTS 946 REFERENCES 946

*To whom correspondence should be addressed. Fax: ϩ1-614-688-4733. 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 tegmental nucleus; mPFC, medial prefrontal cortex; NAC, nucleus accumbens; NMDA, N-methyl-d-aspartate; PPT, pedunculopontine tegmental nucleus; REM, rapid eye movement.

933 934 M. Sarter and J. P. Bruno

1. INTRODUCTION and of the psychopathological consequences of aberrations in the afferent regulation of these cortical input systems. Numerous recent experiments, using a variety of beha- vioral paradigms for the assessment of different aspects of attention, have concluded that the integrity of cortical cholin- 2. BEHAVIORAL AROUSAL AND ATTENTIONAL PERFORMANCE: ergic inputs is essential for the detection, selection and CONCEPTUAL OVERLAPS AND DIFFERENCES processing of stimuli and associations.36,52,146,179,216 Further- The attribution of “arousal” functions to basal forebrain more, basal forebrain neuropharmacological manipulations corticopetal neurons has been derived largely from neuro- known to increase or decrease the excitability of cortical pharmacological evidence supporting a “cholinergic nature” cholinergic inputs in intact rats bidirectionally alter the atten- of cortical arousal, specifically from studies showing relation- tional abilities of rats assessed in tasks designed to measure ships between electroencephalogram (EEG) desynchroniza- sustained or divided attention.94,184 Electrophysiological tion, increases in spontaneous alertness and increases in studies demonstrated that the increases in firing rate in medial cortical acetylcholine (ACh) turnover or cholinergic receptor prefrontal neurons accompanying increases in the demands on stimulation.34,166,201,209 These studies have further corrobor- sustained attention performance depend on the integrity of ated notions that the basal forebrain corticopetal system cholinergic inputs to this region.67 These and other data represents a rostral extension of the ascending reticular acti- support the hypothesis that cortical cholinergic inputs mediate vating system. Such notions have also been substantiated by diverse attentional functions, ranging from the ability to descriptions of the “reticular” anatomical and morphological detect and select stimuli that occur rarely and unpredictably characteristics of basal forebrain efferent projections, and by and require the subjects’ persistent readiness to detect such the innervation of the basal forebrain by projections originat- stimuli (as described by the theoretical construct “sustained ing in brainstem reticular areas.203 Presently, several inter- attention”), to discriminate significant stimuli from invalid related lines of evidence support the role of basal forebrain stimuli or “background noise” (“selective attention”), and to corticopetal projections in the regulation of “arousal”. Manip- allocate processing resources to competing demands on infor- ulations of the excitability of basal forebrain neurons mation processing (“divided attention”). Furthermore, aberra- modify cortical event-related potentials160 and other EEG tions in the integrity or excitability of basal forebrain measures.27,46,224 Likewise, neuronal activity in the basal fore- corticopetal cholinergic neurons have been described to escal- brain correlates with EEG activation.45,150,225 Furthermore, ate into major yet diverse cognitive dysfunctions and thus to basal forebrain neurons are involved in the diurnal regulation contribute essentially to the manifestation of the core cogni- of sleep parameters and associated EEG activity, probably tive symptoms of major neuropsychiatric disorders.181 due to connections with midbrain reticular and pontine struc- This rather recent literature on corticopetal cholinergic tures that represent the primary mediator of sleep–wake projections as a major component of the neuronal circuits rhythm9,107,207,211,212 (see below). Thus, the attribution of mediating attentional functions has rarely attempted to inte- “arousal”-like functions to basal forebrain corticopetal grate conceptually the more traditional descriptions of the projections has remained largely driven by research linking basal forebrain efferent system as a rostral extension of the the basal forebrain with brainstem ascending systems, and by ascending arousal system.1,95,136,210 Similar to Szymusiak’s210 studies assessing EEG and global behavioral states. discussion, the present review stresses the conceptual and A wide range of rather generally defined transitions from empirical overlaps, but also the differences, between the sleep or unconscious states to wakefulness, conscious aware- more traditional constructs of arousal and the more recent ness or the effective cortical processing of information has interpretation of the functions of cortical cholinergic inputs been traditionally collapsed into the construct “arousal”.144,203 in terms of cognitive psychology. The neurobehavioral However, the limitations of such a broad and unitary construct models discussed in the present review suggest that the to further assist in the identification and dissociation of speci- involvement of the basal forebrain corticopetal system in fic functions mediated via ascending systems have become arousal, attention and also in rapid eye movement (REM) evident,171 particularly in light of the unexpectedly complex sleep-associated dreaming can be dissociated on the basis of anatomical organization of ascending systems and their impli- its regulation by telencephalic and brainstem afferent projec- cations in a wide range of behavioral functions.29,97,214 Thus, tions. In other words, the hypothesis that cortical cholinergic in spite of the ubiquitous use of the term “arousal”, a more inputs mediate defined attentional abilities is not in conflict circumscribed description of this construct appears timely. with the more traditional notions about the role of this system “Arousal” may be more precisely defined on the basis of its in arousal or dreaming; rather, the specific nature of the infor- significance for defined behavioral or cognitive processes, mation processing mediated by this system depends on the and thus dissociated from the well-defined constructs of activity of the individual components of its afferent network sustained, selective and divided attention. For example, and the interactions between cortical cholinergic and con- Aston-Jones et al.5,6 describe the arousal associated with verging sensory or associational inputs. emotionally charged stimuli as based on the activation of The present review largely ignores the role of basal fore- the locus coeruleus (LC), which reflects sympathetic activa- brain corticopetal GABAergic projections, as information tion, and the consequent modulation of LC target neurons. In about the afferent regulation of this system and the functions this context, “emotional arousal” is defined as the activation of GABAergic corticopetal projections is scarce. As will be of the forebrain mediating the biased processing of emotional discussed last, such information, as well as data about the information and the initiation of adaptive responses.16 cortical interactions between basal forebrain GABAergic Conceivably, related types of arousal, such as those asso- and cholinergic projections, is key to a more comprehensive ciated with novel stimuli or stress, also act to enhance gener- understanding of the role of basal forebrain corticopetal ally the gating of forebrain information processing, in part via projections in the gating of cortical information processing stimulation of basal forebrain corticopetal cholinergic Cortical ACh in attention and dreaming 935

1,95,122 neurons (see below); the effects of different qualities of that cholinergic neurons in the basal forebrain bear GABAA “arousing” stimuli on forebrain processing may depend on receptors and that GABAergic transmission can be bidirec- activation of dissociable components of the “ascending acti- tionally modulated by administering benzodiazepine receptor vating system”.136 Furthermore, the involvement of basal (BZR) agonists (which augment the inhibitory effects of forebrain corticopetal projections in “arousal” can be easily GABA) and inverse agonists (which decrease GABA-gated reconciled with the more specific attentional functions of this chloride flux).178,235,238,241 system. For example, the perception of stimuli associated To investigate the GABAergic modulation of corticopetal with fear and anxiety fosters the search, detection and selec- cholinergic neurons, the effects of infusions of such positive tion of contextual information, and is associated with the and negative modulators of GABAA receptor-mediated chlor- allocation of considerable processing resources toward that ide flux (i.e. BZR agonists and inverse agonists, respectively) objective.16,125 Importantly, however, attentional performance into the basal forebrain on cortical ACh efflux were measured and associated cortical activity do not necessarily depend on using in vivo microdialysis. A test of the effects of BZR increases in arousal and associated activation of forebrain ligands was preferred over the use of direct GABAA receptor areas by brainstem ascending systems, particularly noradren- agonists or antagonists, as the former modulate the effects of ergic projections31,37,132 (see Section 3.4 for illustrations). endogenously released GABA. These studies revealed that Thus, “arousal” (as defined above) and attentional functions, basal ACh efflux in animals habituated well to the testing while they may interact in particular