Vol. 281, Issue 3, R683-R698, September 2001
INVITED REVIEW
Differential control of sympathetic outflow
Shaun F.
Morrison
Department of Physiology, Northwestern University Medical School,
Chicago, Illinois 60611
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ABSTRACT |
With advances in
experimental techniques, the early views of the sympathetic nervous
system as a monolithic effector activated globally in situations
requiring a rapid and aggressive response to life-threatening danger
have been eclipsed by an organizational model featuring an extensive
array of functionally specific output channels that can be
simultaneously activated or inhibited in combinations that result in
the patterns of autonomic activity supporting behavior and mediating
homeostatic reflexes. With this perspective, the defense response is
but one of the many activational states of the central autonomic
network. This review summarizes evidence for the existence of
tissue-specific sympathetic output pathways, which are likely to
include distinct populations of premotor neurons whose target
specificity could be assessed using the functional fingerprints
developed from characterizations of postganglionic efferents to known
targets. The differential responses in sympathetic outflows to
stimulation of reflex inputs suggest that the circuits regulating the
activity of sympathetic premotor neurons must have parallel access to
groups of premotor neurons controlling different functions but that
these connections vary in their ability to influence different
sympathetic outputs. Understanding the structural and physiological
substrates antecedent to premotor neurons that mediate the differential
control of sympathetic outflows, including those to noncardiovascular
targets, represents a challenge to our current technical and analytic approaches.
baroreceptor reflex; chemoreceptor reflex; thermoregulation; arterial pressure; cutaneous circulation; adrenal medulla; brown
adipose tissue; periaqueductal gray; renal sympathetic nerve; vasoconstriction
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INTRODUCTION |
RECOGNITION OF THE IMPORTANT role of
the autonomic nervous system (ANS) in coping with life-threatening
challenges led to the earliest concepts of the sympathetic nervous
system as a monolithic effector, activated to globally enhance organ
function and substrate availability for fight or flight and to protect
cerebral perfusion in the event of significant injury. In contrast, the
parasympathetic component of the ANS is engaged in the aftermath of
such challenges to coordinate recovery, a reduction in energy
utilization, and replenishment of energy stores. However, compared with
our ancestors, modern lifestyles have all but eliminated the danger of
predatory aggression, and we rarely engage the central autonomic
networks developed by evolutionary pressure to cope with the most
stressful challenges to homeostasis. In their stead, we are faced with
the increasing awareness and prevalence of diseases such as
hypertension, obesity, cardiac arrhythmia, heart failure, and diabetes,
in which altered development or control of the ANS can play a
significant role. Within this framework and, importantly, with the
availability of more powerful and precise electrophysiological and
anatomic techniques, research on the regulation of autonomic outflow
has eclipsed earlier views with an organizational model that emphasizes the differential central control of sympathetic outflows to
functionally specific targets and the hierarchical interactions among
defined populations of neurons that produce the patterns of autonomic efferent activity supporting behavior and reflex responses. The focus
has evolved toward an understanding of the central neural networks
generating and controlling the levels of ANS activity to specific
tissues, including those with noncardiovascular functions, with the
recognition that the fight-or-flight response is just one of many
options in an extensive repertoire of effector activation states in
which the central autonomic network may exist. Investigators are
challenged to determine how the differential neural responses in
physiological experiments or the patterns of activity-dependent and
organ-specific labeling seen in anatomic studies might reflect the
mechanisms affecting the coordinated series of autonomic changes supporting specific behaviors or mediating reflex responses.
This review describes research results providing anatomic and
physiological evidence for central autonomic networks that allow for
the selective control of the sympathetic outflow to individual tissues
and thus for the expression of patterned autonomic responses. Investigation of the central neural mechanisms underlying differential autonomic responses is an ongoing area of autonomic neuroscience that
has contributed to our understanding of the basis for organ specificity
of autonomic responses. Neuronal tracing techniques, activity-dependent
markers, and immunocytochemical approaches have been used to
characterize neurons in the central and peripheral pathways to
different tissues that provide the structural substrate for their
differential sympathetic regulation. Comparisons of the centrally
evoked and reflex responses of multiple autonomic effectors, in some
cases recorded simultaneously, have demonstrated heterogeneity among
the responses of functionally distinct outputs. Patterns emerge from
these data that suggest multiple, interacting, but modality specific,
hierarchical systems involving neurons in the hypothalamus, midbrain,
and medulla that regulate groups of target-specific output pathways
each comprising premotor neurons [and potentially their accompanying
oscillator (63)], the preganglionic neurons they excite,
and the ganglion cells innervating a particular tissue. The axonal
branching patterns of neurons in such systems, antecedent to premotor
neurons, could provide the basis for coordinating the changes in
sympathetic outflows to an array of target-specific output pathways of
related function. Although the characteristics and responses of the
sympathetic outflows to the blood vessels and heart have been most
extensively studied (45), nearly every tissue in the body
receives a sympathetic innervation. Thus, although we have considerable
information on the central regulation of systemic perfusion pressure,
the organization of neural circuits specifically controlling many other
modalities, such as temperature, circulatory volume, plasma osmolarity,
blood glucose, energy balance, and reproduction, remains to be elucidated.
