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controlled by preganglionic nerves that originate from ... The cell bodies of vagal preganglion ic neurons in- rvatin g ca rdiac .... Inferior Cervical Ganglion.
PHYSIOLOGICAL REVIEWS Vol. 74, No. 2, April 1994 Printed in U.S.A.

Functional Organization of Central Pathways Regulating the Cardiovascular System R. A. L. DAMPNEY Department

of Physiology,

University

of Sydney, Sydney, New South Wales, Australia

I. Introduction ......................................................................................... II. Overview of Central Cardiovascular Pathways ..................................................... III. Autonomic Neurons Controlling Cardiovascular Effecters ......................................... A. Vagal preganglionic neurons .................................................................... B. Sympathetic preganglionic neurons ............................................................. IV. Cardiovascular Sympathetic Premotor Neurons .................................................... A. Rostra1 ventrolateral medulla ................................................................... B. Rostra1 ventromedial medulla ................................................................... C. Caudal raphe nuclei .............................................................................. D. A5 noradrenergic cell group ..................................................................... E. Paraventricular nucleus ......................................................................... F. Other sympathetic premotor cell groups ........................................................ G. Summary ......................................................................................... V. Central Processing of Cardiovascular Afferent Inputs ............................................. A. Sources of afferent inputs ....................................................................... B. Nucleus of the solitary tract ..................................................................... VI. Brain Regions Controlling Cardiovascular Sympathetic Premotor Nuclei ......................... A. Caudal ventrolateral medulla .................................................................... B. Medullary lateral tegmental field ............................................................... C. Area postrema ................................................................................... D. Cerebellar nuclei ................................................................................. E. Parabrachial complex ............................................................................ F. Locus ceruleus .................................................................................... G. Midbrain periaqueductal gray ................................................................... H. Forebrain nuclei ................................................................................. VII. Functional Considerations .......................................................................... A. Specificity of central control of sympathetic vasomotor neurons ............................... B. Central pathways mediating the baroreceptor reflex ........................................... C. Central pathways mediating other cardiovascular reflexes ..................................... VIII. Concluding Remarks ................................................................................

I.

INTRODUCTION

Autonomic postganglionic nerves, together with local autoregulatory mechanisms and circulating hormones, directly influence cardiovascular function by regulating the rate and force of contraction of the heart and the caliber of blood vessels. These nerves in turn are controlled by preganglionic nerves that originate from specific nuclei in the medulla and thoracic and upper lumbar segments of the spinal cord (Fig. I). This review discusses the anatomic and functional organization of pathways within the mammalian brain and spinal cord that ultimately converge on preganglionic neurons controlling the heart and blood vessels. The objective is to provide a concise but comprehensive account of the organization of central cardiovascular pathways and, wherever possible, their functional role. This information is then used to address two specific 0031-9333/94

$3.00 Copyright

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Physiological

Society

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questions. I) What is the functional organization of central cardiovascular pathways that permit the autonomic outflow to different cardiovascular target organs to be controlled in a highly differentiated and specific fashion? 2) What are the central pathways that mediate cardiovascular reflexes? These questions have been discussed in previous reviews (126,445). Recently, however, there have been significant advances in our knowledge of central cardiovascular pathways, so it is timely to consider these questions again in the light of these new findings. II.

OVERVIEW CARDIOVASCULAR

OF CENTRAL PATHWAYS

Figure 1 shows schematically the four classes of neurons that constitute central cardiovascular path323

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hea adrenal medulla blood 7-. vessels



1111-1111

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,1,1,I,111,11,,IIII1I,,,,,,‘, = < primary afferent neuron interneuron

FIG. 1. Four cular pathways. inputs or higher (indicated by X)

classes of neurons that constitute central cardiovasFor simplicity, interneurons linking primary afferent brain centers to cardiac vagal preganglionic neurons are not shown.

ways. These are I) preganglionic autonomic motor neurons with a cardiovascular ‘function (controlling the heart, blood vessels, and adrenal medulla), 2) autonomic premotor neurons that project to and control the activity of these preganglionic neurons, 3) primary afferent neurons that transmit signals from peripheral receptors which reflexly influence cardiovascular function, and 4) interneurons that link primary afferent inputs or higher brain centers controlling cardiovascular function to autonomic premotor neurons. This review considers the functional organization in the mammalian brain and spinal cord of each of these four classes of neurons in turn before discussing the particular questions listed above. III.

AUTONOMIC CARDIOVASCULAR

NEURONS

CONTROLLING EFFECTORS

A. Vagal Preganglionic Neurons The cell bodies of vagal preganglion ic neurons innervatin g cardiac ganglia in mammalian species are lo-

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cated mainly in, and surrounding, the nucleus ambiguus within the ventrolateral medulla, but to a lesser extent also within the dorsal motor nucleus of the vagus and the region in between (49, 23’7, 238, 251, 265, 385, 402). The cell bodies of cardiac vagal neurons in the nucleus ambiguus are larger than those in the dorsal motor nucleus, and it has been suggested that the two groups have different effects on cardiac function (385). Cardiac vagal preganglionic neurons fire in synchrony with the cardiac cycle, due to an excitatory input arising from peripheral baroreceptors (337). Under normal conditions, the baroreceptor input appears to be the dominant influence on the activity of cardiac vagal preganglionic neurons, but they also can be powerfully excited by inputs arising from peripheral chemoreceptors, cardiac receptors, and trigeminal receptors activated during the “diving reflex” (445). In addition, the neurons are also inhibited during the inspiratory phase of the respiratory cycle. Electrophysiological and anatomic observations suggest that the baroreceptor input to cardiac vagal fibers is mediated by a direct pathway from the medial part of the nucleus of the solitary tract (5,453), while the respiratory modulation originates from medullary inspiratory neurons (337). The inspiratory inhibition may be mediated by acetylcholine, since it is blocked by application of atropine (188). It is also likely that a number of other neurotransmitters regulate the activity of cardiac vagal neurons. Iontophoretic application of excitatory amino acids increases the firing rate of the neurons (337), although the physiological role of these compounds is not established. Terminals immunoreactive for y-aminobutyric acid (GABA) have been shown to synapse directly onto the soma and dendrites of the neurons (326), while immunohistochemical and pharmacological studies also indicate that serotonin (5-HT) and opioid peptides may also have a neurotransmitter or neuromodulatory function

(135,136,251,252,290). B. Sympathetic Preganglionic Neurons I. Cytoarchitecture In contrast to the relatively few studies on vagal preganglionic neurons, the anatomic, physiological, and chemical properties of sympathetic preganglionic neurons (SPNs) and their synaptic inputs have been extensively studied in the last decade. With regard to the cytoarchitecture of sympathetic preganglionic nuclei, however, there have been only slight modifications of the original findings of Petras and Cummings (397). As reviewed recently by Coote (113) and Cabot (82), the cell bodies of SPNs are located in four regions within the thoracic and upper lumbar segments of the spinal cord: the intermediolateral (IML) cell column, the adjacent white matter of the lateral funiculus, the intercalated cell group lying between the IML cell column and

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the central canal, and a group lying dorsolateral to the central canal, which is commonly referred to as the central autonomic nucleus. The overwhelming majority of SPNs are located in the IML cell column and adjacent lateral funiculus. Sympathetic preganglionic neurons are not uniformly distributed within these four regions, but instead form distinctive clusters or “nests” (227, 387, 409, 413). 2. Morphology The morphology of individual identified SPNs in the IML cell column has been studied in detail using either intracellular injection or retrograde transport of horseradish peroxidase to label the cell bodies and their dendritic processes in cats (143), rats (172), and rabbits (499). Despite differences in species and segmental location of the SPNs, one general finding is that there is a prominent concentration of dendrites in longitudinal bundles, which appears to extend between SPNs in different clusters. Such an arrangement might allow for synchronization of the activation of SPNs with closely apposed dendrites by one presynaptic axon. Apart from longitudinally oriented dendrites, however, SPNs in the IML cell column also have other dendrites that have an extensive mediolateral orientation, in some cases extending into the contralateral side of the spinal cord as well as across the entire lateral funiculus on the ipsilatera1 side (31,172,499). This arrangement would provide a means by which SPNs are innervated by axons descending through the lateral funiculus on both sides of the spinal cord. 3. Location

with respect to target organs

The general organization of SPNs projecting to the major sympathetic ganglia and adrenal medulla has been described by Strack et al. (451), based on experiments using retrograde transport of the fluorescent tracer Fluoro-gold. This study demonstrated that each sympathetic ganglion and the adrenal medulla are innervated by SPNs located at several segments, although one segment is the principal source. Second, even though there is some overlap, the rostrocaudal origins of the SPNs innervating different ganglia correspond to the relative rostrocaudal locations of the target ganglia (Fig. 2). Despite the overlap, recent evidence indicates that SPNs are specific for a particular ganglion (18). It was first suggested some time ago that SPNs located in different spinal regions may have different functions (122, 145, 162), but only recently has direct evidence for this hypothesis been obtained. It has been shown in several species (hamster, guinea pig, and cat) that SPNs whose axons project through the caudal lumbar sympathetic trunk are mainly located in the lateral part of the IML cell column or in the adjacent lateral funiculus (215, 255, 348). The majority of such neurons have a vasomotor function (253). In contrast, SPNs whose axons project through the hypogastric nerve,

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which is principally concerned with the control of nonvasomotor functions in the pelvic organs, are located more medially in the IML cell column and intercalated nucleus (255, 348). Furthermore, even though there is some overlap in distribution of the two types of SPNs, a double-labeling study has shown that they consist of entirely separate populations (215). Similarly, SPNs innervating the adrenal medulla are a largely separate population from those that control the postganglionic outflow to the kidney (296). Thus, in summary, SPNs with vasomotor and nonvasomotor functions form entirely separate populations and have different topographical locations within the spinal cord. One question that arises from these observations is whether there is an even greater degree of topographical differentiation of SPNs. An elegant series of studies by Janig and co-workers, summarized in a recent review (254), has clearly demonstrated that SPNs controlling blood vessels in different end organs (e.g., skin, muscle or viscera) form separate groups, each with their own physiological characteristics (e.g., conduction velocity and pattern of responses to stimulation of peripheral receptors). It is possible that these functionally distinct groups of SPNs also have different locations within the spinal cord, in the same way that sympathetic premotor neurons in the rostra1 ventrolateral medulla that control different vascular beds have been shown to have different topographical distributions (see sect. IVAI). 4. Chemical

properties

It is well known that SPNs contain the neurotransmitter acetylcholine. It is now clear that they also contain neuropeptides such as enkephalin (ENK), neurotensin, somatostatin (SOM), or substance P (SP) (282). Furthermore, in some cases at least two of these peptides coexist within the same neuron, although only certain combinations have been observed (281). All types of SPNs, characterized according to their peptide content, are distributed throughout the thoracolumbar cord, although the proportions of different types vary at different segmental levels (281, 282). This suggests that the peptide content of SPNs may have some relation to the target organs they control. Recently, it has been demonstrated that approximately one-half of the SPNs in the thoracic cord contained nitric oxide synthetase (63), the synthesizing enzyme for nitric oxide. This is a very important observation, because in other parts of the central nervous system, such as the cerebellum or hippocampus, nitric oxide has been shown to play a major role in the modulation of synaptic transmission (177, 180). In particular, because it is rapidly diffusible, nitric oxide may influence neurons at some distance from its site of release, unlike conventional neurotransmitters. In some central neurons, nitric oxide formed in postsynaptic sites can facilitate presynaptic release from surrounding presynaptic terminals and is thought to play a role in longterm potentiation (236). It is therefore possible that ni-

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tric oxide may have a similar function in SPNs. In addition, the fact that nitric oxide is found only in a subpopulation of SPNs raises the question as to whether this subgroup is distinctive in other respects, such as the nature of their target effecters. 5. Functional properties As mentioned in section III&!, the sympathetic outflows to blood vessels in different vascular beds form quite separate channels, each with their own distinctive functional properties (253, 254). The activity of individual SPNs is governed by excitatory and inhibitory inputs, conveyed both by descending fibers originating from supraspinal nuclei and by spinal afferent nerves from the skin, viscera, and skeletal muscle. The functional differentiation of vasomotor SPNs controlling different end organs is, therefore, due to differences in the pattern of inputs that they receive (253). Studies using the technique of intracellular recording‘have revealed that all SPNs, including those that do not generate action potentials under resting conditions, are subjected to a continuous barrage of both excitatory and inhibitory synaptic inputs. The membrane potential shows no gradual waxing and waning, which would be

tracer

indicative of a pacemaker potential (116,142,346). In the most detailed study, Dembowsky et al. (142) showed that ongoing synaptic activity in SPNs arises predominantly from excitatory inputs, mediated over both fastand slow-conducting pathways. Both types of excitatory inputs could also be activated by stimulation of axons in the dorsolateral funiculus, which are believed to arise from pressor neurons in the brain stem (38). In contrast, ongoing inhibitory inputs were less frequently observed. The observations, however, were confined to SPNs in the upper thoracic cord so that it is possible that SPNs in other regions may show a relatively greater dependence on inhibitory inputs. Intracellular recordings from SPNs have also permitted a classification of the neurons into three distinct types, according to the characteristics of their resting membrane potential and action potentials (144). At this stage, however, the electrophysiological properties of SPNs, as determined by intracellular recording, have not been correlated with the end organs that they control. 6. Synaptic inputs: anatomic and histochemical studies

tion

The electrophysiological studies referred to in secIII&T indicate that SPNs receive synaptic inputs

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from many sources. Consistent with this, immunohistochemical studies, in combination with electron microscopy, have demonstrated the presence of several different types of axon terminals, classified according to their neurotransmitter or neuropeptide content, that synapse with SPNs. These include terminals immunoreactive for glutamate (373, 375), GABA (31, 64, lOl), 5-HT (31, 98, 406, 498), glycine (83), and a variety of neuropeptides including angiotensin II, ENK, SP, neuropeptide Y (NPY), thyrotropin-releasing hormone (TRH), and SOM (31,98,176,399,406,498). Synapses between noradrenergic and adrenergic terminals and SPNs have also been demonstrated (48, 99, 100, 358). In addition, terminals immunoreactive for other compounds [neurotensin, oxytocin (OXY), vasoactive intestinal polypeptide, and cholecystokinin-81 are also located in close apposition to SPNs, although synaptic contacts have not yet been demonstrated (18,100,283). It is unlikely, however, that each of these compounds is associated with a separate type of afferent input, since at least in some cases two or more of the above compounds have been colocalized within the same terminal (e.g., TRH and 5-HT, TRH and SP, or NPY and catecholamines) (19, 58). The distribution of chemically distinct terminals surrounding SPNs in different regions is nonuniform. For example, although catecholamine-fluorescent terminals are found at all segmental levels that contain SPNs, some SPNs appear to be only sparsely innervated by catecholamine terminals, while others are densely innervated (347). Similarly, glycine-immunoreactive terminals also show a nonuniform distribution, being associated particularly with SPNs in the central autonomic area and intercalated nuclei (83). As a further example of nonuniformity, the relative densities of terminals immunoreactive for 5-HT and various neuropeptides (e.g., NPY, ENK, SP, SOM, and OXY) have been shown to vary according to segmental level (280, 283). This suggests that SPNs controlling different target organs receive different patterns of chemically distinct afferent inputs. Direct evidence for this comes from a study in which SPNs innervating the adrenal medulla and cervical ganglia were labeled separately (18). Although both types of SPNs received afferents immunoreactive for 5-HT, only the cervical SPNs were innervated by OXYimmunoreactive terminals. 7. IdentiJication of neurotransmitters sympathetic preganglionic neuron

controlling activity

The presence of many different types of putative neurotransmitters in terminals synapsing with, or surrounding, SPNs has led many investigators to study the effects of their direct application to SPNs. These studies, which have been reviewed in detail by Coote (113), show that all the compounds tested have some influence on the activity of SPNs. The observed effects, however, have in many cases not been consistent with the expected effects of an excitatory or inhibitory neuro-