behavioral contexts, environment and to the experimental procedures, remaining represent distinct constructs. The present discussion is guided unaffected by infusions of BZR ligands. However, activated by hypotheses about dissociations and interactions between ACh efflux was blocked and augmented, respectively, by “arousal”, mediated in part via activation of the basal fore- BZR agonists and inverse agonists.178 “Activation” of ACh brain by brainstem ascending systems, and attentional func- efflux was produced by pre-training the animals to associate tions which depend on the regulation of basal forebrain sudden exposure to darkness in the test room with the presen- corticopetal neurons by their telencephalic afferents. Such tation of palatable food, yielding a reliable stimulus-induced hypotheses can be deduced from studies on the interactions increase in ACh efflux of 100–150% over baseline (see below between brainstem and telencephalic afferents of basal fore- for further analyses on the neuronal and cognitive mediation brain corticopetal projections. of the effects of this stimulus on cortical ACh). Collectively, these data indicated that basal forebrain GABAergic afferents 3. DISSOCIATIONS AND INTERACTIONS BETWEEN TELENCEPHALIC serve to dampen the excitability of basal forebrain cortico- AND BRAINSTEM PROJECTIONS TO BASAL FOREBRAIN NEURONS IN petal cholinergic neurons by other, excitatory, afferents. AROUSAL AND ATTENTION These studies did not provide information about the source As briefly summarized above, cortical cholinergic inputs of the GABAergic neurons mediating the effects of BZR mediate attentional functions, ranging from aspects of ligands on cortical ACh efflux. In addition to GABAergic sustained and selective attention to the regulation of process- interneurons in the basal forebrain and the possibility that GABAergic corticopetal neurons possess recurrent col- ing capacity or the allocation of processing resources (divided 76,241 attention). Important tenets of this hypothesis suggest that laterals, an extrinsic GABAergic projection arrives from the NAC.140,236 GABAergic inputs make direct contact changes in the activity of cortical cholinergic inputs are not 96 distinctly cortical area specific,87,99,159,179,228 and that the selec- with cholinergic neurons, and Ingham et al. suggested that tivity of the behavioral effects of cortical ACh is based on GABAergic contacts located more proximally on cholinergic close temporal interactions with converging sensory or asso- neurons serve to modulate, or even block, the effects of the ciational cortical inputs.215 We will discuss next the evidence more distal inputs from reaching the soma. It needs to be in support of the hypothesis that habitual or routine attentional stressed, however, that the origin of these inputs is not settled, performance, as assessed by an extensively practiced task, and may include local interneurons and projections from the depends on the integrity of basal forebrain cholinergic NAC and other sites. Basal forebrain GABAergic and cholinergic neurons may neurons and that, in this case, these neurons are regulated a b g exclusively by telencephalic afferents to mediate attentional possess different GABA subunit combinations, with 3 3 2 performance. Further below, interactions between brainstem subunits preferentially located on cholinergic neurons, while GABAergic cell bodies express a1b2g2 and a3b2g2 subunit afferents and telencephalic afferents to basal forebrain 64,82,86 neurons will be described as the main neuronal mechanisms combinations. The functional implications of such mediating the effects of novel, salient, emotional or stressful differential receptor subunit distributions are unclear, but stimuli (i.e. arousal) on cortical information processing. suggest the potential for differential effects of GABA on cholinergic and GABAergic target neurons.108 The GABAergic projections originating in the NAC may 3.1. GABAergic afferents originating from the nucleus contribute significantly to the regulation of the activity of accumbens: from motivation to attention to action basal forebrain corticopetal cholinergic neurons. Yang and Telencephalic projections, including afferents from the Mogenson233 provided evidence in support of the hypothesis extended amygdala, converge on basal forebrain neurons32,238 that dopamine (DA) receptor stimulation in the NAC dis- and modulate the excitability of basal forebrain corticopetal inhibits basal forebrain neurons via a suppression of neurons in the context of attention-demanding situations70,179 GABAergic output neurons.19,208 In keeping with this hypoth- (Fig. 1). Several studies have focused on the regulation of esis, infusions of DA receptor antagonists into the NAC cortical ACh efflux and associated attentional functions by increased ventral pallidal GABA extracellular levels.55 The GABAergic inputs to basal forebrain cholinergic neurons, hypothesis that NAC DA regulates the excitability of basal presumably originating in the nucleus accumbens forebrain cholinergic corticopetal neurons was tested in an (NAC).178,179,181,184 These studies were based on the facts experiment that assessed the effects of infusions of DA 936 M. Sarter and J. P. Bruno see text for 216 rebrain; BLA, basolateral amygdala; GLU, glutamate. sive anatomical knowledge of basal forebrain afferent and efferent own. Performance in tasks designed to assess sustained, selective or e hypothesized to be primarily regulated by afferent projections from ections because of the paucity of information concerning their afferent rge to regulate the excitability of corticopetal neurons, thereby mediating y mediate attentional performance (including divided attention; the detection, selection and processing of stimuli and associations which, consequently, dominate behavioral and cognitive activity. BF, basal fo definitions and dissociation from theregulation construct and of function. “arousal”). Other Thedivided parallel present attention discussion or depend largely direct ignores crucially feedbacktelencephalic basal on circuits regions. forebrain As the (such GABAergic discussed as integrity corticopetal in the proj of the cholinergic text, basal both projection forebrain glutamatergic to corticopetal stimulation the and cholinergic basolateral decreases neurons in amygdala) and, GABAergic are inhibition in also (i.e. these not disinhibition) situations, conve sh these neurons ar Fig. 1. Afferent regulationcircuits, of but basal rather illustrates forebrain schematically corticopetal the main cholinergic circuits neurons known or in hypothesized attention. to affect This the figure activity of does cortical not cholinergic intend inputs as to the represent the comprehen Cortical ACh in attention and dreaming 937 receptor antagonists into the NAC on cortical ACh efflux.142 attention costs observed following lesions of corticopetal While infusions of these antagonists did not affect basal corti- cholinergic projections.216 cal ACh efflux (which would be predicted from the results of Intra-nucleus basalis infusions of BZR inverse agonists the studies on the effects of intra-nucleus basalis administra- produced a selective increase in the false alarm rate (or a tion of BZR ligands; see above), infusions of the D2-like decrease of its inverse, the relative number of correct rejec- antagonists sulpiride and haloperidol blocked the increase in tions) in animals performing in a sustained attention task.94 cortical ACh efflux that was produced by a systemic admin- Such an increased frequency in the invalid detection of istration of the BZR partial inverse agonist FG 7142.143 Infu- signals has been predicted to result from disinhibition of sions of the DA antagonists into the cortex (through the probe corticopetal cholinergic neurons.177,181 These and other used to collect ACh) remained ineffective. While these data experiments on basal forebrain GABA–cholinergic inter- are consistent with the general hypothesis that the excitability actions, and their role in cognitive functions,145 support the of basal forebrain cholinergic neurons is modulated by NAC hypothesis that GABAergic afferents regulate the excitability D2 receptors via inhibition of the GABAergic output to the of corticopetal cholinergic neurons and thereby mediate atten- basal forebrain, more recent experiments from our labora- tional performance. tories have pointed to a greater complexity in the trans-synap- Conceptual considerations support the assumption that tic regulation of basal forebrain corticopetal cholinergic NAC GABAergic projections to the basal forebrain represent neurons by dopaminergic transmission in the NAC. These a major source of GABA modulating corticopetal cholinergic experiments attempted to determine the contribution of neurons in attention. The NAC is traditionally considered a NAC DA to the increases in cortical ACh produced by the major site where limbic and telencephalic projections systemic administration of amphetamine. Arnold et al.4 converge to mediate the translation from “motivation to demonstrated that infusions of amphetamine into the NAC, action” (as coined by Mogenson et al.139). Numerous studies while producing the expectedly high increases in NAC DA have refined this hypothesis and, importantly, extended it to release (also see Ref. 42), did not robustly increase cortical aversive motivation.172,175 However, for motivation to trans- ACh efflux. Moreover, unlike the case with FG 7142-stimu- late into action, the subject is required to detect and separate lated cortical ACh efflux (see above), intra-nucleus