Anxiogenic or fear-eliciting contexts are associatedwith robust autonomic responses in both humans andanimals, and the DSM-IV recognizes exaggerated vis-ceral reactivity as a common feature of anxiety disor-ders [3]1. The empirical research on the autonomic
features and correlates of anxiety and anxiety disordershas yielded mixed results, however, and the behavioralsignificance of autonomic accompaniments of fear andanxiety remain uncertain. These are important issues,not only because anxiety disorders represent a clear riskfactor for cardiovascular disease and sudden cardiacdeath [96,126], but because they bear on the fundamen-tal nature of anxiety and the underlying neural mecha-nisms that link behavioral processes and autonomic
1 There have been varied conceptualizations of the relations be-tween fear and anxiety, although fear is often considered a moredirect action disposition to explicit proximal stimuli (e.g. those pairedwith pain), whereas anxiety is characterized by a more generalizedreaction to a broader range of contextual stimuli or a more globalapprehension [9,53,170]. Of additional relevance to the present con-sideration is the relation between transient, experimentally inducedanxiety and chronic anxiety disorders. It would appear that patientswith chronic anxiety disorders are characterized by a more potentdisposition toward anxiety reactions than subjects merely experienc-
ing transient, situationally induced anxiety [9]. Although there may bedistinctions between transient and chronic anxiety states, and betweendifferent anxiety disorders, all serious neurobiological models ofanxiety recognize some commonality to substrates underlying thesedisparate manifestations [5,6,53,84,85,142]. This is supported by brainimaging studies in anxiety patients that reveal areas of cortical andsubcortical activation in structures and systems that have been impli-cated in laboratory models of transient fear and anxiety [55,204].Although a detailed neuropsychological model of the relative contri-butions of neural systems and functional processes underlying distinctaspects of anxiety disorders will be important ultimately, it is beyondthe scope of the present paper.
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functions. Some insight into the behavioral features andneural mechanisms of anxiety may be offered by theprototypic anxiolytic actions of the benzodiazepine re-ceptor (BZR) agonists, and the putative anxiogeniceffects of BZR inverse agonists. In the present paper,the literature on autonomic functions in anxiety disor-ders is briefly reviewed, along with the relevance ofthese findings for neurobehavioral models of anxietystates. From this starting point, this paper considers theresearch on BZR agonists and inverse agonists, and theimplications of these studies for the cognitive and neu-ral bases of anxiety. It is proposed that the basalforebrain cholinergic system may constitute an impor-tant component of the central mechanisms underlyingboth the cognitive and autonomic features of anxietystates. Specifically, it is suggested that this cholinergicsystem serves as a crucial link between cortical process-ing substrates, likely involved in the cognitive aspects ofanxiety, and subcortical systems involved in anxietyand autonomic regulation. Finally, the relationships ofthis basal forebrain cholinergic mechanism to neuralsystems that have previously been implicated in anxietyare discussed, and a more comprehensive neurobiologi-cal model that may serve as a conceptual frameworkfor future studies is proposed.
2. Autonomic regulation and its relation toneurobehavioral processes
The autonomic nervous system is often considered tobe a homeostatic regulatory system, serving to maintainvisceral function within adaptive limits. This view hadits historical origins in the early focus on peripheralanatomy, and in conceptions of the autonomic nervoussystem as an ‘involuntary’ or ‘vegetative’ system. Theearly works of Langley and Cannon recognized theimportance of the central components of the autonomicnervous system, but this control for the most part wasconsidered to comprise a set of interoceptive reflexes[36,37,140]. Cannon [37] viewed the autonomic system,including its central components, as a homeostatic sys-tem that responded to perturbations in the fluid matrix.
There is ample basis for such a view. Baroreceptorreflexes are prototypic homeostatic processes that exertpowerful regulatory control over the cardiovascularsystem. With an increase in blood pressure, for exam-ple, enhanced activity of baroreceptor afferents to thenucleus tractus solitarius (NTS) leads to reflexivechanges in autonomic outflows that oppose the pertur-bation [66,243]. Baroreceptor reflexes potently inhibitsympathetic outflow, and exert an excitatory drive onvagal motor neurons. In response to the pressor distur-bance, the reflexive decrease in sympathetic outflowyields vasodilation, a slowing of the heart, and a de-crease in myocardial contractility. The parallel increase
in vagal traffic further decreases heart rate and cardiacoutput. Collectively, these responses oppose the bloodpressure disturbance and promote the restoration ofbasal levels. In direct opposition to the baroreflex,however, psychological stressors can yield both an in-crease in blood pressure and heart rate. It is now clearthat stressors, even as mild as mental arithmetic, canlead to a reduction in the sensitivity and/or a shift in setpoint of the baroreceptor–heart rate reflex[56,141,245,246]2. Consistent with these perspectives,manipulations of limbic and forebrain areas implicatedin behavioral processes have been shown to be capableof facilitating or inhibiting basic brainstem autonomicreflexes, and potently modulating autonomic outflow[113,114,133,146,179,182,187,192]. The specific descend-ing projections and neurochemical mechanisms thatunderlie the links between rostral systems and brain-stem mechanisms for cardiovascular control are begin-ning to be clarified[25,26,39,48,109,179,196,231,237,265].
Of additional relevance for emerging neurobehav-ioral models of stress and anxiety is the fact thatrostral-caudal interactions are bidirectional. Ascendingprojections from brainstem autonomic substrates pro-ject directly to the amygdala and other forebrain anddiencephalic areas that have been implication in neu-robehavioral regulation, and have been shown to po-tently modulate the activity of these rostral brainsystems [5,178,237,279]. This paper will further considerthe interactions between rostral and caudal neural sys-tems that have been implicated in anxiety and auto-nomic regulation. First, however, a brief review is givenof the literature on autonomic function in anxietydisorders.
3. Anxiety and cardiovascular regulation
3.1. Historical literature
Early studies often reported that patients with anxi-ety disorders are characterized by higher autonomicarousal, as evidenced by basal heart rate, skin conduc-tance or other autonomic indices [128,137]. Anxiouspatients were also variously reported in early studies toshow exaggerated or prolonged responses to typicallaboratory stressors [151]; to evidence a slower rate of
2 The concepts of allostatic (allo meaning ‘other’) and allodynamicregulation represent expansions of the homeostatic model, in recogni-tion of the contribution of rostral neural systems in the broaderintegration and orchestration of behavioral, autonomic and neuroen-docrine reactions to adaptive challenge [15,163,247]. These reactionsmay entail direct modulations of central autonomic outflows, alter-ations of homeostatic setpoints and compensatory adjustmentsamong interacting systems that do not adhere to the simple homeo-static model.
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habituation of autonomic responses over trials[137,202]; and/or to be more likely to display defensive-like tachycardia, in contrast to a typical orienting-likebradycardia to innocuous stimuli [94]. In the aggregate,these and other findings led to suggestions that anxietydisorders are associated with: (a) a shift in ’autonomicbalance’ toward sympathetic dominance [271]; (b) anover reactivity of the sympathetic system [63]; or (c) ageneralized hyperattention to environmental stimuli[264].
Results of early studies, however, were not uniform.Baseline differences between anxious and control sub-jects were not always observed, at least on many auto-nomic measures [94,160]. In fact, autonomic responsesto laboratory stressors were sometimes reported to besmaller in anxious subjects [127,128,137]. Although thisattenuated autonomic reactivity of anxiety patients wasconsidered by some researchers to be a ceiling effectsecondary to higher baseline levels [127,151], otherstudies reported neither baseline differences nor grosslyexaggerated autonomic responses in anxiety disorders[94]. To some extent, these variable findings likelyreflected differences in the specific test stimuli andexperimental contexts, categories of anxiety disorderstested, as well as the specific measures employed. It isapparent, however, that early studies do not offer aclear and consistent picture of autonomic control, norpermit a simple characterization of potential autonomicdysfunction in anxiety disorders.
3.2. Contemporary findings
Within the past two decades, a substantial literaturehas accrued on autonomic function in anxiety. Al-though these studies have by no means simplified therelations between anxiety states and autonomic regula-tion, the recent literature does offer important clarifica-tions and insights. Recent studies provide a muchbroader sampling of autonomic function across a rangeof anxiety disorders and experimental contexts, and aremore cognizant of possible differences among cate-gories of anxiety disorders. The literature remains com-plex, but this is not surprising given the heterogeneityof the cognitive, affective, and physiological processesthat likely interact in anxiety states. Further, studiesfrequently employ different or only partially overlap-ping subsets of autonomic measures that do not alwayscovary. Moreover, conditions under which ‘baseline’autonomic measures are obtained can vary widelyacross studies and an important question arises as towhat constitutes an appropriate context to assess basalautonomic state. Experimental contexts, stimuli andchallenges also differ substantially across studies. Thisis an especially important issue because behavioral andautonomic responses can vary among categories ofanxiety disorder, and individual differences are appar-
ent even within a given category. Additional complexityarises as anxiety conditions often show considerablecomorbidity with other psychological disorders[129,148].
Some preliminary generalizations can be derivedfrom the existing literature, and may serve as a startingpoint for the further development of meaningful psy-chobiological models. First, anxiety disorders are fre-quently associated with altered autonomic function,although these alterations may vary considerably acrossnosological categories, and among individuals within agiven category. Second, autonomic reactions often mir-ror the pattern of exaggerated affective/behavioral re-sponse, rather than reflecting a primary abnormality inautonomic regulation. Third, enhanced autonomic reac-tivity is most often apparent in phasic responses tospecific stimuli or contexts, rather than in basalmeasures.