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ANATOMIC BASIS FOR TISSUE-SPECIFIC AUTONOMIC REGULATION |
Langley (104) divided the autonomic outflow from the
central nervous system to the cardiovascular and visceral tissues into parasympathetic and sympathetic components based on their spinal origins as well as the differential effects on various tissues of nerve
stimulation and application of adrenergic and cholinergic agents. The
results of Cannon's (29) functional studies led him to
propose that parasympathetic efferents mediate more precise, target-focused responses than did sympathetic efferents that were considered to have more widespread effects. The tissue specificity of
parasympathetic ganglion cells and thus the ability to provide selective regulation of various autonomic functions would appear manifest by the general anatomic arrangement in which parasympathetic ganglion cells are located within the innervated tissue and are excited
by long preganglionic axons projecting from the central nervous system.
Improved anatomic approaches have complemented physiological studies,
indicating the fine detail to which functionally specific responses can
be evoked by parasympathetic efferents. In examining the vagal
innervation of the heart, chronotropic and dromotropic effects were
found to be mediated by distinct ganglia within the cardiac fat pads
(61), and this arrangement has been extended to the
inotropic effects as well (60). Retrograde tracing and immunohistochemistry have provided evidence that these ganglia are, in
turn, innervated by populations of vagal cardiac preganglionic neurons
that can be distinguished on the basis of location and neurochemical
inputs (59, 114, 115). Target specificity has also been
demonstrated for cranial parasympathetic ganglia innervating the
lacrimal and parotid glands and the iris and ciliary body (105).
Do sympathetic ganglion cells innervate only one target tissue?
Although the axons of sympathetic ganglion cells are, as a rule,
markedly longer than those of their parasympathetic counterparts and
thus would have more opportunity for branching, the results of many
studies support a model in which sympathetic ganglion cells innervate a
single tissue type and thus provide the minimal structural basis
necessary for generation of functionally specific sympathetic
responses. Using retrograde transport from separate tissues, different
distributions were found for ganglion cells innervating the kidney and
the spleen (123) and for superior cervical ganglion
neurons that project to the submandibular salivary glands, eyes, and
pineal gland (111). With the use of immunohistochemical techniques to identify afferent terminals to sympathetic ganglion cells, superior cervical ganglion cells likely to innervate the secretory cells of the submandibular gland were uniquely surrounded by
calretinin-positive terminals (68). Ganglion cells
containing tyrosine hydroxylase and neuropeptide Y (NPY) are
likely to innervate blood vessels, whereas stellate cells containing
calbindin and NPY innervate cardiac tissue (2).
Are sympathetic preganglionic neurons (SPNs) target specific?
Recent experiments in which the transynaptic retrograde tracer,
pseudorabies virus, has been injected into either the rat pinna or the
eye resulted in specific segmental distributions of labeled
preganglionic neurons (155). Similarly, SPNs innervating stellate ganglion cells or the adrenal medulla were intermixed in the
midthoracic spinal cord, but were never double labeled after injections
of two retrograde tracers in the same animal (89).
Neurochemical coding, describing the unique or selective associations
of histochemically labeled terminal fields and transmitter or
receptor-containing neurons, has provided evidence for functionally specific populations of SPNs as well as ganglion cells (see above). For
instance, neurokinin-1 (NK1) receptor is localized on a high percentage of adrenal SPNs, but a low fraction of those projecting to
L5 chain ganglion (69). Calbindin-containing SPNs project to superior cervical and stellate ganglia, but not to the adrenal gland
(67). Calretinin-positive SPNs send terminals to the
vicinity of noradrenergic adrenal medullary chromaffin cells, but not
those synthesizing epinephrine (53). Similar analysis has
been used to indicate a unique identification of SPNs controlling
cardiac function in the rat (2).
Anatomic differentiation of inputs to preganglionic neurons.
Autonomic preganglionic neurons have both excitatory and inhibitory
inputs, arising from spinal interneurons and from brain stem and
hypothalamic sites. "Sympathetic premotor neuron" will be used to
describe those supraspinal neurons that synapse directly on SPNs to
provide the excitatory input that maintains their basal discharge and
through which reflex and evoked responses in SPNs are effected.