accum- behaviorally significant stimuli and contexts from less rele- bens administration of D2 receptor antagonists did not vant information and, more generally, to allocate processing attenuate systemic amphetamine-induced increases in cortical capacity to the evaluation of the behavioral situation and ACh efflux. Based on these findings, present experiments available response alternatives. In other words, Mogenson’s assess the possibility that the effective regulation of cortical apothegm requires extension to “from motivation to attention ACh efflux via NAC–basal forebrain links depends neces- to action”. Indeed, the NAC has been linked to the ability of sarily on interactions between telencephalic (glutamatergic) conditioned stimuli to gain control over attentional processes and mesencephalic (dopaminergic) afferents in the NAC, and and thereby determine response selection.13,17,170,173,191 The that such interactions are not modeled by the administration functional efficacy of such attentional functions depends on of amphetamine alone.26,147,219 NAC GABAergic projections to the basal forebrain, including Several studies have demonstrated that the GABAergic the GABAergic modulation of the excitability of corticopetal afferents to basal forebrain neurons are involved in the regu- cholinergic neurons. lation of the attentional abilities mediated via basal forebrain corticopetal cholinergic projections. Studies assessing the 154 3.2. Glutamatergic afferents: telencephalic stimulation of effects of infusions of direct GABAA receptor agonists are excluded from this discussion, as their effects may be basal forebrain corticopetal projections in attention due to anomalous levels of GABAA receptor stimulation Glutamatergic afferents of the basal forebrain arise primar- and, as discussed above, do not depend on GABA release ily from cortical and amygdaloid areas32,65,80,240 (Fig. 1). and thus may be difficult to interpret.47,48 Infusions of BZR Brainstem regions, including the pedunculopontine tegmental ligands into the basal forebrain impaired the performance of nucleus (PPT), may also send glutamatergic projections to the rats in tasks designed to assess different aspects of atten- basal forebrain.164 However, the projections from the PPT are tion.94,184 The specific pattern of these effects supported the less well documented,32,97 and the ability of intra-nucleus assumption that they were due to the modulation of excitabil- basalis infusions of the non-specific glutamate receptor ity of corticopetal cholinergic neurons. For example, infu- antagonist kynurenate to block the increases in cortical ACh sions of a BZR agonist selectively reduced the relative efflux produced by electrical stimulation of the PPT may be number of hits, but did not affect the relative number of due to polysynaptic, glutamate-mediated effects of PPT correct rejections in rats performing a sustained attention stimulation.164 task.94 Selective decreases in the relative number of hits has Receptors for both a-amino-3-hydroxy-5-methyl-4-isoxa- been demonstrated by other studies to correlate highly with zolepropionate (AMPA)/kainate and N-methyl-d-aspartate the extent of cortical cholinergic deafferentation, produced by (NMDA), the two major classes of ionotropic excitatory intra-nucleus basalis or intracortical infusions of 192 amino acid receptors, have been demonstrated within the immunoglobulin G–saporin.131,133 These data support the basal forebrain.124,152 The greater sensitivity (indicated by hypothesis that the effects of intra-nucleus basalis infusions cell death or induction of the immediate-early gene c-fos)of of BZR agonists on sustained attention performance were due basal forebrain cholinergic neurons to excitotoxins targeting to a drug-induced augmentation of the GABAergic inhibition AMPA/kainate as opposed to NMDA receptors has been of cholinergic corticopetal neurons. Likewise, the effects of interpreted as indicating a greater prevalence of the former intra-nucleus basalis infusions of a BZR agonist on cross- type of receptor on these neurons.153,222 modal divided attention performance184 closely correspond, Although telencephalic glutamatergic projections were quantitatively and qualitatively, with the increased divided suggested to directly contact basal forebrain cholinergic 938 M. Sarter and J. P. Bruno neurons,235 the precise localization of glutamate receptors in the sleep–wake cycle, or not involving novel or stressful the basal forebrain remains unsettled. Furthermore, the major- stimuli, telencephalic glutamatergic afferents represent the ity of studies that introduced glutamatergic agonists into this major excitatory input to basal forebrain cholinergic neurons. region did so solely for the excitotoxic consequences of such Evidence for the assumption that glutamatergic inputs to manipulations, and experiments investigating the modulatory basal forebrain neurons are a major source of basal forebrain role of glutamatergic inputs on corticopetal neurons are neuronal stimulation in attentional task-performing animals is scarce. A few studies have demonstrated that basal forebrain based on recent experiments assessing the attentional effects administration of glutamate excites cholinergic neurons in of intra-nucleus basalis infusions of the competitive NMDA this area113 and increases cortical high-affinity choline receptor antagonist 2-amino-5-phosphonopentanoic acid uptake,223 as well as cortical ACh efflux.112 Conversely, (AP5). Infusions of AP5 dose-dependently and selectively intra-nucleus basalis administration of the competitive decreased the relative number of hits in animals performing NMDA antagonist 3-(2-carboxy-piperazine-4-yl)propyl-1- a sustained attention task.217 Importantly, infusions of AP5 phosphonate was shown to decrease cortical ACh efflux in did not affect the performance of animals assessed in a simple anesthetized rats.69 visual discrimination task that did not explicitly tax atten- With the exception of rather recent studies from our labora- tional functions and was not associated with changes in corti- tory, the behavioral or cognitive significance of basal fore- cal ACh efflux.88 For reasons identical to those discussed in brain glutamate–ACh interactions has remained largely the context of the origin of the glutamatergic activation asso- unexplored.2,70 Fadel et al.54 demonstrated that increases in ciated with the darkness/palatable food stimulus (see above), cortical ACh efflux, which resulted from the presentation of a the effects of AP5 on attentional performance were attributed complex stimulus (sudden exposure to darkness pre-trained to to the blockade of telencephalic glutamatergic afferents of be associated with palatable food), were blocked by intra- basal forebrain cholinergic neurons. The interpretation of nucleus basalis infusions of the non-specific ionotropic gluta- the effects of AP5 in terms of specifically blocking the atten- mate receptor antagonist kynurenate. This effect of kynure- tional performance-associated excitability of basal forebrain nate was attributed to blockade of telencephalic, as opposed cholinergic neurons is again based on the similarity between to brainstem, glutamatergic afferents to the basal forebrain for the pattern of the attentional impairments produced by AP5 the following reasons. The available data do not suggest that and lesions of cortical cholinergic inputs.131 the projections of the PPT mediate motivational mechanisms or are crucial for the effects of conditioned appetitive stimuli.97 As will be discussed below, ascending projections 3.3. Telencephalic afferent regulation of basal forebrain from this area play a major role in sleep–wake cycles and corticopetal neurons in attention: what exactly do telen- arousal168 (as defined above), but they are unlikely to mediate cephalic afferents “tell” basal forebrain neurons? basal forebrain cholinergic neuronal excitation in response to While the available data remain sketchy, it is hypothesized presentations of an extensively conditioned incentive stimu- that, in situations taxing practiced, routine attentional perfor- lus, such as the one used in our experiments (also see Ref. mance, the afferent regulation of basal forebrain corticopetal 202). In contrast, glutamatergic afferents, originating from cholinergic neurons is largely restricted to converging areas which have been extensively documented to mediate GABAergic afferents from the NAC and glutamatergic affer- stimulus–reward associations, such as the amygdala51,186,187 ents from telencephalic areas (see Fig. 1). The view that and limbic cortical areas,11 probably mediated the increase glutamatergic and GABAergic afferents interact to “recruit” in cortical ACh associated with the presentation of the condi- corticopetal cholinergic neurons is further substantiated on tioned stimulus and the effects of kynurenate in the experi- the basis of the functional correlates of amygdala–NAC inter- ments of Fadel et al.54 actions, suggesting parallel circuits within the extended These experiments also demonstrated that infusions of amygdala that orchestrate the GABAergic fine-tuning of NMDA did not affect basal ACh efflux, but such infusions glutamatergic inputs to the basal forebrain. Specifically, the augmented the increase in cortical ACh efflux produced by basal and basolateral amygdala represents the main, though the darkness/palatable food stimulus.54 Similar to the inter- not exclusive, source of glutamatergic projections to the basal pretation of the effects of kynurenate above, it is hypothesized forebrain corticopetal