There continue to be reports of enhanced autonomicreactivity to experimental stimuli in patients with anxi-ety disorders, consistent with the view that anxiety maybe associated with exaggerated autonomic reactivity[102]. This is by no means a universal finding, however,as a number of studies have not observed enhancedautonomic responding, or in fact report reduced re-sponses in anxiety disorders [103–105,214]. In somecases, a reduction in autonomic reactivity may be re-lated to elevated baselines or to autonomic adaptationin chronic anxiety states. Either of these factors couldcontribute to a reduced magnitude of autonomic re-sponse, although exaggerated reactivity may still bereflected in retarded habituation [100,127,213].
The available data continue to reveal considerablediversity in the patterns of autonomic control in anxietydisorders. Two general trends have emerged, however,and offer some organization to the literature. First,among the clearest instances of exaggerated autonomicreactivity are in specific phobias, where anxiety is asso-ciated with a particular stimulus or context [170]. Incontrast, exaggerated reactivity is less apparent in moreglobal anxiety states such as generalized anxiety disor-der [102]. Secondly, behavioral and autonomic re-sponses are often highly concordant in specific phobias,but may be relatively uncorrelated in multi-phobics ormore global anxiety states, such as generalized anxietydisorder [170].
Specific phobias (simple phobias) are common disor-ders, with a lifetime incidence estimated to be greaterthan 10% [148]. Specific phobias are characterized byan exaggerated fear of a particular stimulus or context.These patients may not show a prevalent alteration inbasal autonomic measures [102,170,244], nor do theygenerally show a global increase in either behavioral orautonomic reactivity to experimental stimuli. Rather,enhanced autonomic reactivity is displayed primarily inthe presence of the specific feared stimulus or context
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[46,102,155,170]. McNeil et al. [170] report that spe-cific phobics show normal resting heart rates and typ-ical heart rate responses to non-phobic stimuli, but anexaggerated tachycardia to fear-relevant stimuli. Theseauthors further report a significant correlation be-tween subjective distress and the pattern of exagger-ated autonomic response to fear stimuli in ‘simple’phobias [46,170]. A further illustration of the poten-tial specificity of phobias comes from the demonstra-tion that phobic subjects show a selective dispositionto acquire a conditioned aversive autonomic responseto feared, but not to nonfeared objects [186].
Individual differences are apparent within the gen-eral category of specific phobias. Rather than a char-acteristic sympathetic-like tachycardia to the fearedstimulus, for example, blood-injury phobics oftenshow a transient tachycardia followed by a profoundvagal-like bradycardia and syncope [102,156]. In addi-tion, although subjective distress and autonomic re-sponses may be closely associated in specific phobias,this relationship may not hold for more general pho-bic anxiety conditions, such as social phobias or mul-tiple phobias [46,170]
The literature on posttraumatic stress disorder(PTSD) is somewhat more complex. Based on a re-view of the existing literature, Hoehn-Saric andMcLeod [102] conclude that PTSD patients may notbe generally over reactive, but rather show an exag-gerated autonomic reactivity to stimuli or contextsreminiscent of precipitating traumatic events. Likemany specific phobics, PTSD patients may display apattern of autonomic response roughly parallelingtheir pattern of behavioral/affective reactivity. Al-though these authors note that baseline autonomicmeasures are sometimes elevated in PTSD, they pointout the difficulty of achieving ‘true’ baseline levels aslaboratory contexts may themselves be anxiogenic.
The recent literature on PTSD is in general accordwith these perspectives. Baseline heart rate and otherautonomic measures are not invariably elevated, butexaggerated behavioral and autonomic reactivity totrauma-relevant stimuli are characteristic of this disor-der [78,164,234,235]. This enhanced reactivity appearsto be somewhat more generalized than for specificphobics, however, and may not be limited exclusivelyto trauma-relevant stimuli. Subjects with PTSD mayshow more generalized avoidance or withdrawal ten-dencies, and have been reported to display exagger-ated cardioacceleratory responses to nonsignalauditory stimuli [188,189,234], as well as enhancedbasal somatic startle and especially fear potentiatedstartle responses [176,177,188].
Panic disorder is characterized by powerful,episodic fear-like reactions, typically associated withexaggerated cardiovascular responses [8,9]. Panic hasbeen considered to parallel features of fear, including
a potent fight/flight action disposition, although panicreactions can be seen in the absence of an explicit cue[9]. Elevated basal autonomic measures such as heartrate are sometimes reported in laboratory studies onpanic patients, but ambulatory monitoring studies innatural settings generally have not reported baselinedifferences in autonomic functions in the absence ofanxiety episodes [102]. Although basal differencesmay exist on indirect measures such as plasmaepinephrine [262] and cerebrovascular control [65], thenotable autonomic features of panic disorders are as-sociated with phasic reactions. Striking increases inheart rate, disproportionate to associated activitychanges, have been reported generally during panicattacks [44,72,80,253]. However, spontaneous panicattacks occurring in the absence of an explicitlyevocative context have been reported in some cases tobe associated with minimal heart rate changes [154].
Earlier studies suggested that panic disorder pa-tients may evidence larger autonomic responses and/or slower habituation rates to a range ofenvironmental stimuli [102]. Exaggerated cardiovascu-lar responses and delayed habituation of the skinconductance response in panic disorder patients havebeen reported [106,213], although these findings arenot uniform [214]. Panic disorder patients may bemore likely to panic in laboratory testing contexts,but otherwise they may show relatively normal pat-terns of autonomic reactivity and habituation to labo-ratory stressors [4,105]. Moreover, patients with panicdisorders do not show a generalized increase in eitherthe somatic [88] or cardiovascular [215] componentsof startle. Rather, the primary autonomic characteris-tic of panic disorder is the exaggerated cardiovascularresponse associated with precipitated panic attacks.
A final category to be considered is general anxietydisorder (GAD), one of the more common anxietydisorders, characterized by chronic global anxiety[3,101]. Like panic disorder, GAD does not appear tobe associated with generalized elevations of basal au-tonomic activity [104,158,168]. A decrease inparasympathetic cardiac control, as indexed by res-piratory sinus arrhythmia, has been reported forGAD patients [254], although this is not a universalfinding [135]. Similarly, GAD patients generally havenot been reported to display enhanced reactivity totypical laboratory stressors, and may even showsmaller responses, although responses may be slowerto habituate [101,104]. This has lead to the constructof an autonomic restriction or inflexibility in GAD[104,254]. Exaggerated cardiovascular reactivity, how-ever, has been suggested to characterize a subgroupof GAD patients with cardiovascular complaints[105].
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3.3. Summary
The literature on autonomic functions in anxietydisorders is complex, but altered autonomic measures arefrequently reported in this class of disorders. Thesedifferences are generally more apparent in reactive re-sponses than in baseline measures, and often entail apattern of enhanced autonomic response. Although base-line differences in autonomic state have been reported,these findings are difficult to interpret given the inherentstress of laboratory contexts, and the enhanced auto-nomic reactivity observed in many anxiety disorders.Apparent basal differences may disappear with adapta-tion, and are often not observed during sleep or non-stressful contexts in ambulatory monitoring studies.Secondly, autonomic reactivity may vary between sub-jects and categories, and is often related to the broaderpattern of behavioral and affective reaction. The litera-ture on more global anxiety states, such as generalizedanxiety disorder, is more difficult to fit within a generalorganizing scheme. In fact in some anxiety states, dimin-ished reactivity or reduced autonomic variability may bemanifest [103,105,254]. While it is apparent that auto-nomic functions may be altered in anxiety states, therelations between anxiety and autonomic functions arenot simple. In the next section we consider some perspec-tives that offer an organizing framework.
4. Emerging views and organizing perspectives
4.1. Autonomic regulation and functional reactions
Behavioral manifestations can vary widely amongsubcategories of anxiety disorders, and even betweensubjects within a given category, and there may bemultiple central systems and processes that are differen-tially involved in varied anxiety states. Hence, it may beunrealistic to expect a uniform pattern of altered auto-nomic function or reactivity in anxiety states. Based onthe neuropsychological model of Gray [83], Fowles [71]has suggested that many inconsistencies in autonomicfunction associated with anxiety may be due to aninfelicitous conceptualization of autonomic reactivity.Rather than reflecting simple and rigid stimulus-responserelationships, autonomic responses may correspondmore closely to the pattern of functional reaction to astimulus. Moreover, the reaction to a given aversivestimulus may be dependent on the paradigm or testingcontext, and may entail either a general pattern ofbehavioral activation (e.g. escape/avoidance) or behav-ioral inhibition (e.g. freezing). According to Fowles, agiven stimulus or context will yield cardioacceleration tothe extent to which it activates the behavioral approachsystem of Gray (BAS), whereas diminished BAS activityassociated with activation of the behavioral inhibition
system (BIS) would be expected to result in cardiodecel-eration. Consistent with this suggestion, Martin andFitzgerald [157] report that restrained rats respond to ashock CS with freezing and bradycardia, whereas unre-strained rats display tachycardia. This may reflect funda-mental differences in the adaptive response of theorganism in distinct contexts. Although bradycardia maybe associated with behavioral inhibition, the observedheart rate changes in behavioral paradigms cannot beaccounted for on the basis of simple metabolic conse-quences of the response [69]. The heart rate response tolaboratory stressors typically exceeds that associatedwith metabolic demands [139,185,258], and typical con-ditioned and unconditioned cardiac responses can beseen in curarized animals [60] and paralyzed humans [14]in the absence of somatic activity.