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transmitter. To take one example, there is now good evidence that catecholamine neurons in the rostra1 ventrolateral medulla that project directly to SPNs are sympathoexcitatory (see sect. IVAN). Such neurons are thought to synthesize epinephrine, since they contain the enzyme phenylethanolamine N-methyltransferase (PNMT) (417). Several studies have shown, however, that iontophoretic application of epinephrine to SPNs inhibits their activity (113), although in some cases excitation has also been observed (293,369). Perhaps more significantly, intracellular recording has shown that the effect of applied epinephrine (or norepinephrine), whether it be hyperpolarization or depolarization, is very slow, on the order of seconds or minutes (248,369). Such effects are quite unlike those expected of a fastacting excitatory neurotransmitter. Similarly, even though it has been suggested that SP mediates an excitatory input to SPNs (273, 309), its effects also have a very slow time course (30, 157, 189). Recent work, however, may provide an explanation for these apparent paradoxes. It has now become very clear that colocalization of putative neurotransmitters in terminals synapsing on SPNs is the rule rather than the exception. For example, over one-half of the terminals in the IML cell column of the rat contain both 5-HT and SP (511). It also appears highly likely that the great majority of these contain glutamate, since a recent study has shown that virtually all serotonergic (and catecholaminergic) neurons projecting to the IML cell column from the ventrolateral medulla contain phosphateactivated glutaminase, a marker of glutamate (363). Therefore, it is possible that monoamines and/or peptides may be coreleased with another neurotransmitter (such as an excitatory or inhibitory amino acids) from terminals synapsing with SPNs. In that case, the function of the coreleased compound may be quite different from that observed when it is applied in isolation. A recent study, which observed the effects of applying norepinephrine and an excitatory amino acid simultaneously to SPNs, provides some evidence for this hypothesis. In the presence of low concentrations of an excitatory amino acid (DL-homocysteic acid), norepinephrine had an inhibitory effect, but this was reversed to excitation when the concentration of the amino acid was increased (293). It is therefore possible that other substances coreleased with excitatory (or inhibitory) amino acids may have a similar modulatory function, but this remains to be tested. Recent histochemical studies provide strong evidence that amino acids are important neurotransmitters released from terminals synapsing with SPNs. Approximately two-thirds of all axon profiles making contact with SPNs in the thoracic spinal cord of the rat contain glutamate (303). Furthermore, another study of SPNs in the thoracic spinal cord of the rat has shown that approximately one-third of synaptic boutons contain GABA (31). Glutamate and GABA are not, however, colocalized in the same nerve terminals (303). The pharmacological effects of excitatory amino acids on SPNs have recently been examined in detail, in

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a slice preparation from the cat spinal cord (250). The short-latency excitatory postsynaptic potentials evoked in SPNs by electrical stimulation of their afferent inputs are abolished or depressed by application of excitatory amino acid receptor antagonists and enhanced by a glutamate uptake inhibitor. Furthermore, the release of glutamate and aspartate in the IML nucleus was enhanced by field stimulation of the region containing the nucleus. Similarly, there have been several pharmacological studies supporting a role for GABA (29, 158, 197, 249) and glycine (29, 109, 158, 249, 371) as inhibitory neurotransmitters to SPNs. Although further quantitative studies need to be done, the evidence to date obtained from these studies strongly suggests that excitatory and inhibitory afferent inputs to SPNs release glutamate (or similar excitatory amino acid) and GABA (or glytine), respectively, as their principal fast-acting neurotransmitters. In contrast, as McCall (339) suggested in a recent review, monoamines and neuropeptides may act to set the level of excitability of SPNs.

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paraven nucleus

A5 cell group rostra1 ventrolateral medulla ventromedial medulla

IV.

CARDIOVASCULAR PREMOTOR

SYMPATHETIC NEURONS

Particular nuclei in the brain stem and hypothalamus project directly to SPNs and may therefore be regarded as sympathetic premotor nuclei. Beginning with the study of Amendt et al. (12), many workers have injected tracers into the IML cell column at a thoracic or upper lumbar segmental level, then mapped the location of neurons in the brain stem and hypothalamus that were retrogradely labeled as a consequence (97,225,304, 308,365,432). These studies demonstrated the existence of several different nuclei, mainly within the medulla oblongata, pons, and hypothalamus that project their axons to the vicinity of the IML cell column, although not necessarily to SPNs directly. Recently, the method of transneuronal retrograde labeling by means of viruses has been used to identify sympathetic premotor nuclei (146,450,452,510). Unlike conventional retrogradely transported tracers, the viruses (herpes or pseudorabies varieties) cross the synapse and are transported back to the cell’bodies of the neurons that synapse with the neuron that projects to the injection site. Although this technique has its limitations (452), it has been used successfully to determine the general pattern of organization of sympathetic premotor neurons within the brain stem and hypothalamus that regulate the preganglionic outflow to the major sympathetic ganglia and adrenal medulla in the rat (450). The results of this study reveal that there are five specific cell groups [in the rostra1 ventrolateral medulla, rostra1 ventromedial medulla, caudal raphe nuclei, A5 noradrenergic cell group in the caudal ventrolateral pons, and the paraventricular nucleus (PVN) in the hypothalamus] that innervate the preganglionic outflow to the adrenal medulla and all major sympathetic ganglia (Fig. 3). Other regions [zona incerta, lateral hypotha-

caudal raphe nuclei sympathetic preganglionic nuclei FIG. 3. Major descending pathways synapsing with sympathetic preganglionic neurons, as revealed by method of transsynaptic retrograde transport of pseudorabies virus. VII nerve, facial nerve; IO, inferior olive; NTS, nucleus of solitary tract; PB, parabrachial nucleus; SpV, spinal trigeminal nucleus; VMH, ventromedial nucleus of hypothalamus. [From Strack et al. (450).]

lamic area, and midbrain periaqueductal gray (PAG)] also contain sympathetic premotor neurons, but these outflow only to aPPear to in nervate the preganglionic the superior cervical and stellate ganglia. When used in conjunction with immunohistochemical labeling of neurotransmitters, the method of transneuronal transport of viruses has allowed the neurotransmitter properties of sympathetic premotor neurons controlling specific ganglia, and the adrenal medulla, to be determined (146, 452,510). In the discussion in the following sections, the functional, pharmacological, and anatomic properties of sympathetic premotor neurons in the various brain stem and hypothalamic regions mentioned are reviewed. A. Rostra1 Ventrolateral Medulla

It is now well established that cells in the rostra1 ventrolateral medulla (RVLM) play a crucial role in the tonic and phasic regulation of blood pressure. In particular, studies some years ago showed that bilateral de-

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struction or inhibition of these cells in anesthetized animals can produce a profound fall in blood pressure, similar to that observed following transection of the spinal cord (164,205). This dramatic observation stimulated a great deal of research over the past 15 years on the functions, connections, and chemical properties of these cells (for reviews, see Refs. 85, 105, 127, 131, 208, 411). As a result, much more is known about the role of the RVLM cell group in cardiovascular regulation than any of the other groups of sympathetic premotor nuclei listed in section Iv. I. outputs The properties of the RVLM cardiovascular sympathetic premotor neurons have been studied most extensively in the rat, cat, and rabbit. The precise pattern of distribution of the cells varies between species, but in all cases they are located ventral to the rostra1 part of the nucleus ambiguus (or retrofacial nucleus). Studies using the method of anterograde transport of tracers show that RVLM spinally projecting cells terminate specifically in sympathetic preganglionic nuclei (129, 419). It had been previously inferred that RVLM cells project to SPNs at all levels of the spinal cord, but the study of Strack et al. (450) confirmed that they do in fact exert a widespread control over the sympathetic outflow. Excitation of the RVLM cells, by local microinjection of excitatory amino acids, produces an increase in blood pressure, which has been shown to be due to an activation of sympathetic vasoconstrictor nerves innervating blood vessels throughout the body (131, 332, 335, 517), including the brain (320). In addition, stimulation of the cells also causes an increase in heart rate and the release of adrenomedullary catecholamines (335). These stimulation studies have all been carried out in anesthetized animals, but one study has confirmed that microinjection of excitatory amino acids into the RVLM of conscious unrestrained rats also elicits a marked pressor response (28). Despite the fact that RVLM sympathetic premotor neurons are capable of producing widespread actions on cardiovascular effecters, the same neurons do not appear to influence noncardiovascular functions. This has been studied most thoroughly in the cat. In this species, the RVLM sympathetic premotor neurons are concentrated in a longitudinal discrete column that has been termed the subretrofacial nucleus (335). Excitation of subretrofacial cells, by highly localized microinjections of excitatory amino acids, elicits the cardiovascular effects described above, but does not affect the sympathetic output to effecters controlling noncardiovascular functions such as pupillary dilatation, piloerection, gut motility, or sweat secretion (332, 335). Similarly, mapping studies indicate that antinociceptive and respiratory neurons are located close to, but separate from, pressor cells within the subretrofacial nucleus (331,439). One of the most interesting features of RVLM vasomotor cells is that they do not all exert a uniform con-

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trol over the sympathetic vasomotor outflow, as has been demonstrated by three different experimental approaches. In one study, the activity of single RVLM sympathetic premotor neurons was correlated with the firing pattern of sympathetic nerves innervating different vascular beds (43). This study revealed that the firing patterns of RVLM neurons were not all correlated to the same degree with different sympathetic outputs. Some were most highly correlated with one particular output, while others appeared to be more closely linked to another output. Second, it has been shown that, following bilateral application of glycine to the ventral surface adjacent to the RVLM, the time course of inhibition of sympathetic nerves innervating renal and skeletal muscle vascular beds was different, indicating that the cells controlling these outputs have different locations within the RVLM (140). Third, other studies have clearly demonstrated that stimulation of cells at different sites within the RVLM of the cat, by localized microinjections of excitatory amino acids, elicits different patterns of regional vasomotor effects according to the site of stimulation. In particular, increases in the activity of vasoconstrictor nerves innervating blood vessels in skin and skeletal muscle are elicited preferentially from sites located medially and laterally, respectively, within the RVLM (132). Thus, although there is likely to be considerable overlap, sympathetic premotor neurons specific to the cutaneous and skeletal muscle vasculature have different topographical distributions within the RVLM. Similarly, other studies have shown that RVLM neurons controlling the renal bed are distributed more rostrally than those controlling the hindlimb and mesenteric beds (141, 310, 336). This last observation raises the question as to what is the principle governing the topographical organization of RVLM sympathetic premotor neurons controlling different vascular beds? One simple possibility is that such subgroups of neurons are arranged rostrocaudally within the RVLM, according to the rostrocaudal level of the SPNs that they control. Such an arrangement would be consistent with the general segmental arrangement of SPNs themselves within the spinal cord, since as pointed out in section IIIBQ, this is related to the rostrocaudal location of their target ganglia. In contrast, however, the location of RVLM neurons is related not to the segmental level of the SPNs that they control, but rather to their type. For example, RVLM neurons controlling skeletal muscle beds in the forelimb and hindlimb have the same topographical distribution, despite the fact that the SPNs controlling the two types of beds originate from widely separated segments (336). Another question is whether some RVLM cells provide a generalized excitatory input to vasomotor SPNs with different end organs. The possibility that there are both specific and nonspecific RVLM sympathetic premotor neurons was suggested by Barman and Gebber (38), who found that the axons of some RVLM neurons innervate the IML cell column in only a very restricted part of the thoracic cord, while others project to widely

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separated thoracic segments. As pointed out above, however, even RVLM neurons with collateral axons terminating in widely separated segments may still exert a specific control over SPNs controlling vascular beds of a specific type (e.g., skeletal muscle in hindlimb and forelimb). Therefore, the question as to whether there are RVLM neurons capable of exerting a generalized effect over the entire sympathetic vasomotor outflow remains unresolved. Haselton and Guyenet (219) found that some RVLM neurons with electrophysiological properties indicative of vasomotor cells provide a collateral input to both the spinal cord and to supramedullary regions known to have an autonomic function, such as the parabrachial/ Kolliker-Fuse complex, the midbrain PAG, and the lateral hypothalamic area. They suggested that RVLM vasomotor cells with ascending projections convey information to brain stem and diencephalic nuclei on the degree of activation of the sympathetic vasomotor outflow. The functional significance of this observation is not clear, but it does demonstrate that at least some RVLM vasomotor neurons are not dedicated exclusively to regulating the spinal sympathetic outflow. As mentioned above, inhibition of RVLM cells is immediately followed by a large decrease in blood pressure and in the activity of sympathetic nerves to the kidney, splanchnic bed, and skeletal muscle, indicating that these cells are a major source of tonic excitatory drive to sympathetic vasomotor neurons controlling different beds. The degree of inhibition, however, varies between different sympathetic outflows. For example, in the cat and rat, bilateral inhibition of RVLM cells causes a much greater decrease in renal than mesenteric or splenic sympathetic activity (47,222,521). The residual activity in mesenteric nerves may be of spinal origin, since mesenteric activity is still present even after spinal cord transection (349, 509). The fall in blood pressure caused by bilateral lesions of the RVLM is not sustained. After several days, the resting blood pressure in lesioned animals is similar to that in control animals (111). It therefore follows that tonic inputs arising from other sources are capable of maintaining resting blood pressure when RVLM cells are disabled. 2. Electrophysiological

properties

Apart from effects on resting blood pressure, inhibition or destruction of RVLM neurons causes a loss of reflexes arising from arterial baroreceptors and chemoreceptors, cardiopulmonary receptors, and somatic receptors, and also blocks the pressor effects normally elicited by stimulation of the insular cortex, the hypothalamic “defense area,” the midbrain PAG, and the fastigial nucleus in the cerebellum (95,125,140,202,203, 329,449,501). Similarly, depressor effects normally elicited by stimulation of the prefrontal cortex or sites within the lateral hypothalamus were also abolished by blockade of synaptic transmission within the RVLM (95,

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454). These observations therefore demonstrate that, at least in anesthetized animals, RVLM neurons are a critical component of central pathways integrating cardiovascular responses to stimulation of both peripheral receptors and higher brain centers. Consistent with these observations, electrophysiological studies have demonstrated that RVLM sympathetic premotor neurons are influenced by inputs from peripheral baroreceptors, chemoreceptors, cardiopulmonary receptors, renal receptors, vestibular receptors, and somatic receptors, as well as from several brain regions, including the prefrontal cortex, hypothalamic defense area, midbrain PAG, fastigial pressor area, lobule IXb in the cerebellum, and area postrema (38, 79, 278, 329,330,334,379,426,440,454,457,460-462,480,501,503, 523,524). In addition, RVLM sympathetic premotor neurons are also influenced by inputs from the central respiratory rhythm generator (217, 333, 480). Perhaps the most remarkable feature, however, is the degree of convergence of different inputs on to individual RVLM neurons, as shown most clearly by the work of Kumada and co-workers (426,480,481). In one study (480), barosensory neurons in the RVLM were first identified by their inhibitory response to stimulation of aortic baroreceptors, then further tested for their responsiveness to a range of other inputs. All, or nearly all, were also inhibited by carotid baroreceptor stimulation and excited by inputs from carotid body chemoreceptors and the posterior hypothalamus. Furthermore, other experiments have shown that RVLM barosensory neurons also receive inputs arising from renal and somatic receptors (426, 481). The degree of convergence of inputs on to RVLM neurons contrasts with the relative specificity of responsiveness of neurons within the nucleus tractus solitarius (NTS) to inputs from different types of cardiovascular and other receptors (see sect. vBI). The above observations thus indicate that RVLM sympathetic premotor neurons integrate inputs from many different peripheral and central sources. At the same time, it would be expected that the extent to which individual RVLM neurons are influenced by different inputs would vary according to the type of vascular bed or beds that they control (see sect. IVAI), as is the case with SPNs controlling blood vessels in different regions (254). Such detailed information on the physiological properties of RVLM neurons is lacking at this time. At least in one respect the electrophysiological properties of some RVLM sympathetic premotor neurons differ quite markedly from vasomotor SPNs. Whereas the activity of the latter group of neurons is governed entirely by their synaptic inputs (see sect. IIIBS), some RVLM neurons exhibit a pacemaker-like activity, i.e., a spontaneous regular activity, even in the absence of synaptic inputs (458,465,466). These neurons project to the spinal cord and are inhibited by baroreceptor inputs, indicating that they are sympathoexcitatory (458). Other spinally projecting neurons in the RVLM, however, that do not exhibit a pacemaker-like activity also have functional properties indicative of cardiovas-

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PATHWAYS

cular premotor neurons, i.e., their spontaneous activity is highly correlated with sympathetic vasomotor activity, and they are inhibited by baroreceptor inputs (40,218). The pacemaker and nonpacemaker cardiovascular neurons within the RVLM differ with respect to their resting firing rates and axonal conduction velocities; the pacemaker cells have, on average, much higher firing rates and conduction velocities (210). Furthermore, as discussed in more detail in section IVAS, the two types of cells also have markedly d ifferent chemical properties.

da1 ventrolateral medulla, and midbrain PAG terminate within the RVLM region that contains the highest concentration of sympathetic premotor neurons (91, 129, 300, 422,492). It is likely that these pathways subserve cardiovascular reflexes, as well as cardiovascular changes associated with complex behavioral responses. The functional role of these afferent inputs to RVLM cardiovascular neurons is discussed in more detail in section VII.