neurons,32,238,242 as well as to the that telencephalic glutamatergic afferents contribute mostly to NAC57,62,130,158,231 (Fig. 1). The dorsomedial shell of the the voltage-dependent removal of the magnesium blockade of NAC, in which the GABAergic projections to the basal fore- NMDA receptors in the infusion area. To exclude possible brain originate,218 also receives input from the basolateral “arousal” components of this stimulus that may have been amygdala, yielding a closed parallel circuit via which the mediated by a noradrenergic stimulation of the basal fore- amygdala, in addition to its direct projections to the basal brain (see below), Fadel et al.54 also assessed the effects of forebrain, indirectly regulates the excitability of basal fore- co-infusions of the a1 antagonist prazosin into the basal fore- brain corticopetal projections (Fig. 1). A second, closed, brain. The data from this experiment demonstrated that parallel circuit involved in the regulation of the excitability neither the increases in cortical ACh as a result of the dark- of basal forebrain neurons via telencephalic afferents consists ness/palatable food stimulus nor the augmenting effects of of the medial prefrontal cortex (mPFC), with its strong 33,185 intra-nucleus basalis NMDA depend on basal forebrain a1 bidirectional connections with the basolateral amygdala, receptor stimulation. The repeated presentation of the dark- and direct projections to the shell of the NAC22,77,126 and to ness/palatable food stimulus is speculated to have gained basal forebrain corticopetal, mostly non-cholinergic, inhibi- sufficient incentive salience to elicit extensive attentional tory neurons.240 processing that is mediated via activation of corticopetal As has been discussed previously,179 the anatomical organ- cholinergic projections. Collectively, the data of Fadel et ization of neither the basal forebrain cholinergic perikarya nor al.54 support the hypothesis that, in situations unrelated to their cortical terminals suggests that this projection is Cortical ACh in attention and dreaming 939 sufficiently topographically organized to mediate a selective to mediate associations between motivational and emotional activation of specific cortical areas and layers. In other words, qualities and stimuli and associations.163,185,186 Moreover, the cholinergic corticopetal projections are not “pre-wired” Everitt et al.51 provided evidence in support of the hypothesis for the processing of selected stimuli (also see Ref. 169). As that the close interactions between the amygdala and the NAC discussed above, the effects of activation of this system on the mediate the ability of conditioned incentives to control beha- cortex are likely to be global, permitting an enhanced infor- vior. Thus, it may be speculated that direct stimulation of the mation processing via converging cortical inputs, mainly basal forebrain neurons by amygdaloid afferents mediates an from thalamic or other cortical areas. What type of informa- increase in the attentional processing of stimuli associated tion, therefore, may be processed or “carried” by the with distinct motivational or emotional qualities. The con- GABAergic and glutamatergic afferents to cholinergic basal verging, disinhibiting and thus additionally stimulating influ- forebrain neurons? ence from the NAC may mediate a further elevation of the Assuming that activation of NAC DA receptors inhibits the attentional processing of these stimuli, to the extent that they GABAergic output to the basal forebrain, at least under condi- gain motivational salience. tions which shift accumbens neurons into the “up state”,151 the Although these suggestions may appear highly speculative, functional correlate of the disinhibition of basal forebrain they correspond with the interpretation of results of an neurons via this pathway can be fairly precisely postulated. ingenious experiment by Everitt et al.50 In their study, lesions Recently, Berridge and Robinson17 integrated a vast literature of the basolateral amygdala did not affect instrumental and provided new evidence in support of the hypothesis that responses elicited by a primary reinforcer (an estrous female), NAC DA mediates hedonic and aversive processes. Specifi- but suppressed responding under a second-order schedule cally, they propose that activation of NAC DA mediates the maintained by a conditioned reinforcer (a previously neutral motivational salience attributions to the neural representa- stimulus that gained incentive salience by repeatedly being tions of stimuli associated with rewarding or aversive experi- associated with the female). Importantly, infusions of ences. In essence, this hypothesis describes attentional amphetamine into the NAC ameliorated the lesion-induced functions of NAC DA that convert “an event or stimulus decrease in conditioned reinforcer-maintained responding. from a neutral ‘cold’ representation (mere information) into This finding supports the speculations about the synergistic an attractive and ‘wanted’ incentive that can ‘grab attention’” interactions between the NAC and the amygdala in the (p. 31317). Likewise, stimuli repeatedly associated with aver- processing of motivationally salient stimuli (see above). sive events may gain “frighteningly salient” properties Collectively, these data demonstrate that the amygdala’s (p. 34817) and thus dominate the attentional processing. involvement in the ability of previously neutral stimuli to Stimuli or mental representations that gained motivational gain behavioral control (also see Refs 63, 84 and 174), salience increasingly control behavior, at least in part, presumably as a result of gaining motivational salience,17 because such stimuli are more extensively processed and depends on the route via the NAC, and thus the present their processing consumes substantial processing resources, model adds on the converging stimulation and disinhibition thereby limiting the processing of behavioral alternatives and of basal forebrain corticopetal projections. thus triggering compulsive responses.17,181 The functional contributions of direct and indirect connec- Increases in the excitability of basal forebrain corticopetal tions between the mPFC (Fig. 1), the basal forebrain, the NAC cholinergic neurons are likely to represent a crucial com- and the basolateral amygdala are less well understood, ponent of the NAC efferent circuits mediating such atten- although some data allow the speculation that cortical inputs tional processes. As discussed above, and summarized in to the NAC gate amygdaloid inputs,147,213 thereby possibly Fig. 1, increases in the dopaminergic modulation of NAC allowing cognitive variables to influence the NAC-mediated efferents to the basal forebrain may disinhibit basal forebrain incentive salience attribution to stimuli.25 cholinergic neurons and allow the excitatory afferents to more In summary, the afferent regulation of basal forebrain effectively stimulate these neurons, thereby mediating the cholinergic neurons as they mediate attentional performance prevalent processing of stimuli that gained motivational is largely restricted to inputs from telencephalic areas. Among salience. Our experiments on the attentional effects of intra- these afferent projections, the projections originating specifi- nucleus basalis infusions of BZR inverse agonists, which cally in the NAC and the basolateral amygdala are hypothe- augment activated cortical ACh efflux (see above), support sized to mediate, via their effects on cortical cholinergic the hypothesis that increases in the (re)activity of cortical inputs, the increases in detection, discrimination and process- cholinergic inputs mediate the enhanced or even over- ing of previously neutral stimuli that thereby gain motiva- processing of stimuli which, depending on the type of task tional salience and increasingly control behavior. and attentional processing requirements, may assist or even impair attentional performance.44,94,184 Thus, the description of the role of the NAC in a process from “motivation to 3.4. Arousal-induced attention and the role of basal forebrain attention to action” (see above) gains substance by integrating noradrenergic afferents for the functional activation of the basal forebrain as a main target of NAC efferents (also see telencephalic inputs to the basal forebrain Ref. 227). “Arousal” is defined in the present context as the activation Obviously, the dense interconnections between the areas of the forebrain in order to mediate the biased processing of afferent to the NAC, particularly the amygdala and the emotional, novel and/or stress-related information, and the prefrontal cortex, and their parallel excitatory projections to initiation of adaptive responses (see above). Cognitively, the basal forebrain (Fig. 1), suggest that the NAC efferent the early steps of arousal-induced attentional processes differ disinhibitory regulation of basal forebrain neurons converges fundamentally from the processing that underlies the more with glutamatergic inputs, particularly from the amygdala. habitual, well-practiced attentional performance assessed by Circuits involving the amygdala are traditionally considered standardized tasks. Arousal-induced attention is typically 940 M. Sarter and J. P. Bruno