Although further work is necessary to clarify therelations between psychological states and autonomicreactions, it is clear that autonomic responses are oftenmore closely associated with the pattern of functionalresponse than with the specific physical features of thestimulus. A novel stimulus that evokes a typical orient-ing-like bradycardia in a familiar environment, for exam-ple, may trigger no cardiac response in a novel contextwhere other stimuli compete for attention [216]. Thisdifferential pattern of response to the identical stimulusindicates that autonomic responses may correspondmore closely to the organism’s reactions to the stimulus,rather than the physical characteristics of the stimulus,per se. In this regard, specific phobics can show normalbasal autonomic states, and typical cardiac responseseven to negative or aversive stimuli. In accord with theirenhanced psychological reactions, however, exaggeratedautonomic responses are displayed to stimuli associatedwith the specific phobia of the subject [90,131].
4.2. Le6el of processing of anxiogenic stimuli
Aversive or anxiogenic stimuli can be processed atmultiple levels of the neuraxis, and these multiple pro-cessing substrates may have differential links with centralautonomic mechanisms. Pain stimuli can trigger sympa-thetic reflexes even at the level of the isolated spinal cord[220], and decerebrate organisms with only an intactbrainstem show characteristic evoked cardiovascularresponses to a wide range of sensory stimuli [212,257].These findings document inherent links between environ-mental stimuli and central autonomic mechanisms, orga-nized at the lowest levels of the neuraxis. Higher neuralstructures, such as the amygdala have been shown to bemore important for classically conditioned fear re-sponses, as amygdalar lesions can block the acquisitionand expression of conditioned autonomic responses to afear CS [125,142,217]. In fact, a direct pathway from thethalamic auditory relay nucleus (medial geniculate) to thelateral nucleus of the amygdala appears to be sufficient
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for the development of a conditioned fear response to asimple auditory stimulus, in the absence of higher corticalprocessing of the auditory signal [142]. Similarly, presen-tations of photographs of phobic objects followed by avisual masking stimulus can evoke characteristic auto-nomic reactions in phobic subjects, despite the fact thatsubjects are unable to describe or identify the phobicstimulus [186]. These findings indicate that anxiogenicstimuli can be evaluated by lower processing substrates,in the absence of cognitive mediation or even awareness.
On the other hand, cortical mechanisms appear to becritical for the processing of more complex stimuli andfor contextual fear conditioning [142,195]. Indeed, corti-cal/cognitive processing mechanisms appear to be capa-ble of inducing fear and anxiety even in the absence ofa relevant environmental fear stimulus. Mental imageryof aversive or anxiogenic contexts induces cortical activa-tion, especially in limbic, paralimbic and associatedcortical areas as evidenced by PET studies [136,205,206].Mental imagery can: (a) trigger autonomic responses[232,273]; (b) potentiate startle responses in a fashionsimilar to classically conditioned fear CSs [263]; and (c)trigger anxiety symptoms in patients with phobias orPTSD [170,205,206]. These findings attest to the potentialimportance of cognitive variables in anxiety states—vari-ables that are likely mediated by cortical systems.
In the aggregate, these findings document the multipleprocessing level for anxiogenic stimuli. They furtherdemonstrate that the multiple levels of evaluative process-ing may function in at least partial independence fromother levels. The existence of multiple processing sub-strates for anxiogenic stimuli introduces considerablecomplexity for conceptual models of autonomic functionin anxiety states, and likely underlies some of the apparentinconsistencies in the literature.
4.3. Complexities of autonomic control
An additional contribution to the complexity of theliterature on autonomic function in anxiety is the intricacyof central autonomic control. The historical view of thesympathetic branch as a globally organized, undifferen-tiated system is no longer tenable. Although a somewhatgeneralized activation of the sympathetic innervations ofdiverse organs may be apparent under some conditions,it is now clear that organ-specific patterns of activationare also possible [266]. Consequently, measures of sym-pathetic control of different organ systems may notalways be concordant. Laboratory stressors, for example,can selectively increase activity in forelimb muscle sym-pathetic nerves without altering activity in hindlimbinnervations [266]. Indeed, these findings raise seriousquestions as to the appropriateness of a global constructof autonomic ‘hyperactivity’.
Moreover, the traditional concept of a reciprocalcentral control of the two autonomic branches has
undergone considerable qualification in the light ofcontemporary findings, and it is now clear that the twoautonomic branches can vary reciprocally, coactively, orindependently [17,18,21,134]. Many basic reflexes such asbaroreceptor reflexes do exert powerful reciprocal controlover the autonomic branches, but descending influencescan inhibit or otherwise modulate baroreceptor reflexes[122,243]. These include peptidergic systems, such ashypothalamic neurons containing corticotropin releasinghormone or vasopressin that can alter the baroreflex setpoint or otherwise modulate autonomic outflow [53,93].In fact, hypothalamic stimulation can evoke all of thebasic modes of reciprocal, coactive, or independentchanges in the activity of the autonomic branches[130,133,197]. Descending influences from rostral neuralsystems are capable of generating highly flexible patternsof autonomic outflow.
The findings outlined above introduce considerablecomplexity in the quantification and interpretation ofautonomic control. Autonomic control cannot be viewedas lying along a single, reciprocal autonomic continuumextending from sympathetic dominance at one end toparasympathetic dominance at the other. Rather, auto-nomic control of dually innervated organs is moreappropriately represented by a bivariate autonomicplane, consisting of orthogonal sympathetic andparasympathetic axes. This is illustrated by the model ofthe autonomic plane and the overlying cardiac effectorsurface in Fig. 1, which depicts the chronotropic state ofthe heart for any given combination of sympathetic andparasympathetic activities.
The relative lengths of the sympathetic and parasym-pathetic axes are proportional to the overall dynamicranges of the two autonomic branches, and reflect theconsiderably greater dynamic range of the parasympa-thetic division (for development and review of thismodel see [18] for the human, and [21] for the rat). Theshape of the parasympathetic marginal function isbased on the almost universal finding that vagal nervefrequency is linearly related to cardiac chronotropicstate, when expressed in heart period, as documentedby neurophysiological recordings and direct nerve stim-ulation [20,21]3,4. In contrast, the sympathetic function
3 Linear functions in biological systems are uncommon. The quan-titative biophysical model of Dexter et al. [54], however, suggest thatthe essential linearity of the vagal effect on heart period is a resultantof two nonlinear processes. The first is a negatively acceleratingfunction relating vagal frequency to the quantity of acetylcholinereleased at the sinus node, and the second is a positively acceleratingfunction relating the concentration of acetylcholine in the synapticregion to the prolongation of the sinus rhythm.
4 There may be species- and even individual-differences in themaximal effects of vagal activity. Some studies suggest a plateau invagal effects, whereas others report a relative linearity to the point ofcardiac arrest.
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is somewhat less linear, with diminishing effects at higherfrequencies [20,21]. The effector surface of Fig. 1 depictsonly the simple additive effects of the autonomic branches,although potential interactions may occur betweenthe branches at higher levels of co-activation [145]5.
Because these interactions and the precise quantita-tive features of the effector surface do not appreci-ably alter the implications of the present model, they willnot be further considered here (for further discussion see[200]).
An important feature of the bivariate model of au-tonomic control is the fact that a given chronotropiclevel can be produced by varied combinations of sym-pathetic and parasympathetic activities. Hence, thechronotropic state of the heart is ambiguous with re-gard to its autonomic origins. This is illustrated bythe curved lines on the autonomic plane of Fig. 1.These lines represent isofunctional contours that de-pict the multiple combinations of sympathetic andparasympathetic activities that yield equivalent effectson the chronotropic state of the heart. This ambiguitycan cloud interpretations of basal chronotropic stateand reactive response.
As suggested above, descending influences from ros-tral systems appear particularly likely to yield nonre-ciprocal modes of autonomic outflow in behavioralcontexts. This is illustrated by a comparison of theautonomic response of human subjects to an ortho-static stress (assumption of an upright posture) com-pared with their response to typical psychologicalstressors such as mental arithmetic and a speeded re-action time task [16,30]. Quantitative estimates of thesympathetic and parasympathetic contributions tocardiac responses were derived from single and dualautonomic blockade studies [16,19,30]. At the grouplevel, the orthostatic and psychological stressorsyielded an essentially equivalent pattern of heart rateincrease, associated with sympathetic activation andparasympathetic withdrawal. For the orthostatic stres-sor, the cardiac response reflected a relatively tightreciprocal central control of the autonomic branches,as evidenced by the significant negative correlationbetween the responses of the autonomic branchesacross subjects (r= −0.71). Although the group re-sponse to psychological stressors was similar, therewere considerable individual differences in the patternof autonomic response, and there was no significantcorrelation between responses of the two branchesacross subjects (r=0.09). Although the individualmodes of response were highly reliable across differ-ent psychological stressors, subjects differed consider-ably in their pattern of response. Some subjectsshowed primarily sympathetic activation, some recip-rocal sympathetic activation and parasympatheticwithdrawal, and others, primarily parasympatheticwithdrawal.