3. Aferent

$. Pharmacological

inputs

The origins of afferent inputs to RVLM cardiovascular neurons have been studied by anatomic means, using the method of retrograde transport of tracers. Although such a method is able to identify the sources of inputs to the RVLM region, it cannot by itself distinguish between inputs specific to cardiovascular neurons and those that innervate neurons such as respiratory or pain-modulating neurons that are also located within the RVLM. Nevertheless, some very important information has been gained, particularly in studies in which small volumes of tracers were injected into the functionally identified pressor cell group in the RVLM. The findings of such studies are summarized. In the rat, rabbit, and cat, major projections to the RVLM region containing cardiovascular sympathetic premotor neurons arise from the NTS, caudal ventrolatera1 medulla, Kiilliker-Fuse nucleus, midbrain PAG, hypothalamic PVN, and the lateral hypothalamic area (91, 129, 130, 422) as illustrated schematically in Figure 4. Smaller projections from the central amygdaloid nucleus (475) and medullary raphe nuclei (129) have also been demonstrated. There is not yet direct evidence that any of these afferent inputs to the RVLM synapses directly with sympathetic premotor neurons. Nevertheless, studies using the method of anterograde transport of tracers have confirmed that the projections from the NTS, cau-

properties

Pharmacological studies have demonstrated a diversity of membrane receptors within the RVLM whose activation can influence cardi .ovascular function. Experi mental investi .gations to date have demonstrated that receptors for glutamate, GABA, acetylcholi ne, opiates, catecholam .ines, 5-HT, and angiotensin are all capable of regulating the activity of RVLM cardiovascular neurons. These studies are briefly reviewed in this section. It is well known that RVLM cardiovascular sympathetic premotor neurons, like virtually all central neurons, are powerfully activated by excitatory amino acids. It has been shown that application of kynurenic acid, a nonspecific blocker of excitatory amino acid receptors, blocks excitatory inputs to RVLM cardiovascular neurons that originate from peripheral receptors or other central nuclei (278,456,457,491). These inputs do not appear to be tonically active, since the resting level of blood pressure is not altered by blockade of RVLM glutamate receptors (209, 278456,491). In contrast, cardiovascular sympathetic premotor neurons in the RVLM are tonically inhibited by GABAergic inputs. Blockade of GABA receptors in the immediate vicinity of the neurons, but not surrounding regions, results in an increase in their firing rate as well as in blood pressure (128,285,455,514). y-Aminobutyric acid receptors on the neurons also mediate the inhibi-

FIG. 4. Major afferent and efferent connections of rostra1 ventrolateral medulla (RVLM) region containing presympathetic vasomotor neurons, as revealed by anatomic studies in rat, rabbit, and cat. CVLM, caudal ventrolateral medulla; IML, intermediolateral cell column; KF, Kiilliker-Fuse nucleus; LHA, lateral hypothalamic area; NTS, nucleus of solitary tract; PAG, periaqueductal gray; PVN, paraventricular nucleus. (From Dampney, R. News Physiol. Sci. 5: 63-67, 1990.) I RVLM

inputs

....................

vasomotor nucleus

output

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R. A. L. DAMPNEY

tion arising from stimulation of arterial baroreceptors or cardiopulmonary receptors (128, 457). In addition, however, a substantial part of the tonic GABAergic inhibition of RVLM cardiovascular neurons is independent of baroreceptor inputs (128,285,340). Acetylcholine also plays a major role in regulating the activity of RVLM cardiovascular neurons. Microinjection of cholinergic agonists into the RVLM increases blood pressure (291,468, 516). Furthermore, the RVLM appears to be a specific site of action of acetylcholine, since the pressor response evoked by systemic administration of the drug physostigmine (a cholinesterase inhibitor) results specifically from the augmented action of acetylcholine released from cholinergic terminals within the RVLM (192). The specific receptor involved is of the muscarinic M2 type (192,467) and has a high density within the RVLM (21). Furthermore, it is likely that acetylcholine is tonically released, since inhibition of its synthesis or blockade of its receptors within the RVLM produces a marked fall in blood pressure (21,291, 516). It is not clear whether the sympathoexcitatory actions of acetylcholine in the RVLM are due to a direct effect on sympathetic premotor neurons or to disinhibition via a local interneuron. Although iontophoretic application of acetylcholine has been shown to cause a weak excitation of RVLM sympathetic premotor neurons, an ultrastructural study has demonstrated that the majority of synaptic contacts made by cholinergic terminals on RVLM neurons appear to be of the inhibitory type (360). It has been suggested, therefore, that cholinergic terminals inhibit local inhibitory (for example, GABAergic) neurons in the RVLM (192), but this remains to be established. Activation of opiate receptors in the RVLM, by microinjection of stable analogues of ENK, produces a decrease in blood pressure and heart rate; naloxone, an opiate antagonist, prevented or reversed these effects (408, 430). A detailed study on the ultrastructure of transmitter-identified neurons in the RVLM by Milner et al. (362) showed that one of the primary targets of ENK-immunoreactive terminals is a group of catecholamine cells referred to as the Cl group. These cells, which were first described and named by Hokfelt et al. contain the epinephrine-synthesizing enzyme ww, PNMT. As discussed in detail in section IVAN, Cl neurons are believed to directly excite cardiovascular SPNs in the spinal cord. Thus these observations indicate that ENK is released from terminals in the RVLM and directly inhibit cardiovascular sympathetic premotor neurons. The functional significance of the ENK inputs to RVLM neurons is not known, but it has been shown that one source of the ENK axon terminals is the NTS (372). Thus this ENK pathway could be a component of the central pathways mediating cardiovascular reflexes. It is known, for example, that the decompensatory phase of severe hemorrhage, whereby the reflex vasoconstriction is reversed to a vasodilatation, is prevented by central administration of an opiate receptor antagonist (316). It is therefore possible that the ENK pathway

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from the NTS to the RVLM subserves the reversal of vasoconstriction under these conditions. The cardiovascular effects elicited by ENK in the RVLM are very similar to those elicited by adrenergic agonists such as clonidine or cu-methyl-norepinephrine (68). Furthermore, it has been suggested that opiate receptors and adrenoreceptors of the cr,-subtype may be linked (288). Consistent with this, it has been shown that Cl neurons in the RVLM, many of which are innervated by ENK terminals, also contain a,-adrenoreceptors (218). Activation of 5-HT receptors in the RVLM can also produce significant cardiovascular effects, but these vary according to the subtype of the receptor. Activation of 5-HT,, receptors in the RVLM elicits a fall in blood pressure, whereas activation of 5-HT, receptors elicits a rise in blood pressure (120, 224, 311, 323, 324, 386,497). The depressor response to activation of 5-HT,, receptors is not affected by destruction of serotonergic nerve terminals in the RVLM, indicating that the receptors have a postsynaptic location (224). In contrast, the 5-HT, receptors may be located on presynaptic nerve terminals, since direct iontophoretic application of a 5HT, agonist to RVLM neurons had no effect on their firing rate (108). It has been known for some years that angiotensin receptors are located in the brain, particularly in regions that play an important role in blood pressure regulation and body fluid homeostasis, such as the circumventricular organs and the NTS (9,345). More recently, however, it has been clearly demonstrated in several species that there is a very high density of angiotensin receptors in the RVLM, particularly in the region corresponding to the location of sympathetic premotor neurons (7,8). Activation of these receptors leads to a rise in blood pressure and sympathetic vasomotor activity (8, 16,381,431), but has no effect on respiratory neurons in the same region (299). Local injection of a specific antagonist to angiotensin receptors causes a decrease in blood pressure and sympathetic nerve activity (382, 431). It thus follows that endogenous angiotensin, or an angiotensin-like compound, is tonically released from nerve terminals in the RVLM and acts specifically on cardiovascular neurons. Nerve terminals immunoreactive for angiotensin have been demonstrated in the RVLM (301), although their cells of origin have not been identified. Vasopressin is another peptide that has recently been shown to excite RVLM cardiovascular neurons. Microinjection of this compound into the RVLM produces a pressor response (194), which is blocked by prior administration of a Vl receptor antagonist. Unlike angiotensin, there is no evidence that vasopressin is tonically released under resting conditions, although this may occur during extreme conditions such as hemorrhage (194). It is likely that other receptors may also regulate RVLM cardiovascular neurons. The RVLM contains receptors for a variety of neuropeptides apart from angiotensin and vasopressin (423), although whether these specifically influence sympathetic premotor neurons is not known. There is more definitive evidence in the case

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1994

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of the compounds ATP and inositol hexakisphosphate, both of which have been shown to directly excite the sympathetic premotor neurons (463, 464). In summary, then, the evidence to date clearly demonstrates that the activity of RVLM sympathetic premotor neurons is strongly influenced by a variety of receptors, exerting both excitatory and inhibitory effects. Some of these receptors are tonically activated, such as those for GABA, acetylcholine, and angiotensin. Our knowledge of the role of these RVLM receptors in subserving cardiovascular reflexes is sparse, although it is well established that the baroreceptor-mediated inhibition of RVLM sympathetic premotor neurons is mediated by a GABA receptor. Thus the identification of receptors on RVLM sympathetic premotor neurons, and the elucidation of their functional roles, is a major challenge for the future. 5. Chemical properties

The ventral medulla is known to contain several groups of bulbospinal cells with different chemical properties (104,226). One of the largest groups of such cells is the PNMT-immunoreactive cells of the Cl group (256, 417, 419, 452). In addition, however, ventral medullary neurons immunoreactive for 5-HT and a wide variety of peptides, including NPY, SP, SOM, ENK, and TRH, have also been shown to project to sympathetic preganglionic nuclei (97, 225, 233, 432, 452). Although all these cell types are found in the RVLM, all except the NPY-immunoreactive neurons are most abundant medial to the RVLM, in the region which has been referred to as the ventromedial medulla (452) or parapyramidal region (226). In some cases two or more of the above putative cotransmitters are localized in the same RVLM neurons. In particular, PNMT and NPY (56, 226) are frequently colocalized, and PNMT and SP are occasionally colocalized (226,359,400). Thus it is clear that RVLM neurons are heterogeneous with respect to their chemical properties, just as they are heterogeneous with respect to the vascular beds that they control. This raises the possibility that RVLM cardiovascular neurons controlling different vascular beds may be chemically coded. At this time, however, there is not yet any direct evidence for this hypothesis. More definitive conclusions can be made with regard to the question as to whether the putative epinephrine-synthesizing Cl neurons in the RVLM are sympathoexcitatory. It was first suggested several years ago (125, 418) that the Cl cells may provide a tonic excitatory input to vasomotor SPNs, but there has been considerable opposition to this view. One major reason for this is that, as pointed out in section II@?‘, SPNs are usually inhibited by iontophoretically applied epinephrine. Furthermore, Head and Howe (223) showed that inhibition of epinephrine synthesis by pretreatment with a PNMT inhibitor did not affect the pressor response to RVLM stimulation. These observations there-

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fore strongly indicate that epinephrine is not the excitatory neurotransmitter released from the terminals of RVLM neurons synapsing with SPNs. Nevertheless, there is now considerable evidence that Cl neurons are in fact sympathoexcitatory. As discussed in section IVAZ?, RVLM sympathetic premotor neurons can be subdivided into two groups, according to whether they demonstrate a pacemaker-like activity or not. Sympathoexcitatory neurons in the RVLM that show a pacemaker-like activity are not immunoreactive for catecholamine-synthesizing enzymes and thus cannot be Cl neurons (466). On the other hand, nonpacemaker sympathoexcitatory cells do appear to be Cl cells, on the basis of a combined anatomic and electrophysiological study by Haselton and Guyenet (218). These authors (218) found that nearly all spinally projecting RVLM neurons that also provide a collateral innervation of supramedullary regions belong to the Cl group. When the activity of such collateralized RVLM cells was recorded, it was found that they did not exhibit a pacemaker-like activity but were inhibited by baroreceptor inputs, indicating that they are sympathoexcitatory. Studies by other workers also support the view that Cl spinally projecting neurons are sympathoexcitatory. In a single-unit extracellular recording study in the rat, Morrison et al. (378) identified RVLM neurons projecting to the IML column. These neurons could be subdivided into two groups on the basis of the conduction velocity of their axons, but both types had electrophysiological characteristics indicative of sympathoexcitatory neurons. The recording sites were consistently located within 100 ,um of identified Cl cell bodies. Moreover, the conduction velocities of the two groups of neurons corresponded closely to the estimated conduction velocity of myelinated and unmyelinated spinal axons that were immunoreactive for PNMT, indicating that they originated from Cl cells. Similar findings have been made in the cat. In this species, as pointed out in section IVAI, there is a distinct column of cells within the RVLM (the subretrofacial nucleus) which, when stimulated, elicits an increase in blood pressure and sympathetic activity. Furthermore, when the activity of a randomly selected sample of spinally projecting cells within the subretrofacial nucleus was recorded, it was shown that nearly all displayed a cardiac rhythmicity and were powerfully inhibited by baroreceptor inputs (330, 335), indicative of sympathoexcitatory neurons. In an immunohistochemical study, Polson et al. (403) found that -50% of neurons in the subretrofacial nucleus in the cat are Cl cells. Thus, when the electrophysiological and chemical properties of this cell group are correlated, it seems highly probable that at least some of the identified sympathoexcitatory cells within the subretrofacial nucleus are Cl epinephrine-synthesizing cells. For the reasons set out above, it is unlikely that epinephrine is the excitatory neurotransmitter released from the terminals of Cl neurons. There is evidence, however, to indicate that the excitatory transmitter is glutamate, or a glutamate-like compound. First, the