Fig. 2. Afferent regulation of basal forebrain corticopetal cholinergic neurons mediating arousal-induced attentional processing. Novel, salient or “emotionally charged” stimuli activate ascending noradrenergic systems, possibly via afferents of the LC originating in the nucleus paragigantocellularis (PGi), a sympathoexcitatory structure.5,6 Noradrenergic stimulation of the basal forebrain cholinergic neurons may allow telencephalic glutamatergic inputs to the basal 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. initiated by a very salient external stimulus (novelty, threat), constructs (see Section 2). As will be discussed next, arousal- triggering “low-level” pre-attentional responses, including induced attentional processing is hypothesized to be mediated orientation responses, defensive reflexes and global via the ability of ascending noradrenergic projections to the search,16,155 that are followed by the more controlled, effortful basal forebrain to activate (or even “recruit”) the telence- attentional processes of stimulus detection, discrimination phalic afferent inputs to basal forebrain neurons (Fig. 2). and extended stimulus processing.56,162,190 It should be noted Obviously, this specific perspective ignores the functions of that sustained attention performance has often been suggested other telencephalic, particularly cortical, noradrenergic to rely on adequate levels of arousal; therefore, it should be projections which may directly contribute to the modulation reiterated that, based on the more refined definition of of cortical information processing. As will be discussed “arousal” to maintain its usefulness as a construct, sustained below, however, evidence supports the assumption that attention performance and arousal represent separate basal forebrain noradrenergic–cholinergic interactions Cortical ACh in attention and dreaming 941 represent a crucial link in arousal-induced attentional hypothetically, described as follows: sustained attentional processing. performance necessarily requires the integrity of basal fore- Noradrenergic projections to basal forebrain cholinergic brain corticopetal cholinergic projections, but not of their neurons originate in the LC and the A5 group in the ventro- noradrenergic afferents (or of the dorsal noradrenergic bundle lateral tegmentum.103,118 The cholinergic neurons of the basal in general). Optimization of the subjects’ attentional process- forebrain receive a particularly dense noradrenergic input and ing in response to urgent (e.g., aversive) stimuli is mediated the distal segments of their dendrites are repeatedly contacted via noradrenergic mechanisms that facilitate the ability of by noradrenergic fibers.200,235,237,239 Basal forebrain cholin- telencephalic afferent circuits to regulate the excitability of ergic neurons are predominantly depolarized via a1 receptors, basal forebrain corticopetal neurons (Fig. 2). driving cholinergic cells into a tonic mode of firing and The noradrenergic projections to the basal forebrain and increasing their rate of repetitive spike discharge.30,60 In to other telencephalic structures, including the shell of the addition to direct noradrenergic inputs to basal forebrain NAC and the central nucleus of the amygdala (CeA; cholinergic neurons, other evidence suggests polysynaptic Fig. 2)5,6,43,59,104,114 may collectively mediate such salient pathways, including the possibility that projections from the stimuli-induced attentional processing. The hypothesis that amygdala (see above) receive terminal input from ascending noradrenergic inputs to the basal forebrain are an essential noradrenergic systems.35 component of these functions of the ascending noradrenergic While the performance of rats in a sustained attention task system gains support from studies on the effects of infusions firmly depends on the integrity of basal forebrain corticopetal of noradrenergic drugs into the basal forebrain on cortical cholinergic neurons and on the GABAergic and glutamatergic ACh efflux,54 and from the recent suggestion that basal fore- innervation of these neurons from telencephalic areas (as brain noradrenergic–cholinergic interactions are particularly discussed above), lesions of the dorsal noradrenergic bundle, crucial in the processing of anxiogenic stimuli and contexts.16 which decreased forebrain noradrenaline contents by more The data of Fadel et al.54 allow the speculation that nor- than 90%, did not affect performance in this task.132 This adrenergic stimulation of basal forebrain neurons is sufficient finding closely corresponds with the lack of effects of similar to permit telencephalic glutamatergic afferents to stimulate lesions on the performance of rats in the five-choice serial basal forebrain neurons via NMDA receptors. Furthermore, reaction time task, even under conditions of decreased stimulus Fadel et al. demonstrated that, in animals in which cortical discriminability.31,37,111 However, Robbins and co-workers31 ACh efflux is already activated by the presentation of a condi- also demonstrated that brief bursts of white noise presented tioned stimulus for palatable food,53 or in which NMDA just prior to the presentation of the stimulus in the five-choice augmented the increase in cortical ACh efflux produced by 54 reaction time task resulted in a decreased response accuracy such a conditioned stimulus, infusion of the a1 antagonist and increased omissions in lesioned animals. These effects prazosin into the basal forebrain did not affect cortical ACh may be interpreted as reflecting the ascending noradrenergic efflux. These data suggest that, while noradrenergic stimula- system’s mediation of arousal-induced biasing of attentional tion of basal forebrain cholinergic neurons may facilitate the processing.171,176,193 Although the significance of conclusions ability of telencephalic inputs to stimulate the basal forebrain derived from studies on the effects of lesions of the noradren- corticopetal system, noradrenergic inputs do not further ergic system may generally be limited by the well-docu- modulate the excitability of this system once it is functionally mented plasticity in this system, even following extensive innervated by telencephalic inputs and via their postsynaptic deafferentation (see the discussion in Ref. 132), the arousal- NMDA receptors. In other words, these data may be specu- mediating functions of the ascending noradrenergic system lated to reflect the ability of noradrenergic inputs to initiate are supported by studies showing that novel, salient or aver- attentional processing, but they are not capable of further sive stimuli, capable of eliciting orienting and defensive influencing this processing once initiated. responses, evoke phasic discharges in LC activity.58,72,120 These speculations can be further substantiated by data Aston-Jones et al.5 hypothesized that the projections of the from experiments designed to determine the forebrain areas nucleus paragigantocellularis, a sympathoexcitatory nucleus, involved in the processing of anxiogenic stimuli and contexts, to the LC import information about the sympathetic activation and the role of sympathetic activation elicited by such stimuli produced by novel, “emotionally charged” or stress-like in the processing of anxiogenic information by forebrain stimuli to the LC (see their Fig. 11). The ascending projec- circuits. Berntson and co-workers15,16,81 demonstrated that tions of the LC mediate the biasing of forebrain information if anxiogenic situations are associated with demands on processing toward the processing of such stimuli and elaborate processing of stimuli or contexts (as opposed to contexts. This abbreviated discussion of their hypothesis the effects of unconditioned stimuli and classically condi- would predict that lesions of the noradrenergic bundle may tioned stimuli for aversive events), such stimuli elicit not affect habitual attentional performance (as assessed by specified increases in cardiac reactivity, reflecting sympa- using a well-practiced task such as our operant sustained thetic activation (as well as parasympathetic withdrawal). attention task132), as such performance does not involve suffi- Furthermore, this psychophysiological response, as well as ciently provocative stimuli (see above). In contrast, the the ability of animals to process contextual information in a performance effects of a stressor (bursts of white noise) conditioned suppression paradigm, depend on the integrity of observed in the experiments by Robbins and co-workers31 basal forebrain cholinergic neurons, specifically on the (see above) may be associated with the necessary sympathetic projections to the mPFC. These findings correspond with a activation to affect LC activity which, in lesioned animals, model outlined by Berntson et al.,16 which suggests that the reveals the consequences of a dysfunctional ascending nor- presentation of anxiogenic stimuli initiates the effective adrenergic system. evaluation of relevant contextual information, and that the Thus, the functional significance of basal forebrain initiation of this attentional processing depends both on noradrenergic–cholinergic interactions can be, at least sympathetic activation (indexed by increased cardiac 942 M. Sarter and J. P. Bruno reactivity) and on the integrity of basal forebrain corticopetal mystical animals or fairy tales, while in dreams it may be cholinergic function. As would be predicted from the work by followed by a lawn mower, and these two items are forged Aston-Jones et al. (see above), ascending noradrenergic into a chain of events in dreams. The resulting dissociated or projections are hypothesized to mediate the attentional effects incongruous contents of dreams are typically characterized as of an “emotionally charged” (e.g., anxiogenic) stimulus, and bizarre.3 Thus, dreaming cognition can be described to be the data of Berntson