Regarding the central anatomic substrate for functionally specific
autonomic responses, the question arises whether populations of
tissue-selective premotor neurons provide unique driving inputs to
their respective target groups of tissue-specific preganglionic neurons. Although the physiological data described below strongly suggest that this is the case, several complicating factors have prevented a direct anatomic answer to the question. Due to the intermixing of preganglionic neurons within the intermediolateral column of the spinal cord (89), it is not possible to
apply classical retrograde tracers to populations of functionally
homogeneous preganglionic neurons. The situation is improved by the
recent advent of the pseudorabies viral tracing technique, which has been used in separate experiments to identify premotor neurons regulating the autonomic efferents to peripheral tissues with different
functions (147, 156, 158). The target-specific differences that have been observed in the intensity and in the temporal and spatial qualities of the labeling at different central sites
(158) are suggestive of underlying distinctions in the
relative importance of the inputs from these areas to SPNs controlling
different targets. However, the fact that relatively few tissues have
been studied with this technique and the inherent limitations on the
interpretation of the resulting data (particularly the infection of
functionally different populations of sympathetic efferents innervating
the different tissue types in the injection site) have thus far
restricted the identification of tissue-specific premotor neurons.
Application of two histochemically distinct viruses at different sites
in the same experiment has the potential to reveal individual neurons that regulate the sympathetic outflow to more than one target tissue.
Although this approach has resulted in double-labeled neurons in
hypothalamic and brain stem sites (90), it is not possible
to determine from a single time point whether such labeling resulted
from direct infection of the neuron by viruses from two populations of
preganglionic neurons or whether one of the infections may have
resulted, for instance, from a virus in the axonal branches of a
different population of brain stem sympathetic premotor neurons.
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PHYSIOLOGICAL EVIDENCE FOR DIFFERENTIAL AUTONOMIC REGULATION |
Characterization of functionally distinct populations of peripheral
autonomic outputs.
Characterization of the physiological and reflex response properties of
individual pre- and postganglionic axons or nerve fascicles in the
sympathetic nerves of humans and experimental animals has been used to
segregate sympathetic efferents into distinct categories related to the
potential target tissues they regulate. This has been accomplished by
correlating changes in efferent discharge with some unique behavior of
an end-organ tissue in the distribution of the efferent being recorded.
These are important data. The ability to establish a different
characteristic pattern of reflex responses (see examples below) that
define a functional fingerprint for the autonomic innervation of each
target tissue is strong evidence that its autonomic regulation occurs via a unique, tissue-specific population of preganglionic and ganglion
neurons (reviewed by Janig, Refs. 84, 86). In
addition, with the exception of the preganglionic innervation of the
adrenal medullary chromaffin cells, the end-organ target tissue of a
central neuron in a sympathetic pathway can only be inferred from a
correspondence between its behavior and one of the functional
fingerprints that has been established for the peripheral innervations
of a variety of tissues. Finally, because the majority of reflex- and
behaviorally evoked responses is mediated via supraspinal networks and
sympathetic premotor pathways, these results are consistent with a
model of central autonomic regulation that includes tissue-specific
populations of premotor neurons. It is the detailed descriptions of the
response characteristics of functionally defined sympathetic
postganglionic or parasympathetic preganglionic axons that will provide
the principal source of information for the physiological
identification of such antecedent (i.e., sympathetic preganglionic,
premotor, etc.) neurons in target-specific pathways.
The use of single-fiber recordings is a key aspect of the physiological
differentiation of functional classes of efferent autonomic axons and
their antecedent central regulatory pathways. The complexity of most
organs, in that they are comprised of multiple tissues (a minimum of a
vascular and a parenchymal component), predicts that their autonomic
innervations will be comprised of many, functionally differentiated
populations of axons. Thus whole nerve recordings, even those made from
autonomic nerves in the immediate proximity of the organ they
innervate, will represent a summation of the basal activities and
evoked responses of a functionally heterogeneous group of efferent
axons. This is an analogous situation to that described above in which
the neurons in central pathways identified with retrograde transport of
viral tracers will include a conglomerate of those controlling the
autonomic efferents to each of the tissues in the original infection
zone of the virus injection. Some prominent examples in which this situation complicates the interpretation of data from nerve bundle recordings are 1) the multiple functions represented within
the renal nerves (49, 106); 2) the existence of
many fiber types within the adrenal nerves, including not only
preganglionic axons to the two types of medullary chromaffin cells
(128, 141) but also postganglionic inputs to adrenal
cortical cells and blood vessels, vagal efferents, and sympathetic and
vagal afferents (31, 34, 80, 136, 141, 169); 3)
the vascular and adipocyte innervation within sympathetic nerves to
brown adipose tissue (28, 127); and 4) the wide
distribution of fibers in the rat splanchnic nerve and the cat lumbar
splanchnic nerves to vascular, gastrointestinal, reproductive, and
adipose targets (85).
The meticulous studies carried out over many years in the laboratory of
Wilfrid Janig (84, 85) have provided a significant portion
of the information available on the behavior of a variety of peripheral
sympathetic efferents in the cat and rat lumbar and cervical
sympathetic outflows. They have characterized sympathetic efferent
channels as 1) vasoconstrictors to muscle and viscera, 2) cutaneous vasoconstrictors, 3) sudomotor,
4) pilomotor, 5) "inspiratory" potentially
innervating vessels of the nasal mucosa, 6) pupillomotor,
and 7) motility regulating for the gastrointestinal system
and for the reproductive system. The extensive studies of Gunnar Wallin
and colleagues (16, 51, 87) provided considerable data
indicating a strong correlation between the functional fingerprints of
muscle and skin sympathetic outflow in experimental animals and those
determined from recordings of human sympathetic nerve activity.