Importantly, the distinct modes of autonomic controlmay not be apparent in simple measures of end organstate. Iwata and LeDoux [116], for example, observed
Fig. 1. Autonomic plane and overlying cardiac effector surface. Theeffector surface depicts the relative chronotropic state of the heart forall possible combinations of sympathetic and parasympathetic activi-ties. The length of the autonomic axes are proportional to the relativedynamic ranges of the autonomic branches, and beta is the intrinsicheart period level in the absence of autonomic influences. The dashedlines at the highest levels of vagal control represent the ambiguity inthe shape of the surface at the highest levels of vagal control. Thecurved lines on the autonomic plane depict isofunctional contours,along which varied combinations of sympathetic and parasympatheticactivities yield comparable heart period levels.
5 The chronotropic effects of sympathetic activation have beenreported to be enhanced by concurrent vagal activity, a phenomenontermed accentuated antagonism that is assumed to represent aninteraction among the autonomic innervations of the sinoatrial node[145]. The magnitude of this interaction, however, may be substan-tially overestimated by the common use of heart rate rather thanheart period in this literature [200]. Considerable species differenceshave been reported in autonomic interactions, and accentuated antag-onism has not yet been documented in human subjects. More re-cently, neuropeptide Y which is co-localized with norepinephrine inmany sympathetic terminals, has been found to be released with highfrequency activation and may produce a profound effect of vagalchronotropic control [267]. Consequently, there remains some ambi-guity in the precise form of the upper right corner of the effectorsurface of Fig. 1.
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Fig. 2. Autonomic response vectors to a conditioned stimulus, forconditioned and pseudoconditioned animals. Axes represent a seg-ment of the cardiac effector surface of Fig. 1, with the basal (prestim-ulus) position depicted at the 0,0 point on the axes. The arrowheadsrepresent the change in autonomic state at the peak of the response,depicted as milliseconds of heart period change derived from selectivepharmacological blockades of the autonomic branches. Data derivedfrom [116].
In the Iwata and LeDoux study, the similar (un-blocked) cardiac response in conditioned and pseudo-conditioned animals failed to reveal the autonomicdifferentiation associated with distinct behavioral pro-cesses. Measures of the cardiac chronotropic responsemay similarly fail to reveal lawful psychosomatic rela-tionships. There is now considerable literature suggest-ing that individual differences in cardiovascularreactivity to laboratory stressors may be associatedwith differential risk for cardiovascular and other dis-eases [161,258]. Cardioacceleratory responses to labora-tory stressors, however, can arise from distinctautonomic modes of control, as an increase in heartrate may result from sympathetic activation, parasym-pathetic withdrawal, or both. This differentiation isimportant, as endocrinological and immune functionshave been shown to be more closely related to thesympathetic component of the cardioacceleratory re-sponse than to the overall heart rate reactivity [29].These findings are in accord with the report that im-munologic consequences of acute cognitive stressorsmay be prevented by sympathetic blockade with b-adrenergic antagonists [13].
In summary, these findings suggest that the mode ofautonomic control may be more closely related tobehavioral states and processes than are simple mea-sures of end organ state. It is likely that many of theinconsistencies and ambiguities in the literature on anx-iety and cardiovascular regulation may be resolved bycloser attention to the underlying patterns of auto-nomic control. This applies not only to patterns ofreactive response of the autonomic branches, but topotential differences in basal autonomic state.
4.4. O6er6iew and implications
Anxiety disorders are diverse, and vary widely alongthe dimension of specificity generality, the nature andrange of the evocative contexts, and psychological orbehavioral manifestations. Hence, it should not be sur-prising that the literature fails to reveal simple, univer-sal relationships with autonomic function. At the sametime, many apparent inconsistencies in the literaturelikely relate to limitations of conceptual models, ratherthan the lack of lawful relationships between anxietystates and autonomic control. One possible strategy fordisentangling the complex interactions between psycho-logical and physiological processes in anxiety is throughthe use of pharmacological models.
In humans, benzodiazepine receptor (BZR) agonistseffectively reduce the symptoms of anxiety. Likewise, in
equivalent cardioacceleratory responses to a fear CS inboth conditioned and pseudoconditioned rats. Thismight lead to the erroneous conclusion that autonomiccardiac control is not sensitive to the learning history ofthe subjects. As illustrated in Fig. 2, the application ofselective pharmacological blockades of the sympatheticand parasympathetic innervations of the heart, how-ever, revealed that the similar cardioacceleratory re-sponses of the two groups of animals arose fromdistinct modes of autonomic control. Blockade analysesrevealed that the tachycardia of pseudoconditioned ani-mals arose largely from selective sympathetic activa-tion, as it was virtually eliminated by b-adrenergicblockade and unaffected by atropine. In contrast, thecardioacceleratory response of conditioned animals wasenhanced by vagal blockade, being significantly largerthan that of pseudoconditioned animals under identicalblockade conditions. This suggests that, in the un-blocked state, vagal responses opposed the larger sym-pathetic effects on the heart in the conditioned animals.Consistent with this interpretation, ß adrenergic block-ade not only eliminated the cardioacceleratory responsein this group, but unmasked a sizeable deceleratoryresponse of putative vagal origin. These findings sug-gest that the sympathetic response of conditioned ani-mals was appreciably larger than that ofpseudoconditioned animals, but that the cardiac mani-festations were dampened by a coactivation of theparasympathetic branch. Importantly, this differentialpattern of autonomic control was not apparent insimple measures of end-organ state.
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animals, BZR agonists potently attenuate the behav-ioral manifestations of fear and anxiety in a variety ofparadigms [75,183,218]. Despite almost 40 years ofclinical use and research on BZR agonists, however, thebehavioral/cognitive mechanisms mediating the anxi-olytic effects of these compounds have remained un-clear. The complexities inherent in attempts toconceptualize anxiety in behavioral or cognitive termsmay have contributed to the rather limited research onthe mechanisms underlying the attenuation of anxietyby BZR agonists [86,87]6. Gray’s neuropsychologicalmodel of anxiety explains the antianxiety effects ofdrugs by antagonizing the actions of a ‘behavioralinhibition system.’ This system normally responds tosignals of punishment, non reward, and novelty byinhibiting ongoing behavior and by increased arousaland attention to anxiety related stimuli [84]. It may bespeculated that, conversely, drug induced anxiogenesisresults from an augmentation of the actions of the‘behavioral inhibition system’ which would be charac-terized predominantly by hyperarousal and hyperatten-tional processing of fear and anxiety associated stimuli.As chronic anxiety is associated with an emerging biastoward the selection and processing of fear or threatassociated stimuli [11,159,169], drug-induced augmenta-tion of that processing may be a primary mechanismmediating drug-induced potentiation of fear and anxi-ety [184].
Cognitive theories of anxiety have consistentlystressed attentional dysfunctions as a major componentin the development and persistence of anxiety disorders.Eysenck [64] describes anxious groups as more likely toattend to threat-related stimuli and having more nar-rowly focused attention. According to this theory ofanxiety, antianxiety drugs are hypothesized to producetherapeutic effects largely via their attention-reducingproperties [47,132,167].
BZR agonists exert their anxiolytic actions by anallosteric interaction with the BZR–GABA receptor
complex, and the resulting enhancement of GABAergictransmission. In contrast, BZR inverse agonists andpartial inverse agonists attenuate GABAergic transmis-sion, and have effects that are generally opposite thoseof the BZR agonists. These agents, for example, havebeen shown to enhance the punishing effects of shock[59], to parallel the behavioral and analgesic effects ofinescapable shock [58,98], to enhance corticosteronelevels in a novel environment [193], and to increasefear-like behaviors and central catecholamine responsesof monkeys in threat contexts [124]. In accord with thepresent view, the anxiogenic effects of BZR inverseagonists may derive, at least in part, from their effectson cortical information processing. Specifically, theseanxiogenic agents may promote an over processing ofstimuli and contexts associated with fear and anxiety[107,229].
Clearly, such a theoretical perspective remains lim-ited and oversimplifies the role of cognitive variables inanxiety and drug-induced alterations of anxiety states.In particular, the long-term and dynamic effects ofbiased attentional processes for the mnemonic aspectsof anxiety rarely have been conceptualized. However,numerous studies [147] demonstrate that subjects suf-fering from phobia and panic attacks show a recall biasfor fear- and anxiety-associated information. Suchmemorial biases would be expected to further escalatethe preoccupation with and processing of fear- andanxiety-related stimuli. The hypothesis that attentionaland associated mnemonic biases contribute to the de-velopment and persistence of anxiety disorders providesa fruitful basis for experimental approaches to theneural and psychophysiological mechanisms of anxiety.
The available studies on the anxiogenic effects ofBZR inverse agonists, and the prototype anxiogenicpartial inverse agonist FG 7142, were not designed todetermine the specific behavioral or cognitive compo-nents of drug-induced anxiety. Consequently, they donot permit a critical evaluation of the hypothesis thatdrug-induced augmentation of the processing of fear-and anxiety-related information contributes to theemergence of anxiety-like symptoms.