et al. demonstrate that this process hyperassociational, as unrelated fragments of information depends on the integrity of basal forebrain cholinergic projec- are fused into a bizarre scene. tions to the mPFC, thus conceptually linking ascending nor- Dreaming cognition can be described in terms of atten- adrenergic projections with basal forebrain cholinergic tional processing. Dreaming cognition is characterized by efferents to the cortex (Fig. 2). the random selection of representational stimuli (or associa- Basal forebrain noradrenergic–glutamatergic–cholinergic tions), the lack of discrimination between relevant (or interactions are not likely to represent an exclusive mechan- “bound”) features of such stimuli and the activation of ism mediating the effects of alerting stimuli on attentional unrelated information, and the immediate, extensive process- processes. For example, the failure of rats with lesions of ing of such information (as opposed to the normally effortful the CeA to acquire conditioned orienting responses may be steps through multiple attentional “bottlenecks” to assign attributed to the disruption of a circuit consisting of noradren- processing resources to a particular stimulus39,156). To ergic inputs to the CeA and their effects on projections to the continue with the illustrative example used above, the fact basal forebrain.36,93 This circuit may also be involved in the that the lawn mower follows the red dragon in the chain of mediation of the processing of anxiogenic stimuli discussed events does not result in the rejection or filtering of the lawn above (see the effects of CeA lesions on conditioned suppres- mover as an unlikely association, as would be the case in the sion demonstrated by Killcross et al.110). Likewise, noradren- awake state. Furthermore, in dreams, the processing of the ergic inputs to the NAC modulate NAC DA release114 and lawn mower next to the dragon will be as extensive as it thus may, via the NAC efferents to the basal forebrain would be in the wake state as a valid contextual association, discussed above, also disinhibit basal forebrain cholinergic such as elicited by thoughts about Saturday’s chores. In neurons, thereby mediating the initiation of attentional dreams, there is no division of attention that would allow processing by alerting stimuli.28,31 Furthermore, similar to the maintenance of parallel or competing streams of imagery, the effects of noradrenaline in the basal forebrain, noradren- and there is no capacity for prioritizing one content over the ergic inputs to the NAC may sufficiently stimulate these other. In contrast, all the available processing capacity neurons to open NMDA receptors, thus allowing telence- appears to be allocated to the single sequence of dissociated phalic glutamatergic inputs to the NAC to regulate NAC items and the construction of a scene into which those items efferent processing (see Fig. 2). Taken together, these are fused. If dreaming is disrupted and thus may be recalled, scenarios suggest multiple parallel pathways, all of which the perceived intensity of dreaming sequences which con- eventually converge on basal forebrain neurons, and all of textualize emotions, however bizarre they may be,83 particu- which allow noradrenergic ascending projections to stimulate larly well illustrates the “single mindedness” of dreaming and disinhibit the corticopetal projections of the basal fore- cognition.106 brain, thereby allowing the subject to engage in the evaluation Cognitive theory predicts two major consequences result- of novel or emotionally significant stimuli and contextual ing from such an exhaustion of processing capacity, both of information. which are highly characteristic of dreaming cognition. First, the suppression or filtering of irrelevant stimuli normally requires processing resources; conversely, the exhaustion of 4. “AUTOSTIMULATION” OF BASAL FOREBRAIN CORTICOPETAL CHOLINERGIC NEURONS BY BRAINSTEM ASCENDING CHOLINERGIC such resources diminishes the ability to prevent irrelevant 115,157,167 PROJECTIONS MEDIATES DREAMING stimuli from being selected and processed. As discussed above, this ability is completely absent in dreams; 4.1. Dreaming as hyperattentional processing thus, the sequential, incongruous selection of stimuli in Hobson90 described dreaming as characterized by visual dreams represents an expected consequence of the depletion imagery, inconstancy of place, time and person, a scenario- of processing resources. like knitting of disparate elements, and amnesia about dream- Second, as a result of the depletion of processing resources ing contents (recall of dreams is usually restricted to those and/or limitations in the allocation of resources to activities “rehearsed” when the subject awakes from REM sleep). other than the processing of a particular representational While the extent to which dreaming differs from waking stimulus, there is no processing capacity left to “network” cognition has remained a matter of debate,105 the amnesia, or integrate a particular stimulus with stored information, the predominant processing of internal data (as opposed to thereby preventing a later recall of this stimulus40 (similar sensory stimuli) and the hyperassociated processing of implications apply to Baddeley’s “central executive”;7 also unrelated information represent distinct cognitive character- see Ref. 162). (Once again, dreams that are seemingly istics of dreaming.106,117 Kahn et al.106 further conceptualized recalled are those immediately rehearsed once awakened the bizarreness of dreaming cognition as a result of “defective during REM sleep. This issue is beyond this discussion.) To binding over time”, i.e. the inability of the self-activated brain continue with our example, in the awake state, a picture of a to move from one stimulus to the processing of related stimuli red dragon may initiate the processing of related associations, or associations. This contrasts with the processing in the wake ranging from phonological features to mnemonic information state that is typically dominated by the multiple features of a (e.g., “curious that dragons are part of fairy tales as well as stimulus that are perceived in some temporally synchronized medieval epics”), and this associational processing represents way (and thus are “bound”). To illustrate the point, in the the basis for subsequent recall of having seen the picture. In awake state, a red dragon may spur associations about dreams, however, such associational networking does not take Cortical ACh in attention and dreaming 943 place, probably because of the lack of processing resources in cortical ACh release via projections terminating in the for this task, thereby limiting subsequent recall. Moreover, basal forebrain.164 To the extent that this effect may be attrib- the random and usually incoherent sequence of events in uted to stimulation of PPT cholinergic efferents to the basal dreams would require particularly extensive associational forebrain, it may be mediated indirectly via presynaptic processing to allow later recall of those contents (similar to, cholinergic stimulation of glutamatergic inputs to the basal for example, recalling the contents of an illogical movie). forebrain.164 While the exact distribution of cholinergic ter- However, in dreams, extremely limited residual processing minals in the basal forebrain remains unsettled and may resources allow little, if any, such integration of contents include direct contacts of cholinergic terminals with basal into mnemonic contexts. forebrain corticopetal cholinergic neurons,243 it seems more likely that the majority of cholinergic inputs does not synapse directly onto basal forebrain cholinergic neurons (also see 4.2. Increased cortical acetylcholine release and underlying Refs 195 and 236). The origin of the glutamatergic inputs afferent regulation in rapid eye movement sleep mediating these effects is unknown (but see above). It is not Similar to the increases in cortical ACh release associated clear, in this context, whether PPT glutamatergic/aspartat- with the arousing events or manipulations, REM sleep has ergic projections reach the area of basal forebrain cholinergic been documented to be associated with increases in cortical neurons.32 ACh release for almost 30 years.98,123 The available evidence Collectively, the available data provide the basis for the consistently suggests that the levels of cortical ACh efflux hypothesis that the increases in cortical ACh efflux during during REM sleep are similar to those during waking and REM sleep are due to increases in the cholinergic stimulation twice or more the levels observed during slow-wave sleep. of the basal forebrain which, possibly via a glutamatergic Correspondingly, high discharge rates of basal forebrain trans-synaptic mediator, activate basal forebrain corticopetal neurons during REM sleep have been reported.212 The impor- cholinergic neurons. An extension of this hypothesis suggests tance of cholinergic mechanisms for REM sleep has also been that the hyperattentional processing during REM sleep, i.e. suggested by results showing that the systemic administration dreaming, depends on such basal forebrain interactions, of physostigmine, a cholinesterase inhibitor, in sleeping possibly in interaction with the activation of the thalamic– humans induced REM sleep and dreaming, without altering cortical projection system via parallel and even collateralized mentation during non-REM sleep.14,61,199 cholinergic projections from the LDT/PPT to the thala- A substantial body of evidence indicates that