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R. A. L. DAMPNEY

large majority of Cl neurons in the RVLM contain phosphate-activated glutaminase, a glutamate-synthesizing enzyme (363). Second, as mentioned in section IIIB’Y, glutamate-like immunoreactivity has been demonstrated in axon terminals and synapses within the IML cell column (303,373,375), and it has been shown that some of these terminals originate from RVLM neurons (374). Third, iontophoretic application of the glutamate receptor antagonist kynurenic acid to SPNs projecting to the splanchnic nerve blocks the excitatory response normally elicited by stimulation of Cl cells in the RVLM (375). Finally, the pressor response elicited by stimulation of the RVLM causes an immediate increase in the release of glutamate and aspartate, measured using dialysis (268). It is unclear, however, which glutamate receptor subtype mediates the excitatory actions of RVLM sympathetic premotor neurons on SPNs. On the one hand, it has been reported that the pressor and sympathoexcitatory effects of RVLM stimulation are blocked by spinal administration of an antagonist of the N-methyl-Daspartate (NMDA) receptor subtype (469). On the other hand, Morrison et al. (375) reported that iontophoretic application of a NMDA antagonist to SPNs did not have any such effect. In summary, the electrophysiological, pharmacological, and immunohistochemical observations taken together support the view that the Cl cells are sympathoexcitatory and may use glutamate as their principal excitatory neurotransmitter. The observations are also consistent with the more general hypothesis put forward that glutamate is the principal fast-acting neurotransmitter utilized by all excitatory afferent inputs to SPNs (see sect. IIIB7). In the case of Cl neurons, even if this hypothesis is true, the role of the other colocalized putative neurotransmitters (epinephrine and NPY) remains unknown at this stage. 6. origin

of spontaneous

activity

As discussed in section IVAI, it is clear from many studies that RVLM neurons are tonically active and generate a large component of the resting sympathetic vasomotor activity in anesthetized animals. The question as to how tonic activity in RVLM vasomotor neurons is generated has been considered by different groups of workers, and at least three different mechanisms have been proposed. One suggestion is that the RVLM sympathetic premotor cells are chemosensitive and are tonically excited even at normal levels of blood pH, PO,, and PCO~ (133). In support of this theory, the blood flow and capillary density within the RVLM have been shown to be significantly greater than in surrounding areas (193), while an ultrastructural study has shown that the somata and dendrites of Cl neurons in RVLM are closely apposed to small capillaries (361). Furthermore, Seller et al. (436) demonstrated that sympathetic activity is rapidly and markedly increased by perfusion of the RVLM with a hypercapnic solution, even when synaptic

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inputs to RVLM neurons are blocked by local injection of cobalt chloride. Finally, localized hypoxia induced by microinjection of cyanide causes a short-latency excitation of RVLM bulbospinal neurons (459), which further supports the view that these cells can function as oxygen sensors. It is thus conceivable that the chemosensitivity of RVLM cells could contribute to the resting level of their tonic activity. Another suggestion, proposed by Guyenet et al. (ZIO), is that the pacemaker cells in the RVLM (see sect. 1vA2) are largely responsible for generating resting activity in sympathetic vasomotor neurons. This hypothesis is based on the observations that pacemaker cells exhibit a spontaneous activity even in the absence of synaptic inputs and have electrophysiological properties indicative of sympathoexcitatory neurons (465,466). Even if pacemaker cells make some contribution to the genesis of basal sympathetic tone, however, other observations by Guyenet et al. (210) indicate that they cannot be the sole source. Pacemaker cells are insensitive to clonidine (ZIO), yet microinjection of clonidine into the RVLM produces a marked fall in blood pressure, as mentioned in section 1vA4. On the other hand, Cl sympathoexcitatory cells in the RVLM, which do not have pacemaker-like properties, are inhibited by clonidine (218). Thus these observations suggest that this nonpacemaker group of RVLM sympathoexcitatory neurons also contributes to the resting sympathetic vasomotor tone. A third theory regarding the origin of resting activity in RVLM sympathoexcitatory neurons has been put forward by Barman and Gebber (40). They have proposed the existence of an ensemble of neurons (referred to as a “network oscillator”) in the brain stem that generates a basal level of activity, which in turn is then transmitted to RVLM sympathetic premotor neurons via an excitatory synapse. In anesthetized cats, most of the power of this activity lies in the 2- to ~-HZ frequency range, but more recent observations indicate that in unanesthetized decerebrate animals there is an additional component at a higher frequency, close to 10 Hz (42, 526). One difficulty with this model, however, is that bilateral injections of either cobalt or magnesium ions, which cause a nonspecific blockade of all synaptic transmission, do not reduce resting sympathetic activity or blood pressure (488). Furthermore, blockade of glutamate receptors within the RVLM, which appear to mediate excitatory inputs from a variety of central and peripheral sources, also does not reduce resting sympathetic activity or blood pressure (209, 278, 456, 491). Thus, although synaptic inputs to RVLM neurons may play an important role in determining the pattern of activity of these neurons (488), they are not essential for maintaining basal activity. In summary, there is not yet convincing evidence that any of the three proposed mechanisms described is the main generator of resting activity in RVLM sympathetic premotor neurons. It is possible that all may contribute to some extent, but their relative importance is unknown.

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B. Rostra1

CENTRAL

Ventromedial

CARDIOVASCULAR

Medulla

Neurons in the ventral medullary region just lateral to the pyramidal tract have been shown to project directly to SPNs innervating the adrenal medulla and all the major sympathetic ganglia in the rat (450,452). Various terms have been used to describe this region, including the parapyramidal region, nucleus interfascicularis hypoglossi, paraolivary nucleus, and the medial aspects of the nucleus paragigantocellularis lateralis (226). In this review the term rostra1 ventromedial medulla (RVMM) is used [Strack et al. (450)] to distinguish it from the more laterally located RVLM. Sympathetic premotor cells in the RVMM region can be distinguished from those in the RVLM principally on the basis of their chemical properties, although some recent work suggests that their functional properties also differ. The most striking feature of the chemical neuroanatomy of the RVMM is that it contains a high concentration of 5-HT cells, which are regarded as lateral extensions of the Bl and B3 cell groups (308, 448). Further details concerning the chemical properties of RVMM cells are discussed in section IV&?. I. Functional

properties

A study by Minson et al. (364) has demonstrated the pressor function of the RVMM, at least in the rat. In their study, stimulation of cells in the RVMM by microinjection of glutamate was shown to result in a modest rise in blood pressure. This effect was not mediated by pressor cells in the nearby RVLM, since it was unaffected by electrolytic lesions of the RVLM. On the other hand, it was abolished by pretreatment with 5,7-dihydroxytryptamine, a selective neurotoxin for 5-HT neurons. Thus these results suggest that the pressor effects produced by glutamate stimulation of the RVMM are mediated by 5-HT neurons, which are known to project directly to SPNs (226, 450, 452). One striking feature of the RVMM is that, like the midline raphe nuclei, it has a high density of 5-HT,, receptors (483). Direct activation of these receptors by selective agonists leads to a marked fall in blood pressure (191, 224). It is believed that activation of these receptors specifically inhibits 5-HT neurons (341), providing further support for the view that 5-HT neurons in the RVMM have a pressor function. Unlike the more extensively studied RVLM neurons, however, there does not appear to be any published information on the role of RVMM neurons in cardiovascular reflexes, or on the electrophysiological properties of single RVMM neurons. 2. Chemical properties

As reviewed recently by Helke et al. (226), the chemical properties of RVMM cells projecting to the IML cell

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column, the major location of SPNs, are complex. The compounds 5-HT, SP, TRH, and ENK have all been identified within these cells (226, 452). Furthermore, there is also extensive colocalization of such compounds within the same neurons. In particular, various combinations of 5-HT, SP, and TRH have all been colocalized in RVMM cells projecting to sympathetic preganglionic nuclei. There is not complete colocalization, however, so that some cells may contain only one or two of these compounds. In particular, ENK cells in the RVMM projecting to the IML cell column do not contain SP (226). Thus, in summary, there are several different types of RVMM cells projecting to the IML cell column that differ according to the combinations of putative neurotransmitters they contain. As discussed in detail in section 111B6, axon terminals containing the same combinations of neurotransmitters as found in RVMM cells have also been demonstrated within the IML. It is thus probable that the RVMM is a major source of these inputs to SPNs in the IML cell column. Furthermore, the existence of several chemically distinct descending pathways from RVMM sympathetic premotor neurons raises the possibility that they may also differ with regard to their specific functional roles. Unfortunately, our knowledge of the functions of RVMM sympathetic premotor neurons is still very sparse, so that any link between the chemistry and function of RVMM neurons is a matter only for speculation. C. Caudal Raphe Nuclei

The caudal raphe nuclei (raphe obscurus and pallidus) are located in the midline of the medulla. These nuclei are one of the major sources of descending inputs to the IML cell column (12, 304, 365), and their axons synapse with SPNs that innervate the adrenal medulla and all major sympathetic ganglia (450). I. Functional properties

Electrical or chemical stimulation of the medullary raphe nuclei can elicit either an increase or decrease in blood pressure and sympathetic activity, depending on the site of stimulation and the experimental conditions (3,153,175,220,340,344,364). The most likely explanation for these variable patterns of response is that the nuclei contain both sympathoexcitatory and sympathoinhibitory neurons, as revealed by single-cell recording experiments. The electrophysiological properties of raphe neurons that project directly to the IML cell column have been studied by Gebber and co-workers (41, 376, 377). Such neurons have firing patterns that are correlated with the sympathetic nerve activity and are excited by baroreceptor stimulation, indicating that they are sympathoinhibitory (41,376,377). Other raphe neurons are inhibited by baroreceptor stimulation and are therefore considered to be sympathoexcitatory. These, however,

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do not project to the IML cell column and thus are not sympathetic premotor neurons (376). Although some raphe neurons receive baroreceptor inputs, they are not a crucial component of the baroreceptor reflex pathway, since the reflex is maintained following lesions of the midline medulla that include the caudal raphe (342).

SPNs (81, 450, 452), its role in controlling the sympathetic outflow to cardiovascular effecters is not clearly established, largely because different types of physiological and pharmacological studies have yielded contradictory results.

2. Chemical

I. Functional

properties

Many sympathetic premotor neurons in the raphe nuclei are immunoreactive for 5-HT and are thus presumed to be serotonergic neurons (308,448). In addition, a variety of neuropeptides (SP, TRH, ENK, and SOM) have also been identified within these neurons (97,233, 432,452). It is likely that, as is the case with sympathetic premotor neurons in other regions, two or more of these transmitters may be colocalized in some raphe neurons, although there is little direct evidence regarding this point. The transmitter content of the raphe sympathoinhibitory neurons projecting to the IML cell column is not known. Recent work, however, suggests that they are not serotonergic neurons. McCall and Clement (341) identified individual IML-projecting 5-HT neurons in the raphe by several criteria, then compared their firing pattern and response to baroreceptor input with those of other IML-projecting raphe neurons that did not have the characteristics of 5-HT neurons. The putative serotonergic neurons had a regular firing pattern but were not affected by baroreceptor input. In contrast, the nonserotonergic neurons had an irregular firing pattern and were excited by baroreceptor input. In summary, then, the nonserotonergic neurons are likely to be sympathetic premotor inhibitory neurons, while the function of the serotonergic group remains to be determined. It has been speculated that such neurons may act as neuromodulators, setting the general level of excitability of SPNs rather than conveying inputs to functionally specific groups of SPNs (341). 3. Aferent

inputs

Electrophysiological observations indicate that cells within the medullary lateral tegmental field project to, and tonically excite, sympathetic premotor inhibitory neurons in the raphe nuclei (41). Anatomic tracttracing studies have described inputs to the caudal medullary raphe nuclei from the NTS, RVLM, and hypothalamus (239, 306, 318), although it is not clear whether these inputs project specifically to cardiovascular neurons in the raphe or to neurons subserving other functions. There is thus very little information on the origin of afferent inputs to raphe cardiovascular neurons, and even less on the role that such inputs may play in the central pathways subserving cardiovascular reflexes. D. A5 Noradrenergic

Cell Group

Although the A5 cell group in the pons (Fig. 3) is one of the major sources of noradrenergic innervation of

properties

Chemical stimulation of the A5 region produces decreases in blood pressure and heart rate, which are due mainly to inhibition of sympathetic vasomotor activity (156, 307, 383). The simplest interpretation of this finding is that spinally projecting A5 cells directly inhibit vasomotor SPNs. It is more likely, however, that the depressor response is mediated by nonadrenergic cells in the A5 area, since it is only slightly reduced when the norepinephrine content of the spinal cord is virtually completely eliminated by administration of the neurotoxin 6-hydroxydopamine (307). Spinally projecting A5 cells are more likely to be excitatory rather than inhibitory to SPNs, since they are inhibited by baroreceptor inputs (15,81,207,246). In support of this, a recent study has shown that stimulation of the A5 region produces an increase in renal and splanchnic sympathetic activity, an effect which is abolished by administration of 6-hydroxydopamine (245). An alternative hypothesis, suggested by Byrum and Guyenet (80), is that the A5 cells are not simply the source of an excitatory input to SPNs, but rather have a function analogous to that of the other major pontine group of noradrenergic cells in the locus ceruleus. Just as the locus ceruleus is believed to influence the overall responsiveness of cells in many different parts of the brain to internal and external stimuli (22, 171), so the A5 cells may affect integrated cardiovascular responses by widespread actions on cardiovascular nuclei located in several different regions (80). Consistent with this hypothesis, A5 cells have been shown to have widespread projections to autonomic nuclei distributed throughout the central nervous system, in the medulla oblongata, pons, midbrain, hypothalamus, and limbic system (80, 307). In this regard, it is interesting that although A5 cells are inhibited by baroreceptor inputs, they do not exhibit a cardiac rhythmicity as displayed by RVLM cardiovascular neurons (246). Clearly, more information on the physiological properties of A5 cells is required before firm conclusions can be made about their precise role in cardiovascular regulation. 2. Anatomic

inputs

Retrograde transport studies have shown that the A5 region receives inputs from the perifornical area and PVN in the hypothalamus, the Kolliker-Fuse nucleus and lateral parabrachial nucleus in the pons, and the NTS in the medulla oblongata (80,518). Presumably, the pathway from the NTS transmits signals from baroreceptors and other peripheral receptors to A5 cells, but

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the functional is unknown.