The original report on the anxiogenic effects of FG7142 in healthy volunteers [57] was based on an opentrial. Moreover, as discussed by Thiebot et al. [256],self-reports about severe anxiety may have been biasedby uncontrolled experimental variables, as the volun-teers were instructed to expect symptoms of anxiety[256] (p. 453). In the study by Dorow et al., FG 7142produced marked peripheral effects (e.g. increases inblood pressure, pulse rate, and muscular tension) aswell as self-reports of anxiety. Nevertheless, the avail-able evidence from human and animal studies collec-tively supports the hypothesis that FG 7142 and otherBZR partial inverse agonists can induce or potentiateanxiety [76,77,219,256].
6 Behavioral drug effects are often ‘explained’ by their neurochemi-cal effects, e.g. the anxiolytic effects of BZR agonists are ‘explained’by their allosteric effects on GABAergic transmission. Such an at-tempt, of course, violates the doctrine that a behavioral effect firstrequires an explanation and reduction in the behavioral domain. Tocontinue with an example used by Frith [73], the idea that ‘‘alienthoughts are caused by inappropriate firing of dopamine neurons’’ (p.26) is unlikely to describe a productive isomorphism between the(mal)operations of neuronal circuits and function [221]. Neuropsy-chopharmacological theories of ‘antianxiety’ effects require reduction-ist explanations in behavioral or cognitive terms which arepresumably closer to the entities of information processing by neu-ronal networks of interest. In this context, it should also be notedthat, as neuronal systems process information rather than emotionalqualities, it is difficult to see the basis for a productive dissociationbetween cognition and emotion [190], although LeDoux takes a morepractical approach to maintain a dissociation between cognitive andemotional variables [142].
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6. Central cholinergic systems: lessons from FG 7142
As considered above, BZR inverse agonists havebeen reported to have potent anxiogenic actions. Anespecially important subclass of these compounds isrepresented by the BZR partial inverse agonists, whichdisplay a differential potency for the multiple actions ofthe inverse agonists. An example is the b-carboline FG7142, which has potent proconflict and anxiogenic ef-fects, but minimal convulsive actions when comparedwith full inverse agonists. Anxiogenic effects of FG aresuggested by the fact that it decreases open arm entriesin the elevated plus maze [45,211], enhances measuresof anxiety in social interaction tests [12,67,207], andmimics the effects of inescapable shock on social pro-cesses [238]. Moreover, the physiological state inducedby FG 7142 generalizes to novelty and shock conditionsin a drug discriminative paradigm [143]. In comparisonto other compounds assumed to produce anxiogeniceffects (e.g. sodium lactate or yohimbine), the behav-ioral effects of FG are relatively specific and do notreflect the rather global behavioral consequences of adrug-induced state of ‘stress’. Thiebot et al. [255] reportthat in an operant task, relatively small doses of FGenhance the behavioral suppressive effects of with-drawal of a ’safety signal’ (from shock), but do notaffect appetitively-motivated responding during safetyperiods. Lending further support for FG 7142 as apharmacological model for anxiety is the fact that theapparent anxiogenic effects of this agent can be blockedby anti-panic drugs such as clonidine, imipramine andadinazolam [68,123,193,194].
More recently, we have found that FG 7142 yields anotable potentiation of the cardioacceleratory responseto a moderately intense, nonsignal acoustic stimulus inrats. As illustrated in Fig. 3, this cardioacceleratoryresponse is mediated by sympathetic activation, andbased on the stimulus characteristics and response fea-tures, is consistent with a defensive response [82]. TheFG-induced potentiation of this cardioacceleratory re-sponse is in general accord with the enhanced cardio-vascular reactivity after FG, as reported for humans[57] and monkeys [180]. The exaggerated cardioacceler-atory response observed after FG is reminiscent of adefensive response, and is similar to the effects ofincreasing stimulus intensity or contextual aversive con-ditioning [199].
Among the more general effects of BZR agonists andinverse agonists is the bidirectional modulation of corti-cal information processing [225,229]. BZR agonists in-hibit, and inverse agonists enhance, basalforebrain-cortical cholinergic activity [174,175,222], andrecent findings suggest that the basal forebrain cholin-ergic system may mediate the FG-induced enhancementof the cardioacceleratory response. This is evidenced bythe following: (a) the FG-induced enhancement of the
cardioacceleratory responses is paralleled by intracere-broventricular administration of the cholinergic agonistcarbachol; (b) the effects of both FG and carbacholwere blocked by intracerebroventricular pretreatmentwith the cholinergic antagonist atropine; and (c) FG nolonger potentiated the cardiac response after selectiveimmunotoxic lesions (192 IgG-saporin) of basal fore-brain cholinergic neurons [22]. Although basal fore-brain cholinergic projections terminate in the amygdala,as well as the cortex, additional considerations impli-cate the cortical projections in the effects of FG on thecardiovascular defensive response. The neurotoxin 192IgG-saporin specifically targets the p75 low affinitynerve growth factor receptors that reside on corticallyprojecting basal forebrain neurons. The subset ofcholinergic neurons that project to the amygdala, how-ever, seems not to bear these receptors and hence islargely spared by the immunotoxic lesion [97]. Conse-quently, the lack of effect of FG on the cardiac defen-sive response, after the basal forebrain lesions, appearsto have resulted from the selective loss cortical choliner-gic projections.
The above findings implicate basal forebrain corticalcholinergic projections in the cardiovascular actions ofFG 7142, and suggest a hypothesis concerning thebehavioral origins of anxiogenic effects of this agent.Because the cortical cholinergic innervation appears toenhance or amplify ongoing cortical processing[172,223], alterations in cortical acetylcholine might beexpected to selectively impact on cognitive processes
Fig. 3. Autonomic response vector depicting the defensive-like car-dioacceleratory response to a moderate intensity, nonsignal stimulus.Axes represent a segment of the cardiac effector surface of Fig. 1,with the basal (prestimulus) position depicted at the 0,0 point on theaxes. The arrowhead represents the change in autonomic state at thepeak of the response, depicted as milliseconds of heart period changederived from selective pharmacological blockades of the autonomicbranches.
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that are heavily dependent on cortical substrates. Inthis regard, BZR agonists such as chlordiazepoxideimpede cognitive and attentional processing of a broadrange of stimuli [167,229], and their anxiolytic effectsmay well be due to the reduction in the exaggeratedcortical processing of anxiogenic stimuli [64]. In con-trast, BZR inverse agonists or partial inverse agonistssuch as FG 7142, can enhance cognitive and atten-tional processing [225,229], and their anxiogenic effectsmay be attributable in part to an exaggerated process-ing of fear or anxiety relevant stimuli.
FG, however, may not potentiate all features ofanxiety. Although FG consistently enhances the car-diac response to a nonsignal stimulus, it does notincrease and may even suppress the somatic and car-diovascular components of the startle response [23,24].Similarly, FG does not enhance fear-potentiated startle[95] a commonly reported feature of anxiety states.These findings support the view that anxiogenic stim-uli may be processed at multiple levels of neuraxialorganization, and suggest a potentially important di-mension of differentiation in the neural substrates ofanxiety. We hypothesize that the basal forebraincholinergic projection is primarily involved in aspectsof anxiety that arise from or depend on cortical pro-cessing of fear and anxiety-associated stimuli and asso-ciations.
This hypothesis offers an explanation for the differ-ential effects of FG on startle and defensive responses.The basic startle circuit is largely organized at thelevel of the brainstem, and is not dependent on corti-cal or other forebrain systems [51]. Hence, startle re-sponses might not be expected to be potentiated byBZR agents that enhance cortical cholinergic activity.In contrast, defensive-like responses to a novelnonsignal stimulus likely arise from an active cogni-tive/affective evaluation of the stimulus, that would beexpected to be highly dependent on cortical processingsubstrates. This may be the basis for the selectiveeffect of FG on the defensive response.
Although the basic startle circuit is organized at abrainstem level, the amygdala contributes importantlyto conditioned fear and to fear-potentiated startle[34,50,52,125,142,159], and this structure also receivescholinergic projections from the basal forebrain. Inthis regard, FG not only fails to potentiate basalstartle responses, but also does not enhance fear-po-tentiated startle [95]. Again, the primary locus of FG-induced anxiogenesis may be within cortical processingsubstrates, as the cortical cholinergic projections of thebasal forebrain specifically are implicated in the FG-induced potentiation of the cardiovascular defensiveresponse. Although the amygdala may be criticallyinvolved in fear-potentiated startle, cortical systemsmay not be pivotal, at least for fear-potentiated startlebased on a simple conditioned fear CS. In keeping
with this view, although lesions of the nucleus basalismay impair acquisition of conditioned heart rate re-sponses to an aversive stimulus, perhaps by an atten-tional mechanism, they do not block the expression ofconditioned fear responses [79].
In the aggregate, studies outlined above suggest aspecial role for basal forebrain cortical cholinergicprojections in the anxiogenic effects of the BZR par-tial inverse agonist FG 7142. These findings raise apotentially important distinction between features offear and anxiety that derive from cortical processingand those that may be mediated largely by subcorticalstructures. This differentiation is not likely to be abso-lute, but is offered as a conceptual heuristic that mayserve to organize empirical findings and guide subse-quent theoretical developments.