muscarinic mus78,129,194,226,229 (see Fig. 3). The discussion below will receptor stimulation in the medial pontine reticular formation focus on this hypothesis and further detail the hyperatten- is sufficient and necessary for the induction of REM tional characteristics of dreaming cognition as mediated via sleep.8,66,68,89,92,101,196,220 The cholinergic cell bodies in the cortical interactions between activated cholinergic and thala- brainstem releasing ACh in the medial pontine reticular mic projections. It should be noted that the determination of formation and thereby mediating the production of REM neuronal circuits, including the basal forebrain, that may be sleep originate mainly from the PPT and laterodorsal teg- necessary and sufficient to initiate or maintain REM sleep or mental nucleus (LDT) region (Mesulam’s Ch5 and Ch6).75,137 to mediate somnogenic effects is not within the scope of this Cholinergic neurons in these areas increase their firing rates topic.12,107,161 substantially during REM sleep and, possibly via polysynap- tic reciprocal connections with the LC, depress LC neuronal activity during REM sleep.101,119,127 4.3. Cortical cholinergic hyperactivity and hyperattentional The ability of the tegmental cholinergic neurons to mediate processing cortical desynchronization has traditionally been assumed to depend on connections via the thalamus, specifically because As stated at the beginning of this article, the mediation of ACh release in the thalamus is highest during REM attentional functions (sustained, selective, divided) by cortical sleep.41,102,128,203,204,226 However, the PPT and LDT also ACh has been extensively characterized in recent years. project to the basal forebrain,79,103,189,195,200,229 suggesting While this literature has mostly focused on the effects of that the increased cortical ACh efflux during REM sleep is loss of cortical cholinergic inputs in different aspects of atten- due mainly to stimulation of basal forebrain corticopetal tion, and on intact cortical cholinergic input-mediated aspects cholinergic neurons by these ascending cholinergic projec- of attention,24,67,88 some evidence has supported the hypoth- tions. The basal forebrain area of humans shows notable eses that an increased (re)activity of cortical cholinergic increases in metabolic activity in REM sleep,20,149 and it is inputs mediates hyperattentional impairments (discussed hypothesized that this activity reflects cholinergic receptor above). It should be noted that significant increases in cortical stimulation-mediated excitation of corticopetal neurons.113 ACh efflux or cholinergic receptor stimulation (the latter as The cholinergic innervation of the basal forebrain by the produced, for example, by the application of a muscarinic or tegmental projections was supported by demonstrating, in nicotinic receptor agonist) cannot reflexively be assumed to animals, that lesions of the PPT resulted in a decreased benefit or facilitate cholinergically mediated functions; rather, cholinergic innervation of the basal forebrain.38 Moreover, increased tonic levels of cholinergic transmission are more increases in ACh release in the basal forebrain following likely to interfere with the normal, phasic ACh efflux and the systemic administration of scopolamine were not blocked associated receptor stimulation, and thus produce detrimental by excitotoxic lesions of the basal forebrain, suggesting that functional effects.182,232 The attentional effects of manipula- recurrent collaterals of corticopetal cholinergic neurons do tions known to stimulate cortical cholinergic inputs (above) not significantly contribute to the cholinergic, afferent regula- support the assumption that increases in cortical cholinergic tion of basal forebrain neurons.38 Finally, electrical stimula- transmission mediate the lowering of threshold for the selec- tion of the PPT appears to be sufficient to produce an increase tion of signals and the overprocessing of stimuli, and thus 944 M. Sarter and J. P. Bruno

Fig. 3. Schematic illustrations of the main ascending circuits hypothesized to mediate REM sleep-associated cognition, or dreaming. Note that this hypothesis does not necessarily address the neuronal mechanisms of REM sleep induction or termination that appear to include collateral projections from the LDT/PPT to the 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 hypothesized to depend on the activation of basal forebrain corticopetal cholinergic projections and therefore the increases in cortical ACh, and the intracortical interactions between the increased cholinergic receptor stimulation and the converging, stimulated inputs from the thalamus (TH). In REM sleep, both structures are activated via ascending cholinergic projections from the LDT/PPT. At least some tegmental cholinergic neurons may be collateralized and innervate both the thalamus and the basal forebrain. The exact interaction between tegmental cholinergic inputs and basal forebrain corticopetal cholinergic projections is unsettled, 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. support the proposed crucial role of cortical cholinergic of ACh on neuronal activity in sensory cortical areas. For hyperactivity in the generation of dreams. example, in the visual cortex, iontophoretically applied ACh Such hyperattentional consequences of increases in cortical generally enhances stimulus-driven neuronal activity which, ACh can also be extrapolated from studies on the effects importantly, is accompanied by a decrease in directional Cortical ACh in attention and dreaming 945 selectivity of visual cortical units.148,188 Similarly, in the may represent a major contributor to the hyperattentional auditory cortex, application of muscarinic agonists facili- characteristics of dreaming described above. A highly active tates the responses of neurons to frequencies which are thalamus in REM sleep may be speculated to contribute to the outside the band that optimally drives these neurons (“best mediation of impairments in stimulus selection and discrimi- frequency”).134 Likewise, stimulation of the cholinergic basal nation, i.e. the above-described impaired “binding” of dream- forebrain enhances the responses of neurons in the somato- ing cognition. sensory cortex to stimulation of the skin.221 Moreover, Bakin While, with respect to cortical activity, REM sleep and and Weinberger10 demonstrated that pairing auditory stimuli wakefulness appear to represent equivalent states,117 this with basal forebrain stimulation changed auditory cortical discussion stresses that the afferent regulation of the basal receptive fields so that they then become receptive for the forebrain and the thalamus differ fundamentally between frequency of the stimuli as the new “best frequency” (for the two stages. Attentional performance-associated activation analogous findings in the somatosensory cortex, see of cortical activity is based on the telencephalic regulation of Rasmusson and Dykes165). Importantly, cortical muscarinic the activity of basal forebrain corticopetal neurons (Fig. 1), receptor stimulation enhances the excitability of individual and their cortical interactions with modality- and cortical cortical units, but does not appear to enhance the processing area-specific thalamic inputs. In contrast, dreaming cognition via corticocortical connections within the auditory cortex.197 is largely based on the extensive stimulation of basal fore- Although some of these data may be interpreted as reflecting brain and thalamic corticopetal projections by ascending, adaptive consequences of cortical ACh on information primarily cholinergic, projections from the tegmenta (Fig. processing, particularly the receptive field changes following 3). This hypothesis does not exclude the possibility that paired basal forebrain and sensory stimulation, ACh stimula- dreaming cognition would be influenced by telencephalic tion-mediated decreases in direction selectivity of visual afferent regulation of the basal forebrain, as the strong cortical units, or the response of auditory neurons to stimuli emotional context of some dreams may be mediated via that were not previously “best frequencies”, indicate that amygdaloid influences.91,121,149,186,187 Moreover, such influ- sufficiently high levels of cortical ACh release may mediate ences may gain strength or become sensitized in certain an overprocessing of “noise” or of irrelevant stimuli. As tele- psychopathological disorders or following trauma to mediate ncephalic ACh efflux is highest during REM sleep, these data, dreaming cognition that is predominated by particular as well as the attentional effects of treatments which increase emotional concerns.83 cortical ACh efflux (above), support the hypothesis that the hyperattentional characteristics of dreaming cognition are primarily mediated via the increases in cortical ACh efflux. 