Although there are many tissues, such as the heart, adipose, pancreas,
spleen, thymus, thyroid, pineal, gastrointestinal, reproductive, etc.
whose autonomic functional fingerprints cannot be determined in humans
and for which only limited data are available from experimental
preparations, the growing appreciation of the role of alterations in
autonomic regulation in a variety of disease states may stimulate
research that will expand the characterization of these autonomic
outflows as well.
The sympathetic innervation of the adrenal medullary chromaffin cells,
which secrete either epinephrine or norepinephrine (44,
75), provides an example of target specificity at the level of
the preganglionic neuron. Anatomically, terminals of calretinin-containing cat adrenal SPNs terminate in the vicinity of
noradrenergic chromaffin cells, whereas those adrenal SPNs without
calretinin are located preferentially among adrenergic chromaffin cells
(53). Physiologically, adrenal SPNs can be segregated into
two populations. Those with long-latency responses to stimulation of
the rostral ventrolateral medulla (RVLM) and little sensitivity to the
baroreceptor reflex are strongly stimulated by the glucopenic agent
2-deoxy-D-glucose (2-DG), indicating their role in
regulation of adrenal epinephrine secretion, which is markedly
increased by 2-DG (Fig. 1). Conversely,
adrenal SPNs with short-latency responses to RVLM stimulation and which
can be completely inhibited by baroreceptor reflex activation are unaffected by administration of 2-DG and are presumed to control adrenal norepinephrine release (128). These data provide
direct evidence for the distinct functional organization of the central networks governing the release of the two catecholamines from the
adrenal medulla that had been suggested by differences in the
catecholamine secretion previously observed in response to physiological challenges and experimental stimuli (56, 146, 157,
161, 165, 166).
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Fig. 1.
Differential responses of adrenal (ADR) sympathetic
preganglionic neurons (SPNs) regulating epinephrine (EPI) and
norepinephrine (NE) secretion. Left: mean (+SE) peristimulus
time histograms of the responses of EPI ADR SPNs (n = 71, top trace) and NE ADR SPNs (n = 68, bottom trace) to twin-pulse stimuli applied to the
ipsilateral rostral ventrolateral medulla (RVLM). Each bin represents
the mean (+SE) of the values (normalized for number of RVLM stimuli
delivered) for that bin from all of the individual peristimulus time
histograms. Note the marked difference in peak latency. Bin width is 4 ms. Middle: discharges of an EPI ADR SPN (top
trace) and an NE ADR SPN (bottom mid trace) during
stimulation (bar, 3 pulses) of the baroreceptor afferents in the aortic
depressor nerve (ADN) and the mean (+SE) peristimulus time interval
histograms for EPI ADR SPN (n = 37, top mid
trace) and NE ADR SPN (n = 32, bottom trace)
responses to ADN stimulation. Bin width is 10 ms. Counts from stimulus
artifacts were eliminated by zeroing the 2 corresponding bins. Note the
relative absence of a baroreceptor-mediated inhibition in EPI ADR SPN.
Right: mean (+SE) discharge frequency (expressed as
%control) histogram (bin width 1 s) obtained by averaging the
responses of EPI ADR SPNs (n = 20, top
trace) and NE ADR SPNs (n = 17, bottom
trace) to glucopenia evoked by administration of
2-deoxy-D-glucose (2-DG; 250 mg/kg, time 0).
Note that only those ADR SPNs with the long-latency response to RVLM
stimulation are excited by 2-DG. [Modified from Morrison and Cao
(128).]
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DIFFERENTIAL AUTONOMIC RESPONSES TO REFLEX INPUTS |
Baroreceptor reflex.
Baroreceptor reflex-mediated inhibition is a hallmark of sympathetic
outflows regulating muscle and visceral vasoconstrictor targets, the
kidney, and the heart, as would be expected inasmuch as the performance
of these tissues contributes directly to determining the level of
arterial pressure. Strong stimulation of vagal parasympathetic input to
the heart accompanies the sympathoinhibitory responses to pressor
stimuli (57, 96). One criterion that is often used to
assess the sensitivity of a particular sympathetic outflow to
modulation by the baroreceptor reflex is the synchrony between the
bursts in nerve activity and the arterial pressure wave (cardiac cycle). This analysis is based on the premise that the baroreceptor reflex pathway is briefly stimulated during the systolic pressure rise,
which often exceeds 40 mmHg, resulting in a reduced probability of
sympathetic discharge during a portion of the cardiac cycle and an
entrainment of the sympathetic bursts to the frequency of the heart rate.