7. Cardiovascular reactivity and cortical acetylcholine:anatomy and function
The discussion above provides the basis for the for-mulation of several hypotheses. (1) Cognitive evalua-tion of fear- and anxiety-associated stimuli andcontexts represent an important component in theemergence of anxiety. (2) There is a relationship be-tween the manifestation of enhanced autonomic, spe-cifically cardiovascular reactivity and the degree towhich anxiety-related stimuli or contexts are cogni-tively evaluated. The intensity of the actual affectivestate or the amplitude of the behavioral response con-sidered to reflect such a state is less clearly related toautonomic reactivity changes. (3) The cognitive evalu-ation of anxiety-related stimuli and contexts dependson the integrity of the basal forebrain cholinergic sys-tem, and cardiovascular reactivity changes indirectlymodulate basal forebrain cholinergic neuronal ex-citability and thus the processing of fear- and anxiety-associated information.
Cardiovascular–basal forebrain interactions will beconceptualized in terms of the ascending and descend-ing components of these interactions. Specifically, theascending modulation of basal forebrain cholinergicactivity by cardiovascular reactivity changes is hypoth-esized to enhance the evaluative processing of anxiety-related stimuli and contexts. Conversely, thedescending system mediates the expression of anxietyand, in addition, initiates autonomic responses. Thetraditional neuronal circuits implicated in fear andanxiety, specifically, the amygdala and its descendingprojections to brainstem nuclei, represent an integralpart of the descending limb of this model. Finally,several predictions based on this model will be dis-cussed in terms of available evidence and experimentalapproaches.
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Fig. 4. Decending branch of the anatomical model of neuronalsubstrates by which cortical/cognitive processes may contribute to thedevelopment and expression of anxiety and its autonomic features.The model is not intended to present an anatomically completedescription of relevant circuits and transmitters; rather it is conceptu-ally driven and focuses on hypotheses derived in part from experi-mental evidence (see text, and [22]). Abbreviations: ACh,acetylcholine; AMB, nucleus ambiguus; BLA, basolateral amygdala;CeA, central nucleus of the amygdala; DMX, dorsal motor nucleus ofthe vagus; IML, sympathetic preganglionic neurons of the intermedi-olateral cell column; NE, norepinephrine; NTS, nucleus tractus soli-tarius; PGi, nucleus paragigantocellularis; RVL, rostral ventrolateralmedullary ‘pressor’ area [89,108,243].
ries of anxiety [52,142]. The available evidence supportsthe role of telencephalic, including cortical mechanismsin the expression of anxiety and the regulation ofcardiovascular reactivity and provides the basis for adetailed description of the functional significance ofdescending branch of the present model (Fig. 4).
Stimulation of the amygdala has been known forover half a century to elicit fear- and anxiety-like statesand sympatho-excitatory effects [50,52,248]. The attri-bution of emotional, particularly anxiety- and fear-as-sociated qualities to sensory stimuli has beentraditionally assigned to amygdaloid circuits [227,228].Furthermore, the sympathetic and behavioral effects ofconditioned stimuli for anxiety and fear are blocked bycentral amygdala lesions, suggesting a crucial role forthis component of telencephalic/limbic circuits in themediation of fear and anxiety [142,146,192,275].
Several models emphasize additional projections ofthe amygdala to the lateral and paraventricular hypo-thalamus as well as to the midbrain central gray ascritical for the mediation of particular aspects of defen-sive responses and autonomic regulation[2,52,81,142,227,236,241,242]. For example, stress-re-lated increases in plasma corticosterone can be blockedby lesions of the stria terminalis which links the amyg-dala with the paraventricular nucleus of the hypothala-mus [50]. Although the exact contribution of direct andindirect amygdalofugal projections in the acquisitionand expression of anxiety and fear and sympatho-exci-tation is unclear, the direct descending projection (Fig.4) of the central amygdala to the NTS represents asufficient pathway for the regulation of autonomic stateby telencephalic structures [99,115,146,162,196,217,220,231,280]. The NTS also receives direct inputfrom the medial prefrontal cortex [260], an area thathas been implicated in anxiety and affective processes[119,138], as well as cardiovascular regulation [39,261].Stimulation of the medial prefrontal and other corticalareas potently alters heart rate and blood pressure[39,91,92,187], and lesion studies revealed the involve-ment of the medial prefrontal cortex in the acquisitionof autonomic adjustments [74,179,198]. Thus, the pre-frontal cortex can execute direct and indirect (via theamygdala) control of behavior-associated autonomic,particularly cardiovascular reactivity (Fig. 4). Othercortical areas, such as the insular cortex, may also beinvolved in anxiety and cardiovascular control[39,204,261]. The role of the septohippocampal systemin anxiety and contextual fear conditioning has beenrecognized widely, and the hippocampus in turnprojects to structures such as the amygdala, hypothala-mus and bed nucleus of the stria terminalis that canmodulate autonomic functions [38,53,85,152,169,195].The model presented in Fig. 4 is intended to be illustra-tive rather than exhaustive.
7.1. The expression of anxiety and modulation ofcardio6ascular reacti6ity by cortical ACh
The descending branch of the present model system(Fig. 4) describes primary components of the networkmediating the expression of anxiety, and associatedautonomic reactions. These autonomic responses, inturn, may modulate the processing of anxiety- andfear-associated stimuli, via ascending influences dis-cussed below (see Section 7.2). Existing neural modelsof anxiety represent essential components of this de-scending system. These traditional models have focusedgenerally on the descending connections of the amyg-dala and have rarely attempted to integrate the role ofcognitive processes in psychological and neuronal theo-
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Collectively, a substantial amount of evidence sup-ports the long-standing hypotheses about the role of theamygdala in the emotional coloring of sensory stimuliin general and in the acquisition and expression ofanxiety in particular [1,227,228]. Major cortical inputsto the amygdala can supply the sensory stimuli andassociations which may then gain emotional signifi-cance via processing within amygdalo–telencephaliccircuits [34,40,153,227,228]. The efficiency of processingof such stimuli and associations through telencephalic/amygdaloid circuits would be expected to depend, inpart, on cortical ACh (Fig. 5; see also Section 6; for adetailed discussion of the cognitive functions of corticalACh, see [223]). In this fashion, basal forebrain corti-cal-cholinergic activity would modulate the descendingcircuit (Fig. 4) implicated in the acquisition and expres-sion of fear and anxiety. Moreover, this cortical cholin-ergic activity would contribute directly and indirectly tothe regulation of autonomic reactivity via cortical effer-ents to the amygdala, the NTS, and directly to lowerautonomic motor nuclei [25,26,39,109]. It is in thiscontext that we have interpreted the effects of basalforebrain cholinergic lesions on the cardiovascular ef-fects of the anxiogenic FG 7142 [22,23,79].
7.2. Modulation of basal forebrain cholinergic neuronalexcitability by cardio6ascular responses
Basal forebrain cholinergic neurons that are situatedin the substantia innominata and the nucleus basalisMeynert in the basal forebrain innervates all corticalareas and layers, suggesting a uniform modulatoryfunction of acetylcholine on cortical information pro-cessing [223]. Several lines of evidence, including in vivomeasures of cortical ACh release in task-performinganimals [225] and investigations of the cognitive effectsof lesions of this system [166], collectively suggested acrucial role of cortical ACh in the detection and selec-tion of relevant stimuli and in the capacity to subjectsuch stimuli to extended processing, i.e. in attentionalfunctions [223].
The cholinergic neurons in the basal forebrain receiveseveral afferent projections which modulate the activityof the cortical cholinergic projection [222]. A majorafferent projection to basal forebrain neurons origi-nates in the locus coeruleus and employs noradrenalineas a transmitter [121]. The direct innervation of basalforebrain cholinergic neurons by ascending noradrener-gic projections has been extensively described [41,275–278]. In contrast, functional data on basal forebraincatecholaminergic–cholinergic interactions are ratherrare (for indirect evidence see [10,210,252]). However,noradrenaline (NA) depolarizes cholinergic cells in thebasal forebrain via a1 receptors [70] and thus would beexpected to increase cortical ACh release. The exacteffects of NA at basal forebrain cholinergic neuronsmay be more complex, however, as they are modulatedby other inputs to the basal forebrain cholinergic neu-rons, particularly the inhibitory GABAergic projectionfrom the nucleus accumbens [222] and the excitatoryafferents from several telencephalic areas. In essence,however, increases in activity in the LC ascending NAprojection are expected to increase the excitability ofcortical cholinergic inputs.
The LC also projects directly to the cortex [191]. Thepresent model, however, centers around our experimen-tal data on the basal forebrain cholinergic system, andhence emphasizes the LC innervation of basal forebraincholinergic neurons. The regulation of cortical ACh bybasal forebrain noradrenergic afferents represents animportant route by which ascending noradrenergic pro-jections could mediate potential feedback effects ofcardiovascular reactivity in the modulation of corticalprocessing and ultimately, anxiety.
The electrophysiological experiments of Aston-Jonesand co-workers cumulated in the hypothesis that LCascending projections mediate emotional activation [5].These and other researchers observed that LC neuronalactivity robustly increases in response to the presenta-
Fig. 5. Ascending branch of the anatomical model of neuronalsubstrates by which cortical/cognitive processes may contribute to thedevelopment and expression of anxiety and its autonomic features.Ascending pathways illustrate the potential routes by which sympa-thetic activity and visceral afference may modulate rostral systems.Abbreviations: BF, basal forebrain cortical cholinergic system; BLA,basolateral amygdala; LC, locus coeruleus; NTS, nucleus tractussolitarius; PGi, nucleus paragigantocellularis; RVL, rostral ventrolat-eral medullary ‘pressor’ area [89,108,243].