4.5. Afferent regulation of basal forebrain and thalamic corticopetal neurons mediating dreaming cognition: implications for schizophrenia 4.4. Cortical interactions between activated basal forebrain The persisting idea that hallucinations in schizophrenia are and thalamic projections in rapid eye movement sleep due to intrusions of REM sleep into waking168 has not been As was discussed previously,179 basal forebrain cortico- convincingly substantiated. However, the present hypothesis petal cholinergic inputs are likely to be regulated in a about the hyperattentional characteristics of dreaming cortex-wide manner rather than showing changes in ACh mediated via cortical cholinergic hyperactivity relates to efflux that are area or modality specific.87 Accordingly, atten- psychopathological concepts that describe disinhibition of tional abilities were attributed to the ACh-mediated changes basal forebrain corticopetal cholinergic projections as a in the processing of information in the aggregate cortex. This neuronal mechanism contributing to the development and hypothesis is supported by evidence demonstrating that loss escalation of delusions and hallucinations.177,180,181 Thus, the of cholinergic inputs to an individual area, such as to the similarities between the regulation of cortical information mPFC,67 did not affect sustained attention performance, processing in REM sleep and schizophrenia may arise from while a generally modest yet more widespread loss of cortical the functional consequences of cortical cholinergic hyper- cholinergic inputs did.133 As cortical ACh gates information activity in either case. processing across the entire cortex,135,179 an important tenet of The degree to which the hyperattentional mechanisms and this hypothesis suggests that, at the level of individual cortical the associated depletion of processing capacity have been units, the selectivity of the amplifying effects of ACh is due to described as characteristic for psychotic and dreaming cogni- the selectivity of the thalamic afferents activated as a result of tion is intriguing. In both cases, the inability to filter irrelevant sensory stimulation (studies referenced above; also see Refs or unrelated information from being extensively processed, 138, 206 and 215). However, in REM sleep, such a selective, and the related inability to allocate processing resources for modality-specific activation of thalamic efferents appears to source and reality monitoring,100 characterize the attentional be replaced by a more global activation of the thalamus via processing.74,177,192 the ascending afferents from the tegmenta (see above; Fig. 3). As discussed above, the attentional functions of cortical It is noteworthy in this context that the reticular nucleus of the ACh have been extrapolated to mediate such hyperattentional thalamus receives cholinergic inputs from both the PPT and dysfunctions in situations in which cortical cholinergic the basal forebrain.78,116,230 The effects of ACh on reticular inputs are hyper(re)active. Increases in cortical ACh efflux thalamic activity have been suggested to disinhibit thalamo- obviously occur during REM sleep. Based on the evidence cortical projections.204,205 As both cholinergic inputs to the and related theories about the role of abnormally regulated, reticular thalamus can be assumed to be highly active during overactive mesolimbic dopaminergic projections in schizo- REM sleep (Fig. 3), the synergistic convergence of direct phrenia,21,71,73 and on the possibility that increases in meso- cholinergic stimulation of the thalamus and the reticular limbic DA disinhibit basal forebrain corticopetal cholinergic nucleus-mediated disinhibition of thalamocortical projections projections142 (see above), over(re)active cortical cholinergic 946 M. Sarter and J. P. Bruno inputs have been proposed to represent an integral component projections may preferably contact non-cholinergic cortico- of the neuronal circuit mediating psychotic cognition (for a petal neurons of the basal forebrain (see above). Likewise, discussion of evidence and further aspects of this hypothesis, information about the distribution of inputs within the basal including a discussion of the reasons why muscarinic receptor forebrain is desperately needed, particularly with respect to antagonists are not expected to benefit psychotic symptoms, inputs that have been largely ignored in the discussion above, see Ref. 181). This extremely brief summary of this hypoth- including the distribution of terminals of mesencephalic esis suggests that increased activity in cortical cholinergic dopaminergic inputs85,141 and of the brainstem inputs in inputs may represent a common final pathway contributing general. Although recent work has started to determine the to the mediation of dreaming and psychotic cognition. Impor- interactions between different inputs to the basal forebrain tantly, however, the increases in the activity in cortical cholin- with respect to the regulation of cortical ACh efflux (see ergic inputs in REM sleep and schizophrenia are hypothesized above), and while these experiments have generated useful to result from fundamentally different patterns of afferent experimental paradigms and defined conditions under which regulation of basal forebrain cholinergic corticopetal neurons such interactions can be meaningfully studied,24,183 our under- (PPT/LDT stimulated in REM sleep versus loss of GABA- standing of the fundamental interactions between the main ergic inhibition due to mesolimbic DA receptor overstimula- inputs remains limited. Our experiments have also demon- tion in schizophrenia). Although it is also intriguing that strated the importance of systematically varying the state of hallucinating patients show increased activity in the thalamus behavioral or cognitive activity in the analysis of such inter- in addition to telencephalic structures,198 and that some actions,23,24 suggesting that data from animals in one state30 schizophrenics show decreased REM latency and early- may not be generalizable to the role of an input or the inter- onset REM as well as a possible increase in the number of action between multiple inputs in the basal forebrain in cholinergic cells in the tegmenta,234 the available and largely another state of activity. This issue may be of particular circumstantial evidence remains insufficient to proclaim a importance with respect to inputs, such as dopaminergic relationship between psychotic cognition and potentially inputs, that are likely merely to modulate other afferents abnormal neuronal circuits mediating dreaming. However, rather than produce main effects on the excitability of basal the present hypothesis suggests that the similarities between forebrain corticopetal neurons. dreaming and psychotic cognition reflect a cortical hyper- Finally, cortical ACh release, when paired with sensory cholinergic component that may be involved in the attentional stimulation, has long-lasting effects on the sensory field prop- processing characteristic for both states. erties that have been interpreted in terms of neuronal plasti- city.18,49,109,215 Although the adaptive significance of changes 5. CONCLUSIONS in cortical sensory processing that depend on paired basal forebrain stimulation (or cortical application of ACh) and The present review extends previous attempts to reconcile sensory input stimulation remains a subject of debate, this the role of cortical ACh in different cognitive and behavioral possibility has yet to be integrated into the investigation of 210 states. Such a reconciliation does not readily arise from the role of cortical ACh in normal attentional processing, simply increasing or detailing the list of states to which corti- dreaming and models suggesting that abnormal excitability cal ACh contributes, but from an understanding of the funda- of cortical cholinergic afferents mediate the manifestation of mental cognitive processing mediated via cortical ACh, and psychiatric disorders.181 If endogenously released cortical from hypotheses about the role of such processes in different ACh indeed induces lasting modifications in cortical informa- behavioral or cognitive states. The crucial early steps of infor- tion processing, the impact of persistent aberrant regulation of mation processing, i.e. the detection, selection, discrimination cortical ACh release on the development of such disorders and processing of stimuli and associations, depend on the could be described in even more dramatic terms. Moreover, it integrity of cortical cholinergic inputs. These cortical cholin- would be important to clarify whether such changes also ergic inputs may be activated in different conditions as a occur during REM sleep, where corticopetal cholinergic and result of stimulation by dissociable afferent projections of thalamic projections are activated, and to suggest their func- the basal forebrain. Thus, while previous discussions stressed tional implications. Clearly, the incorporation of persistent the fundamental similarities between waking and REM sleep changes in cortical information processing as a result of 117 with respect to cortical activation, and while cortical ACh paired stimulation of cholinergic and sensory inputs into release appears activated in either state, the functions current theories about the cognitive functions of cortical mediated via cortical ACh can be dissociated on the basis ACh awaits more information, particularly with reference to of the different afferent regulation of the basal forebrain. the temporal dynamic properties of the effects of endo- As briefly mentioned above, the discussion and the models genously released ACh on cortical information processing. that are summarized schematically in Figs 1–3 remain pre- mature for several reasons. Most importantly, the lack of data Acknowledgements—Our research was supported by NIH Grants on the regulation and role of basal forebrain GABAergic NS32938, MH57436, NS37026 and AG10173. We are grateful to efferents renders any of these models incomplete, specifically Anne Marie Himmelheber and Janita Turchi for their comments on in conjunction with the possibility that tegmental ascending the final draft of this manuscript.

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(Accepted 27 September 1999)