Pulse-synchronous discharges have been observed in the muscle
vasoconstrictor nerves of the cat and humans (17, 48, 66, 87), renal nerve of the cat and rat (50, 95, 102, 122, 137), cardiac and splenic nerves of the cat (95,
122), and the lumbar and splanchnic nerves of the rat (70,
131). Similarly, the discharge of adrenal SPNs controlling the
chromaffin cells that secrete norepinephrine is strongly modulated by
baroreceptor input (128). However, as illustrated in Fig.
2, averages of sympathetic nerve activity
triggered with the R-wave of the electrocardiogram indicate that there
is relatively little pulse-synchronous modulation of the activity of
most cutaneous vasoconstrictor nerves in cat, rat, or humans (17,
66, 87, 91, 137) or of sympathetic sudomotor fibers in humans
(112). This relative absence of a baroreceptor influence
on sympathetic outflows related to thermoregulation is also supported
by the lack of a cardiac frequency-related component in the
autospectrum of the sympathetic outflow to rat brown adipose tissue
(127). Similarly, the spontaneous discharge of
epinephrine-regulating adrenal SPNs is relatively insensitive to
arterial baroreceptor input (128).
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Fig. 2.
Differential baroreceptor reflex influences on muscle
sympathetic activity (MSA) and skin sympathetic activity (SSA). Records
of electrocardiogram (ECG) and sympathetic nerve activity (SYMP)
indicate an entrainment of the bursts in MSA to the cardiac cycle, also
shown by the large amplitude deflections on the ECG-triggered average
of MSA (bottom left trace). In contrast, there is no
synchrony of the bursts in SSA to the heart frequency, and the
ECG-triggered average of SSA is flat. [Reprinted from J Auton
Nerv Syst, Vol 4, Bini et al., Cardiac rhythmicity of skin
sympathetic activity recorded from peripheral nerves in man, p.
17-24, 1981, with permission from Elsevier Science.]
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Testing the ability of increases (or decreases) in arterial or carotid
sinus pressure to induce an inhibition (or excitation) of sympathetic
discharge has yielded qualitatively similar results: skeletal muscle
vasoconstrictor nerve activity in cat and human (22, 52, 125,
144); pelvic visceral vasoconstrictor nerve activity in cat
(125); splenic, renal, and cardiac nerve discharge in the
cat (137, 138); lumbar, renal, and splanchnic nerve
activity in the rat (131, 148); and adrenal nerve activity
and adrenal norepinephrine-controlling preganglionic neurons in the rat
(33, 103, 128, 134, 148) are very sensitive to
baroreceptor-mediated inhibition, whereas most of the sympathetic
fibers innervating the skin exhibit a markedly weaker baroreceptor
responsiveness (22, 125, 137), as do the sympathetic
outflow to brown adipose tissue and the epinephrine-regulating adrenal
SPNs (128, 132). Extending the hypotensive stimulus to the
decompensatory phase of hemorrhage elicits a dramatic inhibition in
renal sympathetic outflow and a large increase in adrenal sympathetic
nerve activity and epinephrine secretion (33, 100, 154, 159,
160). These responses are significantly dependent on cardiac
vagal afferent input to the nucleus of the solitary tract, from which
similar differential responses can be elicited through activation of
purinergic receptors (149, 150).
Arterial chemoreceptor reflex.
The immediate cardiovascular response to stimulation of arterial
chemoreceptors with hypoxia or reduced blood flow through the carotid
or aortic bodies is an increase in sympathetically mediated
vasoconstriction to reduce tissue oxygen consumption and to increase
arterial pressure and augment cerebral oxygen availability. Cardiac
vagal activation is also present (98), possibly reducing
coronary oxygen consumption through bradycardia. Differential responses
to chemoreceptor reflex stimulation have been demonstrated in the
sympathetic nerves controlling muscle and visceral vasoconstriction vs.
those to the skin. Stimulation of the arterial chemoreceptor reflex
with systemic hypoxia, CO2-saturated saline, or sodium
cyanide excited the preganglionic cervical sympathetic nerve and the
postganglionic sympathetic innervation of skeletal muscle and pulmonary
vasculature and to the kidney in the cat (22, 82, 93, 98,
152), the splanchnic nerve in the rabbit (83), and
the renal and splanchnic sympathetic outflows in the rat (50,
99). Chronic moderate or acute severe hypoxia also elicited an
increase in rat cardiac sympathetic outflow, the latter accompanied by
a rise in adrenal epinephrine secretion (92). In contrast,
cutaneous postganglionic neurons are inhibited (Fig. 3) by arterial chemoreceptor reflex
stimulation in the cat, dog, and rabbit (22, 23, 83).
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Fig. 3.