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tion of stress-, fear- and anxiety-inducing stimuli, butalso to stimuli that are associated with rewardingevents, suggesting that emotionally significant stimuliactivate the LC ascending system regardless of theaffective valence (see also [203]). Aston-Jones furtherstressed that the generality of the LC response to allclasses of emotional stimuli indicates that the quality ofthe emotion is not encoded into LC activation. Rather,LC activation represents a state-setting mechanismwhich facilitates the processing of more specific con-texts and stimuli of discrete emotional quality by morerostral structures efferent to the noradrenergic bundle.The basal forebrain cholinergic system represents amajor component mediating the processing of suchcontexts and stimuli, and the amygdala may representan important switch for determination of the valence ofthe affective response.
The ability of emotional stimuli to activate the nora-drenergic ascending system appears to be a direct func-tion of the state of the sympathetic branch of theautonomic nervous system [208,239]. For example,sympathetic activation induced by nitroprusside-hy-potension was found to be associated with increases inLC firing, and this effect was shown to be mediated viavisceral afferents from the cardiac atrial volume recep-tors [62].
The anatomical basis that allows the LC to monitorsympatho-excitatory events is straightforward. One ma-jor afferent connection to the LC originates from thenucleus paragigantocellularis (PGi) in the medulla, andinvolves several transmitters, including excitatoryamino acids, adrenaline and enkephalin [6]. The PGi, inturn, receives information from a variety of sources inthe brain stem and spinal cord, including the NTS,which collectively suggests that the PGi projections tothe LC transmit information reflecting autonomic activ-ity and visceral afference. The PGi is partially coexten-sive with the rostral ventrolateral medullary pressorarea, a region that directly innervates sympathetic mo-tor neurons of the intermediolateral cell column of thecord [89,108]. These findings suggest that PGi neuronsactivate in parallel the LC and sympathetic motorneurons, and thus modulate the autonomic and cogni-tive (via the LC) aspects of emotional activation [7,239].In addition, the medial prefrontal cortex exerts a potentexcitatory influence on the LC [120], which couldprovide for top-down activation of this system. Whileour model suggests that the autonomic modulation ofbasal forebrain cholinergic neuronal activity is medi-ated via the noradrenergic LC projections to the basalforebrain, it should be noted that evidence for a directinnervation of the basal forebrain by adrenergic ornoradrenergic neurons of the NTS suggests an evenmore direct influence of autonomic states on corticalinformation processing [233].
The anatomy-driven model shown in Fig. 5 attributesthe evaluative processing of anxiety-related stimuli toan ascending system which also serves to integrate themodulatory effects of autonomic state [6,7]. Severalissues require further clarification. An obvious, thoughfrequently neglected, question arises concerning thecausal sequence of events in emotional activation.Clearly, ascending modulation of cognitive processingby autonomic reactions requires an initiation (via de-scending projections) of such reactivity changes (seediscussion below and [31]). The reciprocal telencephalicconnections of the basolateral amygdala are essential inmediating the classification and processing of stimuliassociated with anxiety or fear and are therefore inte-gral parts of both the ascending (anxiety modulating)and descending (anxiety expressing) components of thepresent model (Figs. 4 and 5) [226]. In addition, neu-ronal circuits which include the connections betweenthe amygdala and the hippocampal formation (subicu-lum; not shown in Fig. 5) have been speculated tomediate the evaluation of anxiety contexts and thecognitive biases which characterize pathological statesof anxiety [142,195]. Thus several limbic circuits whichare organized in parallel with the ascending networkillustrated in Fig. 5 are essential for the cognitiveprocessing of anxiety-associated stimuli and associa-tions. Importantly, however, this model hypothesizesthat the ascending recruitment of these limbic circuits,primarily via noradrenergic-cholinergic activation,serves to prime these rostral substrates for processing ofthe cognitive aspects fear and anxiety. Moreover, themodel is permissive of a cognitively-driven, top-downactivation of the descending arm of this system. Theimportance of this possibility is that such a top-downactivation might be expected to trigger a feedbackcascade associated with the ascending component of thesystem. Indeed, there is an intriguing compatibility ofthis view with the irrationality of much anxiety-relatedideation in anxiety disorders.
Although ascending and descending limbs of ourmodel are separated for conceptual and descriptiveclarity, the functional significance of the model lies inthe interactions between the ascending and descendingbranches. The ascending component shown in Fig. 5suggests that alterations in cardiovascular reactivity areable to modulate the efficacy of cortical informationprocessing. As considered above, the available datasuggest that LC discharge, and consequent corticalcholinergic activity, may be modulated by the NTS-PGicircuit in accord with visceral afference. Thus, increasesin cardiovascular activity may bias cortical cholinergicinputs toward increased reactivity and an enhancedprocessing of affective stimuli. Functional evidence todirectly link cardiovascular reactivity with modulationsin cortical stimulus processing, specifically entailingcortical cholinergic afferents, is limited [22,118,173]. As
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discussed above, however, a relatively extensive litera-ture has consistently implicated the locus coeruleus andthe ascending noradrenergic system in the developmentof anxiety. Additional data suggest links between LCactivity, anxiety, and BZR systems, as stimulation ofthe LC results in anxiety-like behaviors in monkeyswhich can be blocked by anxiolytic BZR agonists [27].Similarly, stress- and anxiety-induced increases in NAturnover in telencephalic target regions of the LC areblocked by BZR agonists [111]. Moreover, the anxiety-inducing effects of so-called ‘anxiogenic’ agents, such asCRF and yohimbine, are associated with increases inthe activity of the ascending noradrenergic system, andFG 7142 also activates ascending noradrenergic systems[28,42,110,251,270,274]. In fact, the robust increases incortical ACh release produced by FG 7142 [175] maybe due, at least in part, to noradrenergic driving ofbasal forebrain cholinergic neurons, coupled with anattenuation of local GABAergic inhibition. These find-ings suggest a close functional relationship betweencentral adrenergic activity, BZR/GABAergic mecha-nisms, basal forebrain cortical cholinergic projections,and anxiety.
7.3. Model-deri6ed predictions
The present model provides fertile ground for experi-mental predictions. The descending system has beenmore extensively studied than has the potential influ-ence of the ascending arm on cortical cognitive process-ing. Three predictions based on the present model,serve to integrate the potential ascending and descend-ing influences, and illustrate the heuristic potential ofthe proposed system.
7.3.1. Increases in cortical ACh release augment theexpression of fear and anxiety, as well as associatedautonomic changes
As discussed above, the anxiogenic drug FG 7142augments cortical ACh release [175,222], and enhancesthe defensive-like cardioacceleratory responses [22,201].In this respect, it is intriguing that organophosphateanticholinesterase exposure has been reported to induceanxiety, even at exposure levels that do not yield stan-dard clinical signs of toxicity [144,171]. The later is onlyconsistent with the cholinergic model, as it has not beenshown that putative anticholinesterase-induced anxietyarises from cortical cholinergic effects. Moreover, thegenerality of pharmacological models clearly needs tobe demonstrated by extensions to more natural behav-ioral models of anxiety and anxiogenic conditions.
A secondary issue that warrants attention in thiscontext relates to the hypothesis that BZR inverseagonists enhance certain cognitive functions [223–225].The possibility of drug-induced cognition enhancement,particularly in subjects suffering from the partial loss of
cortical cholinergic inputs is conceptually related to thepotential of these drugs to augment the processing ofanxiety-related information. In fact, it is difficult toconceive of a potential ‘cognition enhancer’ which doesnot also augment a pathologically pre-biased, anxiety-focused selection of stimuli and contexts for extendedevaluation, particularly in intact subjects.
7.3.2. Reduction or normalization of increased corticalcholinergic transmission should reduce symptoms ofanxiety and anxiety-related cardio6ascular reactions
Our previous studies demonstrated that the enhancedsympathetic reactivity to a defensive stimulus after FG7142 can be blocked by specific lesions of the basalforebrain-cortical cholinergic projection [22]. The ef-fects of intraventricular infusions of cholinergic ago-nists and antagonists further supported the critical roleof forebrain muscarinic receptors in the effects of FGon the cardioacceleratory response. Moreover, the anxi-olytic benzodiazepine receptor agonists potently reducecortical ACh release [112,175,222], raising the possibil-ity that their therapeutic effects are mediated in part viadecreases in cortical ACh release. This, of course, doesnot imply that muscarinic cholinergic receptor blockersshould be therapeutically effective in anxiety, as block-ade of cholinergic transmission is not equivalent to anormalization of an enhanced level of transmission.Consequently, therapeutic effects of receptor blockerswould not be expected necessarily.
Less evidence is available as to the direct role ofcortical ACh in the natural expression of fear andanxiety. Some studies, however, do bear on this issue.Stoehr and Wenk [249] demonstrated that lesions of thebasal forebrain area attenuate conditioned freezing toan environmental context. This suggests that the in-tegrity of the basal forebrain cholinergic system isimportant for the expression of context-dependent aver-sive reactions, which have been suggested to be corti-cally dependent phenomena [142,195]. Also consistentwith the present model is the finding that patients withAlzheimer’s disease, which is associated with degenera-tion of the basal forebrain cholinergic system, displayless severe anxiety symptoms than patients with vascu-lar dementias (matched for education, age, and severityof dementia) [250].