significance

E. Paraventricular I. Anatomic

CARDIOVASCULAR

of the other afferent inputs

Nucleus

properties

The PVN in the hypothalamus is one of the major sources of afferent inputs to SPNs (240, 317, 450, 452). The PVN also innervates other autonomic nuclei, including the midbrain PAG, parabrachial region, RVLM, NTS, dorsal vagal nucleus, and the nucleus ambiguus (129,31’7), and it is possible that some PVN cells provide a collateral innervation of some of these nuclei. At least in the case of descending projections to the spinal cord, however, PVN neurons innervating SPNs with different target ganglia arise from separate, topographically distinct populations (452). 2. Functional

properties

In contrast to our detailed knowledge of the anatomy of descending pathways from the PVN (474), the specific role of these pathways in cardiovascular regulation is poorly understood. Experiments in which the PVN has been electrically or chemically stimulated have yielded conflicting results. For example, electrical stimulation of the PVN has been reported to produce both increases and decreases in blood pressure and sympathetic activity (187, 404, 519). Even when PVN neurons are excited by microinjection of excitatory amino acids, both pressor and depressor effects have been reported (184, 266, 272, 519). The explanation for such variable effects, however, may be that PVN cells exert nonuniform effects on SPNs controlling different target organs. In particular, glutamate stimulation of the PVN elicits an increase in adrenal nerve activity and a decrease in renal nerve activity (272), so that the net effect on blood pressure would depend on the balance of these opposing sympathetically mediated changes. Such differential control by PVN neurons of different sympathetic outflows is consistent with the anatomic demonstration of different subgroups of PVN neurons innervating different types of SPNs (see sect. IvEI). In addition, the PVN also projects to other autonomic nuclei in the brain stem, which in turn may also influence the sympathetic vasomotor outflow. Thus the effects of PVN stimulation cannot be attributed entirely to excitation of the PVNspinal pathway. The role of the PVN-spinal pathway in mediating cardiovascular reflexes has not been extensively studied, but some information is available. The NTS, the site of termination of primary afferent fibers arising from arterial and cardiopulmonary baroreceptors and arterial chemoreceptors (see sect. vBQ, projects to the PVN both via.a direct pathway and indirectly via the parabrachial nucleus in the pons (174,434). Lovick and Coote

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(314) recorded the activity of spinally projecting PVN neurons and found that most were inhibited by baroreceptor inputs, which appear to originate mainly from the heart. They found, however, that this inhibitory effect could only be demonstrated when the basal firing rate of the PVN-spinal neurons was artificially increased by application of excitatory amino acids, since these neurons were mainly quiescent under resting conditions in the anesthetized animal. This suggests that these neurons play little role in the moment-to-moment regulation of blood pressure (314). Lesions of the PVN have been shown to have little effect on the cardiac component of the baroreceptor reflex but increase the baroreceptor-induced inhibition of lumbar sympathetic activity (134, 391). Some evidence also indicates that the integrity of the PVN is essential for the production of certain types of neurogenic hypertension (26,107,525). The available evidence, then, indicates that the PVN may modulate the operation of cardiovascular reflexes, possibly via its connections with the NTS (see sect. vB3), and may also play an important role in the regulation of blood pressure in the longer term, or under abnormal conditions such as neurogenic hypertension. F. Other Sympathetic

Premotor

Cell Groups

Other cell groups that project directly to SPNs, as labeled by the method of retrograde transneuronal transport of viruses, are found within the midbrain PAG, the lateral hypothalamic area, and the zona incerta (450). These regions were only labeled following injection of the viruses into the most rostra1 sympathetic ganglia and thus may only innervate SPNs at the thoracic level of the cord. Moreover, these regions are also known to project to other central autonomic nuclei, so that their influence on the cardiovascular system (which is discussed in sect. VI) may be mediated by indirect as well as direct connections to vasomotor and cardiac SPNs. G. Summary

Despite the wealth of information on the anatomy of descending pathways controlling cardiovascular SPNs, there is still a surprising lack of knowledge concerning the precise role of these pathways in cardiovascular regulation. The exception to this is the descending pathway from the RVLM, which has been the most thoroughly studied. Of all the sympathetic premotor nuclei, it is the only one so far identified that is critical for the operation of cardiovascular reflexes and that has been shown to be a major source of tonic excitatory input to cardiovascular SPNs. This does not necessarily mean that other sympathetic premotor nuclei are not important components of the central mechanisms subserving cardiovascular reflexes; rather, the experimental methods so far employed have not yet provided enough infor-

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mation on the functions to allow their functional

V.

CENTRAL

PROCESSING

AFFERENT

INPUTS

A. Sources of Aferent

of these other premotor roles to be defined.

OF

nuclei

CARDIOVASCULAR

Inputs

Signals arising from a large array of peripheral receptors influence the activity of cardiovascular autonomic nerves. As reviewed by Spyer (447), these include the arterial baroreceptors (located principally in the aortic arch and carotid sinus), cardiac baroreceptors (located in the walls of the atria and ventricles), and arterial chemoreceptors (located in the carotid and aortic bodies). The afferent fibers from these receptors are all part of the glossopharyngeal and vagal cranial nerves, and all terminate in the NTS. Collectively, they provide moment-to-moment information about the pressures in the arterial system, cardiac chambers, and great veins, as well as the chemical composition of the arterial blood. Although most textbooks emphasize the role of glossopharyngeal and vagal afferent fibers in cardiovascular reflexes, afferent inputs entering the spinal cord via the dorsal roots also exert powerful influences on cardiovascular function. These arise from a vast array of somatic and visceral receptors, including skin nociceptors, chemoreceptors in skeletal muscle, and receptors in the heart, aorta, pulmonary vasculature, and kidney (321,396,433,482,508). Signals from these receptors elicit reflex changes in sympathetic activity at a segmental level (433) but, in addition, are transmitted over ascending pathways that terminate in various brain stem nuclei, including the NTS, RVLM, and pontomedullary reticular formation (76, 352, 398). Finally, powerful cardiovascular reflexes, such as the diving or nasopharyngeal reflexes (13, 512), can be elicited by stimulation of trigeminal afferents. The central pathways mediating nasopharyngeal reflexes are largely unknown, although signals from trigeminal afferent fibers do reach the NTS (352).

I. Sites of termination

of the Solitary

Tract

It is clear from section VA that the NTS is the principal site of termination of primary afferent fibers arising from many cardiovascular receptors, as well as a major site of termination of second-order neurons receiving inputs from many other visceral and somatic receptors. Furthermore, neurons within the NTS are essential components of the central pathways mediating the principal homeostatic cardiovascular reflexes regulating blood pressure and fluid balance (305, 447). Because of its importance in cardiovascular reflex control, the NTS has been a major focus of anatomic and functional studies in recent years.

of primary

74

aferent$bers

Many studies, using both anatomic tract-tracing and electrophysiological techniques, have demonstrated that different types of cardiovascular afferent fibers have different sites of termination within the NTS. The aortic nerve in the rat and rabbit, which consists mainly of baroreceptor fibers, terminates most densely in the dorsomedial and lateral subnuclei of the NTS, just rostral to the obex, and much less densely in the commissural subnucleus caudal to the obex (103, 504). In contrast, afferents arising from the carotid body in the rat terminate most densely in the commissural subnucleus and in the medial subnucleus at the level of the obex (169), while carotid sinus afferents in the rat and cat (which arise from both baroreceptors and chemoreceptors) terminate densely in all of these subnuclei (106, 241). In support of these anatomic studies, Donoghue and co-workers (149, 150) used the technique of antidromic mapping to demonstrate that identified chemoreceptor afferents terminate mainly caudal to the obex, while baroreceptor afferents terminate mainly rostra1 to the obex. Similarly, terminals arising from cardiac afferent fibers also appear to have their own specific site of termination, within the medial subnucleus of the NTS (151). In summary, therefore, although there is some overlap, it is clear that each type of cardiovascular afferent input has its own specific terminal field within the NTS. Consistent with these observations, Donoghue et al. (148) found that the large majority (-85%) of cells in the NTS that were excited by carotid sinus, aortic, or vagal stimulation only responded to one of these inputs. Even in cases where convergence of inputs occurred, there was no evidence that this reflected an integration of afferent signals from different types of receptors (e.g., baroreceptors and chemoreceptors), rather than receptors of the same type but located in different regions in the cardiovascular system (148). Thus the evidence indicates that signals from different receptor types are transmitted through the NTS largely via separate channels. 2. Neurotransmitters

B. Nucleus

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aflerent Jibers

As reviewed recently by Leslie (292), the NTS is innervated by terminal fibers that contain a wide variety of putative neurotransmitters, including amino acids, monoamines, and neuropeptides. Although it was suggested some years ago that the neuropeptide SP may be the neurotransmitter of baroreceptor primary afferent fibers (190), more recent studies indicate that the excitatory amino acid glutamate is a more likely candidate. The strongest evidence for this hypothesis is that blockade of glutamate receptors in the NTS with kynurenic acid abolishes the baroreceptor reflex (209, 211, 476). In contrast, the baroreceptor reflex is not affected by blockade of SP receptors in the NTS (286). Studies have also been carried out to determine

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which type (or types) of glutamate receptor mediates the synaptic actions of primary baroreceptor afferent fibers. Microinjection into the NTS of a selective antagonist to the NMDA receptor reduces but does not abolish the cardiovascular reflex response to aortic baroreceptor stimulation, suggesting that this glutamate receptor type is involved in baroreceptor afferent synaptic transmission (286). On the other hand, blockade of nonNMDA receptors in the NTS completely abolishes the aortic baroreceptor reflex in vivo (ZOO). Similarly, an intracellular in vitro study has shown that blockade of non-NMDA receptors completely abolishes the shortlatency excitatory postsynaptic potentials normally evoked by stimulation of afferent inputs to NTS cells (17). Thus it has been suggested that glutamate receptors of the non-NMDA type mediate fast synaptic transmission from baroreceptor primary afferent fibers to second-order neurons in the NTS, while NMDA receptors play a modulatory role (17, ZOO). Like the baroreceptor reflex, the chemoreceptor reflex is also mediated by glutamate receptors within the NTS, but the subtypes are not identical. The chemoreceptor reflex is abolished by simultaneous blockade of both NMDA and non-NMDA receptors within the NTS, but not by either group of receptors alone (496). Furthermore, the glutamate receptors mediating the chemoreceptor reflex are located within the commissural subnucleus of the NTS (496), which corresponds to the site of termination of chemoreceptor primary afferent fibers, as determined by anatomic and antidromic mapping studies (see sect. vB1). 3. Modulation

of signal transmission

The NTS receives afferent inputs from nuclei at all levels of the brain, including the cortex, amygdala, perifornical region and PVN in the hypothalamus, parabrachial nucleus, midbrain PAG, A5 area in the pons, cauda1 medullary raphe nuclei, area postrema, and ventrolateral medulla (34,186, 388, 392,416,421,435, 478,485, 494, 495). Stimulation of some of these regions (the amygdala, perifornical region, PVN, parabrachial nucleus, area postrema, and the ventrolateral medulla) has been shown to modulate signal transmission within the NTS (117,165,214,221,267,356,505), but the physiological effects of stimulating the other inputs have not been studied in detail. As mentioned in section vBZ, terminal fibers within the NTS have been shown to contain a wide variety of putative neurotransmitters, including catecholamines, serotonin, ENK, angiotensin II, NPY, and atria1 natriuretic factor (292). There is also a concentration of receptor binding sites for all these compounds in the NTS (25, 289, 319, 322, 351, 484, 490). Activation of these receptors has been shown to either increase or decrease the sensitivity of the baroreceptor reflex (86, 87, 161, 166, 199, 204, 284, 353, 354). There is little information, however, regarding the origin of the neural pathways that activate these receptors, and even less about the

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stimuli that lead to their activation. Furthermore, other receptor types within the NTS, other than those listed here, may also alter the function of the baroreceptor reflex. The most detailed information on the processing of cardiovascular signals within the NTS has come from recent intracellular studies. In particular, the effect of stimulation of the so-called defense area in the hypothalamus on the transmission of baroreceptor signals in the NTS has been examined. Stimulation of this region elicits a pattern of cardiovascular changes referred to as the “defense reaction,” since it resembles that elicited by a threatening stimulus in a conscious animal (263). The defense area corresponds to the perifornical region of the hypothalamus and is believed to contain cells or axons of passage which either project directly to the NTS or synapse with cells within the midbrain PAG, which in turn project to the NTS as well as to other cardiovascular nuclei in the medulla oblongata (34,263). Whatever the details of the central pathways mediating the defense reaction, it has long been known that the baroreceptor reflex is powerfully inhibited when the reaction is elicited by hypothalamic stimulation in anesthetized animals (114). This phenomenon is explained by the observation that excitation of the defense area evokes a long-lasting postsynaptic inhibition of all NTS cells that receive an excitatory input from peripheral baroreceptors (356). The inhibition is mediated by GABA (264) and is graded according to the degree of hypothalamic stimulation. The studies referred to above provide many examples of inputs to the NTS, acting on different membrane receptors, that are capable of altering the effectiveness of the baroreceptor reflex in anesthetized animals. The extent to which such modulation of cardiovascular reflexes occurs during natural behaviors in conscious animals or humans, however, is unclear. To take the example of the defense reaction, the electrophysiological studies in anesthetized animals referred to above imply that, during such behavior in conscious animals, the baroreceptor reflex is powerfully suppressed. In fact, a study in the conscious cat has demonstrated that this is not the case (27). Similarly, although it is often assumed that baroreceptor reflexes are modulated during exercise, studies in humans and animals provide little clear evidence in support of this hypothesis (315). Thus, despite the demonstration of the existence of afferent inputs to the NTS that can inhibit or enhance the operation of the baroreceptor reflex, their physiological importance during different natural behaviors is not known. There have been fewer studies of the role of the NTS in modulating the cardiovascular reflex response to chemoreceptor stimulation. It has long been known that this reflex is subject to respiratory modulation (123,124, 405), and it has been suggested that such modulation may occur at an early stage of the central reflex pathway, such as in the NTS (124,405). However, an intracellular recording study has clearly demonstrated that the response of NTS neurons to chemoreceptor stimulation was unaffected either by central respiratory drive or by

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lung stretch receptor input (355). Therefore, such modulation of the chemoreceptor reflex must occur at a later stage in the central pathway mediating the reflex. 4. Eflerent

outputs

The NTS projects to various regions in the spinal cord, lower brain stem, midbrain, and forebrain that are known to play an important role in cardiovascular control. These regions include the IML cell column, the RVLM and caudal ventrolateral medulla, the medullary raphe nuclei, the A5 area and parabrachial complex in the pons, the midbrain PAG, the PVN, the lateral hypothalamic area, and other forebrain nuclei (Fig. 5) (20, 129,228,305,306,389,414,415,422,442). One feature of these connections is their specificity; different subnuclei within the NTS project to different targets and may

paraventricular nucleus

lateral hypothalamic area lateral parabrachial nucleus

Kijlliker-Fuse nucleus

A5 cell group rostra1 ventrolateral medulla

nucleus solitary

of the tract

caudal ventrolateral medulla

caudal raphe FIG. 5. Major efferent projections from nucleus of solitary tract to nuclei in spinal cord, medulla, pons, and hypothalamus known to have a cardiovascular function. In addition, there are also projections (not shown) to other targets such as midbrain periaqueductal gray, amygdala, and region surrounding anteroventral part of third ventricle. VII nerve, facial nerve; IO, inferior olive; LRN, lateral reticular nucleus; NTS, nucleus of solitary tract; SpV, spinal trigeminal nucleus; VMH, ventromedial nucleus of hypothalamus. [Modified from Loewy (305).]

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also differ with respect to their neurotransmitter content (228, 229, 415). Despite the wealth of information on the anatomic and chemical properties of NTS projection neurons, much less is known about their precise functions. An increasing amount of information is accumulating, however, with respect to the specific NTS efferent projections that convey signals from peripheral baroreceptors to other brain nuclei. The organization of these and other central neural pathways that subserve the baroreceptor reflex is discussed in section VIIB. VI.