Differential responses in a single muscle vasoconstrictor
(MVC) axon and a cutaneous vasoconstrictor (CVC) axon to arterial
chemoreceptor reflex activation. Intracarotid injection of a bolus of
CO2-enriched saline (arrow) increased blood pressure (BP),
carotid sinus afferent nerve activity (CSN), and the spontaneous
discharge of an MVC in a deep peroneal nerve in cat, but inhibited a
simultaneously recorded CVC in a superficial peroneal nerve to hairy
skin. [Reprinted from Trends Neurosci, Vol 15, Janig and
McLachlan, Characteristics of function-specific pathways in the
sympathetic nervous system, p. 475-481, 1992, with permission from
Elsevier Science.]
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The influence of central respiratory generating networks on those
controlling sympathetic outflow is significantly stronger in muscle and
visceral vasoconstrictor sympathetic discharge than in that of
cutaneous sympathetic efferents, although this differential respiratory
modulation is expressed more in the cat than in the rat or human. With
the use of a phrenic nerve discharge to monitor the central respiratory
cycle, a strong respiratory modulation has been observed in the cardiac
vagal outflow (51) and in the amplitude of the bursts in
the sympathetic nerves to the kidney in the cat and rat (4, 95,
137, 139), to the skeletal muscle in the cat and human
(10, 51, 66, 94), to the cardiac nerve in the cat and rat
(4, 95, 139), and to the lumbar, adrenal, cervical, and
splanchnic nerves in the rat (74, 126, 139). Although such
modulation is absent in the majority of cutaneous sympathetic fibers
recorded in the cat (66, 137), it is present in the rat
(72, 91) and human (73, 87) cutaneous
sympathetic outflow.
Thermal stimuli.
Autonomic thermoregulatory responses are directed toward changes in the
level of 1) heat conservation through circulatory adjustments focused on modifying cutaneous blood flow and through changes in sudomotor and pilomotor activity and 2) heat
production through influences on thermogenic mechanisms. Secondary
effects, from arterial and cardiopulmonary baroreceptor reflexes for
instance, would be expected during some thermoregulatory responses, as
in those requiring a large increase in cutaneous blood flow. Thus direct thermoregulatory responses are mediated by differential changes
in the sympathetic outflows to the skin and tissues involved in
thermogenesis, relative to muscle and visceral vasoconstrictor nerve activity.
Exposure to a warm (43°C) environment activated sudomotor sympathetic
activity in humans while suppressing cutaneous vasoconstrictor fiber
discharge (16). Similarly, heating the spinal cord in anesthetized rabbits and dogs produced an inhibition of cutaneous sympathetic nerve activity accompanied by an excitation of the cardiac
and splanchnic nerve activities (42, 153). Peripheral thermal receptor stimulation (heat) elicits an increase in rat renal
sympathetic nerve activity (50), resulting in a fall in renal blood flow. Conversely, a cold (15°C) environment stimulates activity in human cutaneous vasoconstrictor efferents while inhibiting sudomotor sympathetic outflow (16). Exposure to cold
stimulates sympathetic nerve activity to rat brown adipose tissue, but
has only a minor effect on splanchnic sympathetic discharge, at least some of which may arise from sympathetic axons regulating thermogenesis in mesenteric brown adipose tissue depots (127). Spinal
cooling activated cutaneous, as well as splanchnic, sympathetic
discharge in rabbits and dogs, but evoked little change in cardiac
sympathetic activity or heart rate (42, 153). A decrease
in cardiac sympathetic outflow during cold exposure was also seen in
rats (165). Although cold-stimulated increases in plasma
norepinephrine could arise from both sympathetic terminals and adrenal
chromaffin cells, the absence of a change in plasma epinephrine during
cold exposure (58, 163) and a fall in adrenal
norepinephrine content (163) are consistent with the
differential stimulation of adrenal norepinephrine release in response
to cold exposure (165).
Nociceptor stimulation.
Peripheral nociceptor stimulation, such as that produced by pinching
the skin, evokes a strong excitation of muscle and visceral vasoconstrictor sympathetic outflow but a prompt reduction in cutaneous
vasoconstrictor efferent discharge in cat (88). An equally
strong differential response, but in the opposite direction, is evoked
by painful trigeminal stimuli in the anesthetized rabbit. The
"trigeminal depressor response," evoked by stimulation of the
trigeminal nerve or pinching the facial skin, involves a reduction in
splanchnic, renal, and skeletal muscle sympathetic outflow and a
simultaneous increase in that to the cutaneous vessels (101, 167). Cutaneous vasoconstriction has also been demonstrated in anesthetized humans during surgical incision (113, 151).
Ischemic injury evoked a suppression of cardiac sympathetic
discharge and a stimulation of adrenal epinephrine secretion
(164). Recent experiments have suggested an involvement of
sympathetic premotor neurons in the rostral medullary raphe in the
control of cutaneous blood flow as a potential neural substrate
contributing to the differential responses in cutaneous vs. muscle and
visceral vasoconstrictor sympathetic outflow. Activation of raphe
neurons, independent of those in the RVLM, produced a large increase in
the sympathetic outflow to the cutaneous vascular bed in the rat tail
and the rabbit ear, with little effect on the visceral vasomotor
outflow to the kidney or mesentery (20, 143). Inhibition
of neurons in the raphe selectively prevented the cutaneous
constriction in the rabbit ear during trigeminal stimulation, whereas
inhibition of RVLM neurons was necessary to block the mesenteric
vasoconstriction from stimulation of abdominal vagal afferents
(19).