Clearly, a normalization of increased cortical AChrelease as a component of anxiolytic mechanisms repre-sents a testable hypothesis. As considered above, how-ever, no such role would be expected in modelsassessing spontaneous fear- and anxiety-related re-sponses that do not involve cognitive appraisal of stim-uli and/or contexts. The degree to which cortical AChcontributes to fear and anxiety is conceptualized as afunction of the role of cognitive variables in anxiety.This leads to clear predictions. For example, the poten-tiation of startle responding by simple conditioned
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stimuli may not require cortical processing, and hencemay not be substantially affected by the basal forebraincholinergic system. On the other hand, startle potentia-tion based on negative imagery [263] likely entails corti-cal processing, and hence would be expected to behighly sensitive to basal forebrain cholinergic activity.
7.3.3. Increases in autonomic, particular cardio6ascularreacti6ity increases cortical ACh release 6ia adrenergicreceptor stimulation in the basal forebrain
Direct evidence for this crucial hypothesis is lacking,although some relevant literature on the role of visceralafference in emotion will be considered in the nextsection. As discussed above, the afferent inputs to theLC, and the effects of stressors on autonomic reactivityand activity in the ascending noradrenergic bundleprovide circumstantial evidence in support of this cen-tral aspect of the model. However, the assumption thatincreased autonomic activity invariably translates intoactivation of cortical cholinergic afferents may be in-valid. As emphasized above, the ability of nora-drenaline to increase the excitability of basal forebraincholinergic neurons may depend on interactions withother converging afferents, particularly from the amyg-dala and the nucleus accumbens to basal forebrainneurons. In functional terms, such interactions mayrestrict the ascending effects on autonomic reactivity tosituations which involve activation of amygdaloid cir-cuits, or more generally, of rostral limbic areas. Inother words, autonomic reactivity changes may affectcortical processing predominately in situations charac-terized by strong emotional-cognitive appraisal pro-cesses. To the extent this hypothesis is correct, it wouldimply that the functional significance of autonomicreactivity differs substantially between control subjectsand those with a pathological bias toward fear- andanxiety-related information processing.
8. Anxiety and autonomic function: the role of visceralafference
8.1. Historical background
Scientific interest in the somatovisceral substrates ofemotions (e.g. Darwin [49]) was aroused when WilliamJames [117] argued that emotional feelings were conse-quences rather than antecedents of peripheral physio-logical changes brought about by some externalstimulus. Limiting attention to emotions ‘‘that have adistinct bodily expression’’ (p. 189), James [117] main-tained that discrete emotional experiences could beidentified with unique patterns of peripheral physiologi-cal changes, and that the perception of these specificpatterns of response constituted the emotional experi-ence. James’ theory has stimulated debate and researchfor more than a century.
In contrast, Walter Cannon [35] argued that periph-eral autonomic reactions did not contribute to emo-tions, based on five facts: (1) separation of the viscerafrom the central nervous system does not alter emo-tional behavior; (2) the same visceral changes occur invery different emotional as well as non-emotionalstates; (3) the viscera are relatively insensitive struc-tures; (4) visceral changes are too slow to be a source ofemotional feeling; and (5) artificial induction of thevisceral changes typical of strong emotions does notevoke these emotions. Based on these considerations,Cannon relegated autonomic activity to a rather cur-sory role in emotions, and this view dominated theliterature for more than three decades.
8.2. Contemporary perspecti6es and empirical data
Research on emotions in patients with high spinalcord transections [43], and on the influence of cognitiveappraisals in emotion [240,259] suggests that afferentinformation from peripheral autonomic activity is not anecessary condition for emotional experiences. More-over, despite occasional claims that discrete emotionsare associated with distinctive autonomic patterns [61],meta-analyses have not supported the strong version ofthis hypothesis [32]. These findings do not lend supportto James’ theory, but they do not rule out a potentiallyimportant contribution of visceral afference to affectivereactions.
Although there may not be highly unique patterns ofautonomic response and visceral afference associatedwith different emotional states, visceral afferents mayplay an important role in priming affective responses.Administration of epinephrine, for example, has beenreported to potentiate discrete and divergent emotionalstates, dependent on the cognitive context [209,230].Thus, a relatively undifferentiated visceral activity andafference may prime affective reactivity generally, withthe specific nature of the response determined by envi-ronmental cues. Alternatively, top-down perceptual bi-ases could lead to divergent affective consequences evenfrom a relatively undifferentiated pattern of visceralafference [31]. Such a bias may be operating, for exam-ple, when perception of an increase in heart rate trig-gers a panic attack.
Research in two areas suggests the importance ofvisceral afference in emotion and cognition, and thesignificance of interactions between the brain and vis-ceral afference in the response to stress. Systemic ad-ministration of the b-blocker propranolol has beenshown to selectively impair emotional memories, with-out a general effect on memory performance [33]. Inaddition, systemic administration of epinephrine orsubstance P has been reported to potentiate ‘emotional’memories in rats, and these effects can be blocked orattenuated by inactivation of the NTS or subdiaphrag-
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matic vagotomy, or by direct infusions of b-blockersinto rostral affective substrates such as the amygdala[165,181,272]. Further work is clearly needed in thisarea, but the existing data are in accord with thebidirectional interaction between rostral and caudalcentral substrates in the control of emotional and au-tonomic reactivity.
A second literature on brain–immune interactionsfurther supports the potential importance of visceralafference in emotional states and the response tostress. There are common elements to the physiologi-cal response to a wide range of stressors. Pathogens,for example, result in pituitary-adrenocortical andsympathetic activation, characteristic of the responseto psychological stress, and psychological stressorsmay trigger features of the ‘illness’ response to patho-gens, including anorexia and fever [150,268,269]. Thecytokine, interleukin-1-b (IL-1) appears to mediatemany of the neural, endocrine, immunological, andbehavioral consequences of injury and infection [149].The fever associated with pathogens may be due tocentral actions of IL-1, as it can be mimicked by ICVinfusions of IL-1, and blocked by ICV infusions ofIL-1 antagonists [150,268]. Similarly, IL-1 antagonistsblock the enhanced fear conditioning and impairedescape learning produced by inescapable shock [149].These central components of the stress response ap-pear to be dependent on visceral afferent signals, assubdiaphragmatic vagotomy largely blocks the in-crease in body temperature and pain sensitivity associ-ated with pathogens and with psychological stressors[150,268,269]7.
The precise implications of the latter findings foranxiety are unclear, but these studies serve to illus-trate the powerful peripheral/central interactions thatare mediated by visceral afference. At the presenttime, the role of visceral afference in anxiety remainslargely speculative, although the model of Fig. 5clearly reveals a basis for such an afferent influence.The role of visceral afference in anxiety and anxietydisorders is an especially important area for futureresearch.
9. Overview
The relations between anxiety and autonomic func-tion are far from simple. To some extent, the com-
plexity in the literature likely derives from thediversity of anxiety disorders, the intricacies of centralautonomic control, and the multiple neural systemsand processes involved in anxiety states. The pro-posed model is offered to provide a more comprehen-sive neurobiological organizing framework, tofacilitate the elucidation of the relations between anxi-ety states, central mechanisms, and autonomic func-tions. The model is intended to expand and develop,rather than supplant, existing perspectives. Two im-portant features of the present model are the involve-ment of the basal forebrain cholinergic system in thecognitive aspects of anxiety, and the detailing of as-cending routes by which visceral afference may modu-late rostral components of the system.
The proposed model, of course, does not provide acomplete account of systems and structures involvedin anxiety and autonomic control. Indeed, we in-cluded only enough detail to illustrate potential basesfor the cognitive contributions to anxiety and auto-nomic control, the relationships with existing neuralmodels, and the possible routes by which visceral af-ference may modulate activity in these central sub-strates.
There are several directions that will be importantin future development of the model, and further illu-mination of the relations between behavioral statesand autonomic function. First, it will be important toclarify behavioral features and implications of themodel. This includes an elucidation of the specificrange of psychological/behavioral processes that areinfluenced by the basal forebrain cholinergic system,as well as the precise nature of this influence. Simi-larly, there is a need for refinement in our under-standing of behavioral-autonomic relations, and thespecific classes, features or dimensions of anxietystates that are associated with patterns of autonomiccontrol. Secondly, further research is necessary to illu-minate the autonomic components of the model. Thiswill require attention to the multiple modes of auto-nomic control, including the potential origins of theseautonomic patterns and their relations to behavioralstates and processes. This includes clarification of therole of visceral afference in anxiety and cognition, atboth neural and behavioral levels. Finally, it will beimportant to further specify the multiple neural sys-tems and structures underlying fear and anxiety, andthe mechanisms underlying these contributions.
The relations between neural systems, anxiety andautonomic control are intricate indeed, and the litera-ture on autonomic function in anxiety states is attimes bewildering. The nature and origin of these rela-tions are of sufficient importance, however, that fur-ther research and especially the development oforganizing perspectives will be well worthwhile.
7 The origins of the vagal signals for the common central effects ofpathogens and psychological stressors is uncertain, but they may arisefrom vagal paraganglia, which are small clusters of neural crest-derived cells distributed along the vagus. These paraganglia appear tohave chemoreceptor-like functions, have a high concentration of IL-1receptors, and give rise to and/or synapse on vagal afferent fibers[268].
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Acknowledgements
Preparation of this manuscript was supported in partby a grant from the NHLBI (HL52321) and by aResearch Scientist Development Award to M. S.(KO2MH01072).
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