BRAIN

REGIONS

SYMPATHETIC

CONTROLLING PREMOTOR

CARDIOVASCULAR NUCLEI

Apart from sympathetic premotor nuclei (see sect. other cell groups located at different levels of the neuraxis are capable of profoundly altering cardiovascular function, even though they do not project directly to SPNs. The anatomic, functional, and pharmacological properties of these various cardiovascular cell groups are discussed in the following sections. IV),

A. Caudal Ventrolateral

Medulla

The first demonstration of the existence of cell bodies in the caudal ventrolateral medulla (CVLM) that are capable of altering cardiovascular function came from the pharmacological studies of Feldberg and Guertzenstein (164) who found in the cat that application of nicotine to the nearby ventral surface elicited a fall in blood pressure. Detailed studies in the rabbit, using the method of stimulation of cell bodies by microinjection of excitatory amino acids, have demonstrated that the depressor neurons in the CVLM are located mainly in the region between the nucleus ambiguus and lateral reticular nucleus (294, 328). The depressor response evoked by stimulation of cells in the CVLM is due to a decrease in total peripheral resistance and is accompanied by a widespread inhibition of sympathetic vasomotor activity and a decrease in cardiac contractility (57, 154, 517). In contrast, inhibition of CVLM cells, by local injection of the GABA receptor agonist muscimol, results in an increase in blood pressure, total peripheral resistance, and cardiac contractility (59, 154), demonstrating that these cells are tonically active. It is very interesting to note, however, that a recent study by Smith and Barron (441) has shown that in spontaneously hypertensive rats inhibition of CVLM cells has no effect on blood pressure, in contrast to the effect seen in normotensive strains. It therefore follows that CVLM sympathoinhibitory neurons, at least in this particular strain of hypertensive animals, have no resting tonic activity. The identification of the CVLM sympathoinhibitory neurons has been until recently a matter of controversy. Originally, it was suggested that they are part of the Al group of norepinephrine-synthesizing cells in the

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CVLM (60), which were first described by Dahlstrom and Fuxe (El). More recently, however, precise mapping of depressor sites in the CVLM of the rat has shown that these are located outside the Al cell group (65). Moreover, there is now a large body of evidence which indicates that Al cells provide a direct excitatory input to vasopressin-secreting cells in the hypothalamus, so that their stimulation leads to a pressor rather than depressor response (see sect. VIIB3). Another question concerns the pathway connecting CVLM depressor neurons to the sympathetic vasomotor outflow. Although there are spinally projecting cells in the CVLM depressor region (54), these do not appear to project directly to SPNs (450, 452). In fact, the sympathoinhibitory pathway originating in the CVLM includes an inhibitory GABAergic synapse with RVLM neurons (52, 515). On the basis of these observations, therefore, it was suggested that the CVLM depressor neurons are GABAergic and project directly to RVLM sympathetic premotor neurons (52, 515). In support of this, a recent anatomic study has demonstrated a pathway from the CVLM depressor region directly to sympathetic premotor neurons in the RVLM and A5 areas, including catecholamine neurons in both regions (300), while electrophysiological studies have shown that neurons in the CVLM depressor region can be antidromitally activated from the RVLM (4, 185). Pharmacological studies have shown that the CVLM neurons receive both tonically active excitatory and inhibitory inputs. Blockade of NMDA receptors in the CVLM leads to a sharp rise in blood pressure (286), indicating that glutamate or another excitatory amino acid is tonically released. In fact, the release of endogenous glutamate in the CVLM has been demonstrated (286). In addition, CVLM depressor neurons have also been shown to be tonically excited by endogenous angiotensin II, or an angiotensin II-like compound (431), and tonically inhibited by endogenous GABA, glycine (or a glycinelike compound), and opioids (32, 59, 155, 514). In summary, then, CVLM depressor neurons are a site of convergence of both excitatory and inhibitory inputs, the pharmacological properties of which have been at least partly characterized. Much more work is required, however, to establish the origin of these various inputs and their roles in mediating cardiovascular reflexes. The particular question of the role of CVLM vasomotor neurons in mediating baroreceptor-induced inhibition of the sympathetic vasomotor outflow, which has been the subject of several investigations, is discussed in detail in section VIIB. B. Medullary Lateral Tegmental Field

The lateral tegmental field in the medulla is a large area that corresponds to the nucleus reticularis parvocellularis and nucleus reticularis ventralis. Since the original study of Wang and Ranson (506), it has been known that electrical stimulation of this region can elicit large increases in blood pressure, and it therefore

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341

corresponds to the classical pressor area of the medulla. Bilateral destruction of this region will result in a large fall in resting blood pressure (287). Although it has been suggested that the effects of electrical stimulation or lesions of this area are due to activation and destruction, respectively, of the axons of RVLM sympathetic premotor neurons that pass through this area (163,420), there are also neuronal perikarya within the lateral tegmental field which, when stimulated, increase or decrease sympathetic vasomotor activity (39,41,181,195). The electrophysiological studies of Barman and Gebber (39, 41) indicate that both sympathoexcitatory and sympathoinhibitory neurons within the lateral tegmental field exert their effects via direct projections to sympathetic premotor neurons within the RVLM and caudal medullary raphe nuclei, respectively. Moreover, the inputs to the RVLM and caudal medullary raphe from lateral tegmental neurons appear to be tonically active (39,41). Anatomic studies have shown that a few neurons within the lateral tegmental field are retrogradely labeled following injection of a tracer into the RVLM sympathetic premotor cell group, but the projection appears to be a very minor one when compared with the inputs from other regions of the brain stem and hypothalamus (129; Fig. 4). Thus this anatomic study does not support the view of Barman (36) that lateral tegmental field neurons are a major source of direct input to RVLM neurons. It is, of course, also possible that the lateral tegmental neurons may influence sympathetic vasomotor activity via other polysynaptic pathways; for example, via an ascending projection to the parabrachial complex (274). Although it has been shown that neurons within the lateral tegmental field with sympathetic-related activity can be either excited or inhibited by inputs from peripheral baroreceptors (181), there is little information regarding their importance as part of the central mechanisms mediating cardiovascular reflexes. Again, anatomic studies indicate that the lateral tegmental field (apart from the RVLM and CVLM) is not a major target of projections from the NTS (306, 422). At the same time, it should be cautioned that the cardiovascular neurons within the lateral tegmental field appear to be distributed rather diffusely, so the extent of their afferent innervation from other nuclei is difficult to assess. C. Area Postrema

The area postrema is a circumventricular organ located on the dorsal surface of the medulla, which is highly vascular but lacks a blood-brain barrier. Consequently, area postrema neurons are readily accessible to circulating substances including peptide hormones. The area postrema has long been thought to contain chemosensitive elements that trigger vomiting (66, 67), but there is also now a considerable body of evidence which indicates that this structure plays an important role in cardiovascular regulation, particularly by acting as a

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link between circulating hormones and central autonomic pathways. In particular, it has been shown that circulating angiotensin can excite area postrema neurons, which in turn leads to a rise in blood pressure (167). Second, circulating vasopressin has been shown to facilitate the baroreceptor reflex, via an action on neurons in the area postrema (438,489). Consistent with this, there is a major projection from the area postrema to the adjacent NTS (437, 493). Other major projections of the area postrema are to the parabrachial complex and the RVLM (55, 129, 422, 437, 493). The functions of these projections are unknown, but it is possible that they are components of the central pathways mediating the pressor response produced by circulating angiotensin or other peptides (167). D. Cerebellar

Nuclei

Stimulation of certain cerebellar nuclei can elicit marked cardiovascular effects. In particular, it has been known for many years that electrical stimulation of the fastigial nucleus causes a rise in arterial pressure in a number of species (2,73,74,102,147,152,242,384), which is due to an increase in sympathetic activity (2, 147). More recently, however, it has been shown that selective stimulation of cell bodies by microinjection of excitatory amino acids into the fastigial nucleus does not elicit a pressor response (74,366). Furthermore, the response to electrical stimulation persisted after destruction of cell bodies within the nucleus by injection of cytotoxic chemicals (366). It can therefore be concluded that the pressor response elicited by electrical stimulation of the fastigial nucleus is probably due to excitation of axons passing through or near the nucleus. Stimulation of cell bodies within another cerebellar region, sublobule IX (the uvula) in the posterior cerebellar cortex, does elicit cardiovascular and respiratory changes, but the pattern of these effects is dependent on the type of experimental preparation. In anesthetized cats and rabbits, a depressor and sympathoinhibitory response was elicited, whereas in decerebrate animals, a pressor and sympathoexcitatory response was elicited (69, 73). The central pathways mediating these two responses are different. The pressor response observed in decerebrate animals is mediated by a pathway that includes GABAergic synapses in the caudal part of the lateral parabrachial nucleus and in the NTS, while that mediating the depressor response in anesthetized animals includes a GABAergic synapse in the rostra1 part of the lateral parabrachial nucleus and is independent of the NTS (394). Stimulation of the uvula has also been shown to elicit either excitation or inhibition of RVLM neurons, suggesting that these neurons may act as a final common pathway for both the pressor and depressor responses (440). The uvula receives afferent inputs from many sensory nuclei in the brain stem, including vestibular, auditory, visual, somatosensory, and nociceptive nuclei (70).

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This has led to the suggestion that the uvula may play a role in mediating cardiovascular responses to alerting or orientating stimuli (70, 395). In support of this hypothesis, electrical stimulation of the uvula in the conscious rabbit elicited an increase in arterial pressure accompanied by other autonomic, somatomotor, and electroencephalogram (EEG) changes indicative of increased alertness (71). On the other hand, removal of the uvula does not affect the cardiovascular and EEG response to an auditory stimulus (72). However, as pointed out by Paton and Spyer (395), it is possible that the uvula may be more important in mediating responses to other types of alerting stimuli, or even to specific combinations of such stimuli. E. Parabrachial

Complex

The parabrachial complex is located in the dorsolatera1 part of the rostra1 pons. It is separated by the brachium conjunctivum into two nuclei, the lateral and medial parabrachial nuclei, and includes also the KollikerFuse nucleus that is ventrolateral to the brachium conjunctivum. The parabrachial complex is the main relay for the transmission of visceral afferent information from the NTS to forebrain nuclei [for reviews, see Herbert et al. (228) and Loewy (305)]. In addition, various subnuclei within the complex make reciprocal connections with the NTS and with those portions of the RVLM that contain respiratory and cardiovascular neurons (228). Detailed anatomic studies (e.g., Refs. 228, 274) of the connections of the parabrachial complex have led to the general conclusion that afferent inputs representing different visceral sensory modalities are topographically represented within the parabrachial complex much as they are in the NTS (see sect. vBI). Similarly, the efferent projections of the complex to the forebrain and autonomic nuclei in the medulla are also highly specific (174). Despite the detailed information on the connections of the parabrachial complex, less is known about the functional role of this nucleus, particularly in cardiovascular regulation. Electrical stimulation of sites within the lateral parabrachial nucleus elicits increases in blood pressure and sympathetic vasomotor activity (45, 96,212,357,380,393). Microinjections of glutamate into the same region can elicit either increases or decreases in blood pressure, but the magnitude of the responses is rather modest (96,367,393). The results suggest the existence of both sympathoexcitatory and inhibitory neurons in the lateral parabrachial nucleus, but little is known about their role in mediating cardiovascular reflexes. As discussed in section VID, however, different groups of neurons in the lateral parabrachial nucleus are part of the separate pathways mediating pressor and depressor responses, respectively, arising from stimulation of cells in the posterior cerebellar cortex. The output pathways from the lateral parabrachial nucleus mediating these pressor and depressor responses is not clearly defined. There is functional evidence that the NTS relays pressor responses elicited by

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stimulation of the lateral parabrachial nucleus (393). Consistent with this, there are direct projections from the lateral parabrachial nucleus to the NTS (174) and to the RVLM region containing sympathetic premotor neurons (367). In summary, both functional and anatomic evidence clearly indicate that the parabrachial nucleus is an important component of the pathways relaying visceral afferent information to higher brain regions. It also appears to be a component of descending pathways between higher brain regions and SPNs, but the functional significance of these pathways has been only partly characterized. F. Locus Ceruleus The locus ceruleus, also referred to as the A6 group of noradrenergic neurons, has extensive efferent projections to many parts of the brain and spinal cord (24,171, 262). In contrast, its afferent inputs are much more limited, arising from two regions within the medulla oblongata, the ventral medulla and the nucleus praepositus hypoglossi (23). The functions of the locus ceruleus are not established, although there is a growing body of evidence that supports the view that it acts as a site of convergence of afferent information from many different sources and that the level of activity of locus ceruleus neurons is related to the level of vigilance of an animal (22). With regard to its role in cardiovascular control, it has been shown that changes in blood volume or blood pressure are among the many stimuli that can affect the firing rate of locus ceruleus neurons (159, 160). Several studies have also shown that electrical stimulation of the region containing the locus ceruleus elicits an increase in blood pressure (206,407,470,507). These studies were interpreted as evidence that locus ceruleus neurons have a pressor function, although more recent studies (368, 472) have shown convincingly that selective stimulation of noradrenergic cell bodies within the nucleus elicits a decrease in blood pressure, renal sympathetic activity, and heart rate. Thus the pressor effects produced by electrical stimulation probably result from excitation of axons of passage, possibly originating from cardiovascular nuclei in the midbrain or hypothalamus (see sects. VIG and VIH). It has been shown that the depressor response to chemical stimulation of the locus ceruleus is not altered by midbrain transection (368), demonstrating that this response must be mediated by a descending pathway. This pathway is unknown, although it must include a synapse (or synapses) within the lower brain stem, since the locus ceruleus does not project directly to SPNs (173, 450). Similarly, the functional significance of the depressor effects evoked by stimulation of locus ceruleus neurons is also unknown. G. Midbrain

Periaqueductal

Gray

The midbrain PAG has long been known to play an important role in functions such as antinociception and

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defensive behavior [for reviews, see Basbaum and Fields (44) and Bandler (33)], but its role in cardiovascular control has received relatively little attention. Microinjection of relatively large volumes of excitatory amino acids into the PAG of the rat and rabbit has been shown to cause increases in blood pressure accompanied by vasodilatation in skeletal muscle beds (230, 477, 502, 520), which is similar to the pattern of cardiovascular changes originally termed the defense reaction by Abrahams et al. (1). Recently, major advances have been made in our knowledge of the organization and functional role of cardiovascular neurons in the PAG, mainly as a result of a series of physiological and anatomic studies by Carrive and co-workers [for review, see Carrive (SS)]. Focal stimulation of cell bodies in different regions of the PAG of the cat elicits different patterns of cardiovascular changes, depending on the precise site of stimulation. For example, stimulation of cells in the rostra1 part of the lateral PAG elicits a rise in blood pressure accompanied by skeletal muscle vasoconstriction, with little change in renal vascular resistance, while stimulation of cells in the more caudal part of the lateral PAG also results in a rise in blood pressure, but in this case is accompanied by strong renal vasoconstriction with little neurogenic effect on skeletal muscle resistance (92). Thus, as in the medullary subretrofacial nucleus (see sect. IVAI), there are different groups of neurons in the PAG that have different effects on regional vascular beds. Depressor and vasodilator responses can also be evoked from the PAG, by stimulation of sites within its ventrolateral portion (90). In this case, also, stimulation of rostra1 and caudal parts of the ventrolateral PAG preferentially affected the vascular resistance of the skeletal muscle and renal vascular beds, respectively. These functional observations on the viscerotopic organization of PAG vasomotor neurons correlate very well with anatomic observations on the connections between the PAG and the medullary subretrofacial nucleus in the cat (90,92). As discussed in section IvAI, the subretrofacial nucleus contains a high density of RVLM cardiovascular sympathetic premotor neurons, which are organized viscerotopically according to the vascular beds they control. As summarized in Figure 6, neurons in the lateral and ventrolateral parts of the rostra1 PAG, which respectively increase and decrease skeletal muscle vascular resistance, project directly to the caudal part of the subretrofacial nucleus, which preferentially controls the sympathetic vasomotor output to skeletal muscle beds. The same organizational principle also applies to the connections between renal vasomotor neurons in the PAG and the subretrofacial nucleus (Fig. 6). In summary, then, these observations support the hypothesis that vasomotor neurons within the PAG are organized viscerotopically according to the vascular bed or beds that they control and make highly specific connections with RVLM sympathetic premotor neurons (89). Similarly, recent studies in the rat have demonstrated that neurons in different parts of the PAG can