Hypoglycemia.
A fall in blood glucose, sensed by central and hepatic glucoreceptors,
stimulates an autonomic response directed primarily at restoring levels
of circulating glucose through stimulation of hepatic glycogenolysis
and inhibition of insulin-sensitive glucose uptake. Secondary effects
include a reduction in body temperature and a restriction of muscle
blood flow, both of which would reduce glucose utilization.
Experimentally, hypoglycemia is achieved with injections of insulin.
Alternatively, reflex pathways to correct hypoglycemia are activated by
the glucopenia produced by the administration of 2-DG, which blocks
cellular glucose metabolism. Because insulin can have direct effects on sympathetic nerve activity, euglycemic control studies are required to
interpret the results of insulin-induced hypoglycemia.
In humans, muscle sympathetic nerve activity and the sudomotor
component of skin sympathetic activity are stimulated by acute hypoglycemia, whereas the vasoconstrictor component of skin sympathetic activity is reduced (15, 55, 78). The increase in sweating and cutaneous vasodilatation would contribute to a fall in body temperature, as would the inhibition of sympathetic outflow and thermogenesis in rat brown adipose tissue evoked by administration of
2-DG (54, 79). Indirect evidence has also been presented in humans and dogs for an increased sympathetic outflow to the liver
during hypoglycemia (24, 133), which would contribute to
glycogenolysis and an elevation in blood glucose. Hypoglycemia stimulates a large increase in adrenal sympathetic nerve activity and
epinephrine secretion in rats and humans, but decreases or has little
effect on renal and cardiac sympathetic outflows (24, 32, 55, 78,
110, 124, 135, 142, 162, 166, 168). The release of adrenal
catecholamines is differentially affected by hypoglycemia, which is a
much stronger stimulus for the secretion of epinephrine than of
norepinephrine (128, 163).
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DIFFERENTIATION OF PREMOTOR NEURONS CONTROLLING SPECIFIC TARGET
TISSUES |
The prominent role of supraspinal circuits, in particular the
premotor neurons, in the functional organization of the autonomic reflexes described above gives strong support to the view that the
differential reflex responses observed in sympathetic nerves controlling different target tissues are a reflection of the existence of tissue-specific populations of premotor neurons. As alluded to
above, the characterization of these neuronal populations will be
dependent on the precision with which functional fingerprints of the
autonomic outflow to specific tissues can be defined. The requirement
for antidromic activation from the spinal intermediolateral nucleus and
the likely necessity to determine the neuronal responses to a series of
reflex or centrally evoked stimuli represent significant impediments to
obtaining these data. Current evidence, albeit indirect, for
functionally specific populations of sympathetic premotor neurons has
been derived from two approaches: correlation of the activity of
individual neurons with that in multiple, simultaneously recorded nerve
bundles and monitoring the differential responses in multiple nerves
during activation of subsets of premotor neurons. These studies have
been performed in the RVLM and the raphe, which are among the brain
regions identified anatomically as the principal sources of direct
premotor input to SPNs (156).
Correlation of brain stem unit activity to sympathetic nerve
discharge.
If the discharge of a sympathetic premotor neuron contributes to the
synchronous activation (i.e., burst behavior) of a single, homogenous
population of tissue-specific sympathetic ganglion cells, then the
expectation would be for the discharge of that neuron to be more
strongly correlated to the bursts of activity on the nerve that it
influences than to those on nerves regulating other target tissues.
Using this paradigm, Barman and colleagues (12) identified
RVLM and raphe neurons with discharges that were more tightly coupled
to either the cardiac, renal, or external carotid nerves. This analysis
is inherently complicated by the attempt to correlate unit activity
with a group of sympathetic efferents that each regulate a target with
a cardiovascular function: the potential for a variable degree of
coupling among the supraspinal circuits that generate the activity in
each sympathetic channel to cardiovascular target tissues
(63) would make it more difficult to observe differences
among the unit-to-nerve activity correlations. Additionally,
sympathetic nerve bundles, such as the renal and cardiac, are likely to
contain multiple populations of functionally specific axons
(49). The use of partial coherence analysis
(41) has been an improvement on the original approach, but
the conclusions are still limited by the array of efferent nerves one
has available in any particular experiment.
Differential responses from altering the activity of RVLM neurons.