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LATERAL PRESSOR COLUMN

VENTROLATERAL DEPRESSOR COLUMN ‘iI rost ral I I

MIDBRAIN PAG

rostra1 MEDULLARY SRF NUCLEUS

caudal

SPINAL CORD

$+a

KIDNEY SKELETAL MUSCLE inhi bitory inputs exe itatory r inputs

FIG. 6. Proposed descending pathways from midbrain periaqueductal gray (PAG) that regulate sympathetic vasomotor output to skeletal muscle and renal vascular beds. Neurons in rostra1 and caudal parts of lateral pressor column in PAG provide an excitatory input to neurons in caudal and rostra1 parts, respectively, of subretrofacial (SRF) vasomotor nucleus in rostra1 ventrolateral medulla. Similarly, neurons in rostra1 and caudal parts of ventrolateral depressor column in PAG provide an inhibitory input to neurons in caudal and rostra1 parts, respectively, of SRF vasomotor nucleus. Neurons in caudal and rostra1 parts of SRF nucleus project preferentially to sympathetic vasomotor outflows controlling skeletal muscle and renal vascular beds, respectively. Note that at all levels of the neuraxis there are neurons that specifically regulate skeletal muscle and renal vascular beds, indicated by hatched and solid cell bodies, respectively.

produce different patterns of cardiovascular changes, via excitation or inhibition of RVLM sympathetic premotor neurons (312,313). The functional significance of the organization of vasomotor neurons within the PAG is indicated by observations in decerebrate animals. In this preparation, stimulation of different parts of the PAG elicits different patterns of somatomotor effects. For example, stimulation of the pressor region in the rostra1 PAG elicits motor changes typical of a threat display, while stimulation of the depressor region in the rostra1 PAG elicits effects typical of immobility (89). Thus it has been suggested that neuronal subgroups within the PAG subregions are capable of eliciting different patterns of highlv coordinated and integrated autonomic and soma-

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tomotor responses, each of which is appropriate for a particular behavior (89). It has been reported in both humans with essential hypertension and in spontaneously hypertensive rats that alerting stimuli elicit exaggerated cardiovascular responses as compared with normal subjects (170, 213, 232), suggesting that the PAG may play a role in these effects. A recent study by Redfern and Yardley (410), however, has shown that lesions of the dorsal PAG failed to prevent development of hypertension in spontaneously hypertensive rats, and also had little effect on the acute cardiovascular response to an altering stimulus. On the other hand, the PAG lesions in this study may not have destroyed the critical neurons, since, as discussed above, PAG pressor neurons are located laterally rather than dorsally. Thus the question as to the importance of the PAG in neurogenic hypertension remains unanswered. Although the PAG makes reciprocal connections with the NTS, it is not known what role it plays in subserving or modulating cardiovascular reflexes. Now that it is well established that the PAG plays a critical role in the generation of cardiovascular responses associated with particular behaviors, its role in the momentto-moment regulation of the cardiovascular system has become an important question. H. Forebrain

Nuclei

Although it is known that forebrain nuclei are involved in the maintenance of several forms of experimental hypertension (77, 525), it is not clear whether they contribute to maintaining tonic sympathetic vasomotor activity in normotensive animals. Recently, a careful study by Huang et al. (243) has shown that, at least in anesthetized cats, a significant component of resting sympathetic activity arises from the medial diencephalon. After interruption of descending pathways from the diencephalon, however, blood pressure and sympathetic vasomotor activity return to normal (243), which indicates that neural circuits intrinsic to the brain stem can compensate for the lack of this input. I. Lateral

and posterior

hypothalamic

regions

Traditionally, it has been thought that the hypothalamus can be divided functionally into a rostra1 depressor region and a caudal pressor region (401). Several studies using the method of microinjection of neuroexcitatory amino acids, however, have shown that at virtually all sites throughout the hypothalamus selective excitation of cell bodies elicits depressor responses, with the exception of the PVN and the region immediately surrounding the fornix (10,184,230,443,444,456). In the case of the PVN, both pressor and depressor responses have been reported (see sect. IVES!). These observations have been interpreted to indicate that hvpothalamic cell bodies mainlv have a de-

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pressor and sympathoinhibitory function, whereas the pressor effects elicited by electrical stimulation of the posterior and lateral hypothalamus are thought to be due mainly to excitation of fibers of passage (184, 230). Other observations, however, are not entirely consistent with this view. First, injections of the GABA antagonist bicuculline into the posterior hypothalamus of conscious rats lead to an increase in blood pressure, heart rate, and sympathetic activity, whereas injection of the GABA agonist muscimol has opposite effects (513). These cardiovascular changes were usually, but not always, accompanied by behavioral arousal. Second, injection of muscimol was also found to block the increase in blood pressure and heart rate normally evoked by stress in the conscious rat (302). These observations suggest that there are sympathoexcitatory neurons in the hypothalamus and that excitation of these neurons (by GABAergic disinhibition) is necessary for the pressor and tachycardic responses elicited by stress. Consistent with this, single-unit recordings of hypothalamic cells indicate that many have firing characteristics indicative of sympathoexcitatory neurons (37,244). It therefore seems reasonable to conclude that the pressor and sympathoexcitatory effects elicited by a threatening stimulus are mediated, at least in part, by neurons within the hypothalamus. How, then, can this hypothesis be reconciled with the observations that excitatory amino acid microinjections into all parts of the hypothalamus (except for the PVN and perifornical area) usually evoke depressor responses? One possible explanation is that the sympathoexcitatory neurons are scattered rather diffusely within the hypothalamus. Consistent with this possibility, it has been shown that cells projecting to the pressor nucleus in the RVLM are distributed rather diffusely in the lateral and posterior hypothalamus (129). Thus glutamate microinjections into the hypothalamus may excite not only sympathoexcitatory neurons, but also interneurons that inhibit them, with the result that the net effect could be a reduction in sympathetic activity. As has been pointed out previously (196), the method of microinjection of excitatory amino acids may not be an effective method of stimulating scattered groups of neurons. 2. Anteroventral

third ventricle

region

Andersson et al. (14) were the first to demonstrate that the tissue surrounding the most anteroventral part of the third ventricle (AV3V region) is critical for fluid and electrolyte balance (for reviews, see Refs. 78, 345). Later, it was shown that this same general region is also essential for the development of several forms of experimental hypertension (78). Neural pathways arising from or passing through the AV3V region have been shown to influence blood pressure and regional flow distribution (46,168). The descending vasomotor pathways from the AV3V region pass through the hypothalamus and the midbrain PAG (276). With regard to its role in cardiovascular reflexes, it

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has been shown that chronic lesions of the AV3V region reduce the pressor response to carotid occlusion in conscious rats (350). Thus it appears likely that neurons within this region participate in the baroreceptor reflex control of the circulation, as part of the long-loop supramedullary pathways originally proposed by Manning (325). Consistent with this hypothesis, the NTS has been shown to project to the AV3V region (414), and neurons within the region respond to peripheral baroreceptor activation (275). 3. Amygdala

The amygdala is part of the limbic system and has long been known to be an important component of the central pathways that mediate the autonomic and somatomotor responses to emotional stimuli in a variety of species (50,112,269,338). Electrical stimulation of the amygdala in the conscious or lightly anesthetized cat elicits a pattern of cardiovascular changes (a rise in blood pressure and heart rate, skeletal muscle vasodilatation, and visceral vasoconstriction) that is similar to that naturally evoked by a threatening stimulus (487). In the rabbit, electrical stimulation of the amygdala (specifically the central nucleus) evokes a depressor response and bradycardia, which in this species are the pattern of response evoked by a threatening or fear-inducing stimulus (270). Gelsema et al. (183) made excitatory amino acid microinjections into the amygdala of anesthetized rats for the purpose of localizing the cell bodies that mediate the cardiovascular effects of amygdaloid stimulation. In contrast to electrical stimulation, chemical stimulation elicited no response from most sites. This difference cannot simply be explained by assuming that the effects of electrical stimulation are due to excitation of fibers of passage, since there are very few fibers passing through the amygdala. It seems much more likely that the amygdaloid neurons subserving the cardiovascular response associated with emotional stimuli are distributed in different parts of the amygdala so that they cannot be activated by stimulation of cell bodies at one specific site. In contrast, electrical stimulation may excite the axons of the amygdalofugal pathway (231) and thus more closely simulate natural activation of neurons involved in the cardiovascular response to emotional stimuli. There is some evidence to suggest that the amygdala is involved in baroreceptor and other cardiovascular reflexes. Anatomic studies have shown that it receives both direct (414) and indirect [via the parabrachial nucleus; Saper and Loewy (429)] inputs from the NTS. Furthermore, amygdaloid neurons respond to excitation of peripheral baroreceptor fibers (93). Conversely, there are also projections from the central nucleus directly to the NTS (435,494), particularly the dorsomedial subnucleus that is a major recipient area for baroreceptor afferent fibers. This pathway may subserve the facilitatory effect on the baroreceptor reflex observed when the central nucleus is stimulated (390).

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R. A. L. DAMPNEY

4. Septal nuclei The lateral and medial septal nuclei are also part of the limbic system and make extensive connections with cells in a number of nuclei thought to have an autonomic function, including the lateral hypothalamic area, the dorsomedial and ventromedial hypothalamic nuclei, and the parabrachial complex (473). They also receive afferent inputs from these same regions as well as from the amygdala (279). Recently, functional experiments have shown that septal neurons play a role in cardiovascular regulation. Electrical stimulation of septal nuclei elicits variable changes in blood pressure, depending on the site of stimulation (84), whereas chemical stimulation using excitatory amino acids more consistently elicits a decrease in blood pressure (18.2). Electrophysiological studies have shown that some neurons within the septal nuclei, like neurons within other forebrain regions, are excited or inhibited by stimulation of peripheral baroreceptors or chemoreceptors (370). Thus it is reasonable to suggest that the septal nuclei regulate cardiovascular function, possibly as part of more generalized behavioral responses that are integrated by neurons within the septum (75,100). 5. Cortical regions

It has been known for a very long time that the cerebral cortex can influence cardiovascular function [for review of the early literature, see Hoff et al. (234)]. More recently, interest in the possible cardiovascular function of cortical areas has been stimulated by the discovery that neurons in the insular cortex project to a number of autonomic nuclei in the forebrain and brain stem, including the amygdala, lateral hypothalamus, parabrachial complex, and NTS (271,421,425,495,522). Electrical and chemical stimulation of specific sites within the insular cortex, which appear to correspond to the origin of descending pathways innervating autonomic nuclei at subcortical or brain stem levels, leads to rises in blood pressure (94, 95, 425, 522). The pathway mediating these pressor responses appears to include synapses in both the lateral hypothalamus (94) and the RVLM (95). The functional role of the insular cortex in cardiovascular regulation has not been clearly defined. It is known to receive visceral afferent inputs and to be interconnected with limbic structures (427, 428), leading to the suggestion that it is important in the integration of visceral inputs with behavioral and autonomic responses (11). In any case, there is no reason to believe that this part of the cortex is unique in having an autonomic function. The older studies indicated that cortical areas capable of influencing the cardiovascular system were distributed over a very large part of the cortex (234). The specific identification of these cortical areas, their neural connections, and their specific functional roles all remain to be determined.

VII.

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CONSIDERATIONS

The previous sections discussed the properties of specific components of the central neural mechanisms that control the circulation. Such detailed information is necessary to gain an overall picture of the functional organization of central pathways subserving cardiovascular reflexes. In this section, two general questions that were posed in section I regarding the functions of central cardiovascular pathways are addressed. A. SpeciJicity of Central Control of Sympathetic Vasomotor Neurons The old idea that sympathetic nerves innervating different target organs are excited or inhibited in a global fashion (88) has long been abandoned in favor of the view that the activity of such nerves can be independently controlled. For example, there is ample evidence that stimulation of different cardiovascular receptors (such as baroreceptors, chemoreceptors, or cardiopulmonary receptors) evokes different patterns of reflex responses in sympathetic nerves innervating the heart and different vascular beds (447). As discussed in section III& systematic and detailed studies of the properties of pre- and postganglionic sympathetic vasoconstrictor nerves innervating blood vessels in different end organs (e.g., skeletal muscle, skin, and viscera) have revealed that each type of vasoconstrictor nerve has its own characteristic electrophysiological properties and response pattern to different stimuli. There is now clear evidence that SPNs innervating different vascular beds can be preferentially or even exclusively controlled by neurons in supraspinal nuclei, such as the RVLM (90,92,132,310,335). The existence of separate descending pathways controlling different vascular beds does not, however, rule out the possibility that some descending pathways may provide a collateral input to different types of vasomotor SPNs, and thus be capable of generating, at least in some circumstances, a more generalized excitation or inhibition of the sympathetic vasomotor outflow. So far, such nonspecific descending pathways have not been demonstrated, although there is no reason to suppose that they do not exist. The specific pattern of activation of cardiovascular effecters elicited by different afferent inputs can be accounted for by assuming that these inputs activate a specific network of supraspinal interneurons, which in turn produce the particular pattern of activation of cardiac vagal neurons and target-specific sympathetic premotor neurons characteristic of that reflex. In other words, it is possible that such reflex patterns are organized entirely at a supraspinal level. Consistent with this, it has been shown that the respiratory modulation of sympathetic vasomotor neurons can be accounted for entirely by the connections between central respiratory neurons and sympathetic premotor neurons within the RVLM (217,333). Similarly, RVLM sympathetic premo-

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tor neurons exhibit different patterns of response to chemoreceptor stimulation (334), similar to the differential effects of this stimulation on sympathetic vasoconstrictor fibers innervating different types of vascular bed (254). B. Central Pathways

Mediating

the Baroreceptor

Reflex

Signals arising from a vast array of peripheral receptors reflexly influence the activity of cardiovascular autonomic nerves (see sect. VA). A s has been emphasized by Ko rner (277), a disturban .ce to the card iovascular system normally affects the firing rate of several different types of receptors. For example, severe hemorrhage causes arterial hypotension, a decrease in central venous pressure, and in extreme cases tissue hypoxia. The reflex activation of autonomic nerves in response to such a stimulus is therefore the integrated response to inputs from a variety of peripheral receptors. These inputs have been referred to collectively as the “input profile” (277). Of all the different cardiovascular reflexes that are activated by a normal cardiovascular disturbance, the arterial baroreceptor reflex is generally regarded as the most important. Signals arising from arterial baroreceptors reflexly affect heart rate, sympathetic vasomotor activity, and the rate of secretion of vasopressin. In this section, studies aimed at identifying the central pathways that mediate these autonomic and endocrine effects are briefly reviewed. It has long been known that the NTS, which is the site of termination of primary afferent fibers from baroreceptors and other peripheral cardiovascular receptors, is a key component of such central pathways (445, 446). In addition, as pointed out in the previous sections, many studies have identified neurons in other autonomic nuclei in the medulla, pons, midbrain, hypothalamus, and limbic system that also respond to inputs from peripheral baroreceptors. Thus it would appear that neurons located at various levels of the brain are either components of central baroreceptor pathways or else modulate the baroreceptor reflex in some way. Of all these neurons, however, only those within the ventrolatera1 medulla have been shown to be essential components of the central baroreceptor pathways, since, as described in section VIIBI, their destruction or inhibition leads to either partial or complete abolition of the vasomotor and/or endocrine components of the reflex. I. Vasomotor

component

The firing rate of RVLM sympathetic premotor neurons is decreased or abolished by activation of peripheral baroreceptors (see sect. WA@. This decreased activity is mainly due to direct GABAergic inhibition (455), although in one study using intracellular recording, there was some evidence for baroreceptor-induced disfacilitation in a small number of neurons (201). It is also

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347

possible that other pathways that bypass the RVLM also contribute to baroreceptor reflex control of sympathetic vasomotor activity, such as a proposed but so far unidentified descending pathway that directly inhibits SPNs at a spinal level (115,343). In any case, the GABAergic synapse in the RVLM is an essential component of the central baroreceptor reflex pathway, since its blockade with bicuculline abolishes the vasomotor component of the reflex (128,455). The source of the GABAergic input mediating baroreceptor inhibition of RVLM neurons was originally proposed to be the NTS (411), since the NTS is known to be one of the major sources of afferent input to the RVLM (129,130,422). It is unlikely that this is the case, however, since there appear to be no GABAergic neurons in the NTS that project directly to the RVLM (424). Instead, it has been proposed that the central baroreceptor pathway includes a projection from the NTS to the CVLM, which in turn projects to the RVLM (198, 209, 211,286,515). Such a hypothesis is consistent with anatomic studies that have demonstrated a projection from the NTS to the CVLM, as well as to the RVLM (422). The question as to whether the CVLM is an essential component in the central baroreceptor pathway has been somewhat controversial. Experiments in the rat have shown that injection into the CVLM of antagonists to the NMDA subclass of excitatory amino acid receptors blocks the reflex inhibition of sympathetic activity (198, 286) or of RVLM neurons (6) normally evoked by changes in the firing rate of aortic and other arterial baroreceptors. On the other hand, in the rabbit injection of an NMDA receptor antagonist into the CVLM blocked the reflex sympathoinhibition normally produced by excitation of the aortic nerve, but left intact the normal baroreceptor-vasomotor responses elicited by increasing or decreasing blood pressure (53). More recent studies in the rabbit, however, have provided an explanation for these apparently discrepant results. It has been shown that in this species a region located just caudal to the RVLM, but more rostra1 to the CVLM depressor region as originally mapped by Li and Blessing (294), is an essential component of the central baroreceptor reflex pathway. This region has been termed the intermediate ventrolateral medulla (IVLM; Refs. 185,298). Inhibition of cells in both the CVLM and IVLM, or even in the IVLM alone, greatly attenuates the baroreceptor-vasomotor reflex in the rabbit (298, 328). Electrophysiological studies in both the rat and rabbit have identified neurons located in the CVLM and IVLM that can be antidromically activated from the RVLM and that also are excited by baroreceptor inputs (4,185,257,479). Furthermore, these cells have electrophysiological properties quite different from Al catecholamine neurons that are located in the same region of the medulla (185). Consistent with these observations, a recent study in the rabbit using the method of c-fos immunohistochemistry found that neurons activated by baroreceptor inputs are located throughout the CVLM and IVLM, although mainly in the latter region (295). Very few of these neurons were immunoreactive

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R. A. L. DAMPNEY

for the catecholamine-synthesizing enzyme tyrosine hydroxylase (295) and are thus not Al cells. There is also good evidence that some depressor neurons in the CVLM are independent of the baroreceptor reflex pathway. Inhibition of neurons in the CVLM results in a large rise in blood pressure, much greater than that normally elicited by interruption of baroreceptor afferents (62,209). Depressor neurons that are independent of the baroreceptor reflex are located more caudally that those that are part of the pathway (118). In summary, recent evidence supports the view first put forward several years ago (515) that inputs from peripheral baroreceptors are relayed to cardiovascular sympathetic premotor neurons in the RVLM by inhibitory neurons located more caudally in the ventrolateral medulla (Fig. 7). Although it was originally proposed that the inhibitory neurons were Al cells (515), it is now clear that they are not catecholamine cells but may be GABAergic (Fig. 7). In addition, there are other neurons within the CVLM that also inhibit RVLM vasomotor neurons, but which are not components of the central baroreceptor reflex pathway. 2. Cardiac

component

Bilateral lesions of the RVLM block the vasomotor component of the baroreceptor reflex but leave the vagal cardiac component intact (125, 202, 203). As discussed in section IIIA, the nucleus ambiguus is the main location of cardiac vagal preganglionic neurons in most species. These neurons are excited by inputs arising from peripheral baroreceptors (337). There are direct projections from the NTS to the nucleus ambiguus (306, 422) so that it is possible that the baroreceptor-initiated excitation of cardiac vagal neurons is mediated by a direct monosynaptic pathway from second-order neurons in the NTS (Fig. 7). In any case, it is likely that this excitation is mediated by an excitatory amino acid receptor, since injection of the glutamate receptor antagonist kynurenic acid into the region containing cardiac vagal preganglionic neurons in the rat blocks the vagal component of the baroreceptor reflex (209). 3. Endocrine

component

As pointed

out in several recent reviews (51, 137, that neurons within the region of the CVLM corresponding to the location of the Al group of noradrenergic neurons are a critical component of the central pathways mediating the increase in vasopressin release that follows baroreceptor unloading. In particular, inhibition of neuronal activity in the Al region prevents the secretion of vasopressin that normally occurs in response to hemorrhage or severe hypotension (61). It is likely that the Al cells themselves are responsible for this effect, since they are known to project directly to vasopressin-secretine cells in the subraontic and naraventricular nu178, 4159, there is much evidence to indicate

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clei of the hypothalamus (434). Consistent with this view, exogenous norepinephrine has been shown to excite vasopressin-secreting neurons in the supraoptic and paraventricular nuclei (138, 216), although more recent studies suggest that norepinephrine may not mediate synaptic excitation of the these neurons (137). Stimulation of Al cells leads to excitation of vasopressin-secreting cells in the hypothalamus (139), while baroreceptor unloading causes excitation of putative Al neurons antidromically activated from the supraoptic nucleus (297). Finally, there is evidence that the Al cells are tonically inhibited by GABAergic inputs (471) that may arise directly from cells in the NTS, as depicted in Figure 7. On the other hand, the reflex inhibition of vasopressin secretion that follows a rise in blood pressure is not dependent on the pathway from Al cells to the hypothalamus (137). Instead, as shown in Figure 7, it has been proposed that this inhibition is mediated by a polysynaptic pathway that includes excitatory synapses in the locus ceruleus, the diagonal band of Broca, and the supraoptic perinuclear zone (35, 119, 261, 412). According to this scheme, GABAergic neurons in the latter region then project to and inhibit supraoptic vasopressin-secreting neurons (260). Alternatively, or additionally, there is a direct excitatory projection to the supraoptic perinuclear zone from the lateral parabrachial nucleus (259). Furthermore, there are neurons in the lateral parabrachial nucleus that are excited by baroreceptor stimulation (258). These observations, therefore, are consistent with the view that the lateral parabrachial nucleus may also relay baroreceptor signals to vasopressin-secreting neurons in the supraoptic nucleus. In summary, then, studies to date have indicated that at least four cell groups in the medulla oblongata are all essential components of the central pathways required for the full expression of the baroreceptor reflex (Fig. 7). These cell groups are the neurons in the NTS relaying signals from peripheral receptors, the sympathetic premotor cells in the RVLM, the sympathoinhibitory cells in the CVLM and IVLM that relay baroreceptor and other inputs to the RVLM, and the Al cells that project to vasopressin-secreting cells in the hypothalamus. Furthermore, receptors for both excitatory and inhibitory amino acids are also critical components of the central pathways (Fig. 7). Other central autonomic nuclei also receive inputs arising from peripheral baroreceptors, but the extent to which these other nuclei are important for the full expression of the baroreceptor reflex remains unknown. C. Central Pathways Mediating Cardiovascular ReJlexes

Other

Much less is known about the central pathways mediating cardiovascular reflexes other than the baroreceptor reflex, but recent studies have provided some information. In particular, the sympathoexcitatory resnonse to stimulation of carotid bodv chemorecentors in

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PATHWAYS

BB

4 vasomessin CVLM FIG. 7. Proposed pathways that subserve endocrine (top) and cardiac and vasomotor (bottom) components of baroreceptor reflex. Proposed pathways that utilize neurotransmitters y-aminobutyric acid (GABA), norepinephrine (Nad), or an excitatory amino acid (EAA) are indicated. CVLM, caudal ventrolateral medulla; IVLM, intermediate ventrolateral medulla; RVLM, rostra1 ventrolateral medulla; DBB, diagonal band of Broca; IML, intermediolateral cell column; LC, locus ceruleus; NTS, nucleus of solitary tract; PVN, paraventricular nucleus; RVM, rostra1 ventrolateral medulla; SON, supraoptic nucleus.

RtiLM #-q -a

inhibitory inputs excitatory inputs

baroreceptors

CVLM + IVLM

I RVLM

heart and blood vessels the rat has been shown to be abolished by bilateral block of glutamate receptors in the commissural subnucleus of the NTS (496) as well as in the RVLM (278). The reflex was not affected, however, bY block of glutamate receptors located more caudally in the region corresponding to the IVLM, although this procedure does block the baroreceptor reflex, as pointed out in section VIIB. Therefore, although signals from baroreceptors and chemoreceptors ultimately converge on the same neurons in the RVLM (see sect. IvAZ), they are mediated by separate pathways within the brain stem.

There is a direct projection from the commissural subnucleus of the NTS to the Cl neurons in the RVLM (389). This pathway may therefore transmit excitatory inputs arising from chemoreceptors directly to sympathetic premotor neurons. Alternatively, there may be other interneurons subserving this reflex, since the commi ssural subnu cleus also projects to other targets within the medulla and pons (389). Furth er studies are needed to answer this question. Stimulation of vagally innervated chemosensitive receptors in the heart and lungs evokes a powerful car-

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R. A. L. DAMPNEY

diovascular reflex (termed the Bezold-Jarisch reflex), which is characterized by hypotension, sympathoinhibition, and bradycardia (486). The medullary pathway mediating this reflex appears to be similar to that mediating the baroreceptor reflex, in that it includes excitatory glutamatergic synapses in the NTS and CVLM, and a GABAergic synapse with RVLM sympathetic premotor neurons (500). In contrast, the sympathoinhibitory reflex that can be elicited by stimulation of certain somatic receptors does not appear to include a synapse within the CVLM, although it is mediated by GABA receptors within the RVLM (327). In summary, it is clear that much remains to be learned about the organization of central pathways mediating cardiovascular sympathoexcitatory and sympathoinhibitory reflexes. So far, attention has focused on identifying the essential medullary synapses that mediate these reflexes. Even in that case, our current knowledge is incomplete, while virtually nothing is known of the role of supramedullary nuclei in the operation of these reflexes. VIII.

CONCLUDING

REMARKS

The last decade has seen a great increase in our knowledge of the detailed anatomy and chemical properties of neural pathways that link central nuclei thought to have an autonomic function. Such studies have emphasized the complexity and specificity of central autonomic pathways. To take one example, a recent thorough examination of the connections between the NTS and the parabrachial complex has revealed that each subnucleus in the NTS nucleus has its own specific pattern of innervation of subregions within the parabrachial complex (228). Moreover, there seems to be some degree of chemical coding such that each particular pathway consists of neurons with particular histochemical properties (229). Despite the very large catalog of information on the anatomic and chemical properties of central autonomic pathways, however, there is comparatively less information on their detailed functional properties. Despite this, certain principles seem to be emerging with regard to the mechanisms of central pathways controlling the circulation. I) The activity of preganglionic sympathetic and vagal neurons controlling the heart and blood vessels is governed by synaptic inputs (mainly excitatory, but also inhibitory) that originate from a number of sources, both spinal and supraspinal. The afferent terminals synapsing with SPNs are immunoreactive for a variety of neuropeptides and monoamines, but in the vast majority of cases, the terminals also contain either an excitatory or inhibitory amino acid, which may act as the principal neurotransmitter. The neuropeptides and monoamines colocalized within afferents synapsing with SPNs are presumed to have a modulatory role, but this has not yet been clearly defined. In any case, the functional, anatomic, and pharmacological observations

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of SPNs and their afferent inputs clearly demonstrate that a considerable degree of integration occurs at the level of these spinal neurons. 2) Vasomotor SPNs appear to exert a highly specific control over particular vascular beds. Such target-specific neurons differ in their physiological properties, and it is possible, although not yet demonstrated, that they may differ with respect to the chemical properties of their afferent inputs. 3) The descending input to SPNs arising from the RVLM is probably the single most important excitatory input that determines the firing pattern of cardiovascular SPNs. The RVLM sympathetic premotor neurons also integrate inputs fr Noma wide variety of peripheral and central sources. At least some of these neurons are highly specific for certain vascular beds, and it follows that in such cases their outputs are directed predominantly, if not exclusively, to target-specific vasomotor SPNs. Rostra1 ventrolateral medulla sympathetic premotor neurons have nonuniform chemical properties; in particular, some are adrenergic (belonging to the Cl group of adrenergic cells) while others are not. 4) Apart from the RVLM, the NTS and the CVLM and IVLM are crucial components in the central pathways mediating cardiovascular reflexes. Within the NTS, there is considerable processing of signals arising from different peripheral receptors, but there is little evidence for integration within the NTS of signals from different peripheral receptor types. Instead, such integration occurs principally within the RVLM, where inputs from different peripheral receptors, as well as from autonomic nuclei at higher levels of the brain, converge onto cardiovascular sympathetic premotor neurons. Inputs arising from various supramedullary nuclei, in the cerebellum, pons, midbrain, and forebrain, can influence the sensitivity of cardiovascular reflexes by modulating the transmission of signals within the NTS. 5) Cell groups in different subregions of the midbrain PAG are capable of eliciting specific patterns of somatomotor and autonomic (including cardiovascular) changes that closely resemble those observed during certain types of natural defensive behavior. Neural pathways in the forebrain are also critical for the expression of such behaviors, but these have not yet been clearly defined. There appear to be two major gaps in our knowledge of the central mechanisms of cardiovascular regulation. Except for some recent studies on SPNs and medullary neurons (studied in vitro), very little is known about the cellular properties of central neurons thought to have a cardiovascular function. It would be particularly interesting, for example, to identify neurons that control the vasomotor outflow to specific vascular beds, then to determine the pharmacological properties and neurotransmitter content of the same cells. Second, the vast majority of studies on central eardiovascular mechanisms have been carried out in anesthetized animals. Such studies have revealed much about the connections and probable functions of some central cardiovascular pathways but, as others have

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pointed out (179), cannot reveal how such pathways operate in conscious animals during normal behaviors. On the other hand, few studies in conscious animals have focused on the role of specific central neurons in subserving cardiovascular reflexes, although it has been established that virtually all levels of the brain are involved in the production of cardiovascular reflex responses (277). It is possible, however, that new techniques, such as the c-fos method for labeling active neurons (247), will allow a determination of which specific neurons mediate cardiovascular adjustments in normal behaving animals. It can be expected, therefore, that the next decade, like the previous decade, will see dramatic increases in our knowledge of the functional organization of central cardiovascular pathways. Discussions with my colleagues, especially Yu-Wen Li, Robin McAllen, and Jaimie Polson, helped me greatly during the preparation of this manuscript. The work in my laboratory is supported by the National Health and Medical Research Council of Australia, the National Heart Foundation of Australia, and the Clive and Vera Ramaciotti Foundations.

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