With the discovery of cardiovascular sympathetic premotor neurons in
the RVLM, several laboratories began to address the question of whether
there was a viscerotopic organization of premotor neuron populations
within the RVLM. Inherent in finding a distinct tissue topography in
the sympathetic responses elicited by microstimulation within the RVLM
would also be evidence for functionally specific populations of
premotor neurons, thereby establishing that the "private lines"
regulating the myriad of autonomic influences on tissue function could
be traced centrally from the sympathetic ganglion cells and
preganglionic neurons to their antecedent premotor neurons. The focus
of microstimulation experiments within RVLM has been on differentiating
subregions that regulate different cardiovascular tissues.
Activation of neurons in restricted regions of the RVLM in the cat with
microinjections of an excitatory amino acid has produced the following
general results: neurons in pathways controlling the vasoconstrictor
sympathetic outflow to muscle are located more laterally and caudally
in the RVLM, those capable of increasing cutaneous sympathetic nerve
activity were located more medially in the RVLM, and those activating
renal, cardiac, and lumbar splanchnic nerves are found rostromedially
(27, 46, 47, 108, 119). Although there were relatively
large areas from which responses on more than one nerve were evoked,
the finding of restricted regions of the RVLM from which responses in
only one tissue could be recorded is consistent with the existence of
sympathetic premotor neurons directed solely to the regulation of the
SPNs for that tissue. In this scenario, responses evoked in multiple
nerves would arise from the anatomic intermixing of populations of
functionally specific premotor neurons in the RVLM. This and the
relatively smaller anatomic size of the RVLM are likely explanations
for the failure to find similar results in the rat (13,
14). Importantly, simultaneous changes in blood flow to hindlimb
and forelimb could be produced independently of those to the kidney,
suggesting that the variable being regulated at the level of the
premotor neuron is related to the target tissue (skeletal muscle blood
flow vs. renal resistance, in this example) rather than the anatomic
location within the body (118). This organizational
principle is supported by the finding of extensive axonal branching of
individual sympathetic premotor neurons projecting to intermediolateral
nucleus (IML) neurons, possibly SPNs whose ganglion cell
targets innervate the same end-organ tissue, at multiple levels of the
thoracic spinal cord (8, 129). Additionally, as with
cardiac vagal preganglionic neurons in the nucleus ambiguus
(59), the data indicating selective regulation by
different populations of RVLM neurons of cardiac contractility, rate,
and conduction (26) emphasize the degree of functional
specificity residing within the autonomic premotor and preganglionic
efferents. Although relatively few noncardiovascular efferent pathways
have been examined, the failure to demonstrate an excitatory effect of
RVLM neurons on sympathetic regulation of pupillary dilation,
piloerection, sweat glands, retraction of the nictitating membrane, rat
tail blood flow, and rat brown adipose tissue sympathetic activity
(116, 120, 121, 127, 143) is consistent with a selective
role for premotor neurons in the RVLM in regulating sympathetic
functions related to the maintenance of tissue perfusion pressure.
Experimental designs involving the stimulation or inactivation of large
numbers of neurons cannot, however, rule out the possibility that
individual RVLM neurons branch to innervate multiple populations of
SPNs controlling different tissues. Thus, although the available
evidence favors tissue-specific populations of sympathetic premotor
neurons within RVLM, we do not yet have direct evidence for their
existence. Indeed, although sympathetic premotor neurons displaying the
functional fingerprint indicating a role in the regulation of
vasoconstriction have been extensively studied (8, 25, 117,
131), the same rudimentary characteristics would be expected of
those controlling a variety of other functions as well: venous
compliance, cardiac performance, and renal glomerular filtration.
Effects of altering the activity of neurons in rostral medullary
raphe.
The responses evoked from activation of the rostral medullary raphe in
the rat and the rabbit, another locus of sympathetic premotor neurons
(3, 107), provide evidence of a broader functional specificity: the populations of SPNs driven by raphe-spinal neurons are
involved in thermoregulation and possibly energy balance, rather than
the control of organ perfusion pressure, which may be the purview of
RVLM premotor neurons. In studies on the central regulation of the
sympathetic outflow to brown adipose tissue in the rat, disinhibition
of neurons in the rostral raphe pallidus region produced large
increases in brown adipose tissue sympathetic nerve activity, with only
a small increment in splanchnic sympathetic nerve activity
(127). The activation of brown adipose sympathetic outflow
from raphe was independent of the activity of neurons in the RVLM (Fig.
4). Considering the significance of brown
adipose tissue thermogenesis in the overall energy expenditure in small mammals, it seems likely that raphe neurons also play a role in regulating sympathetic outflows involved in metabolism and energy balance. Neurons in the rostral raphe were also found to be a source of
sympathoexcitatory drive to the cutaneous circulation in the rabbit ear
(20) and in the rat tail (143), both of which contribute significantly to thermoregulation through their role in heat
dissipation. In these cases as well, RVLM neurons were found to have
little influence on the sympathetic control of these thermoregulatory
circulations (19, 143). Although it seems likely that
target-specific populations of sympathetic premotor neurons exist
within the raphe-spinal projection, the identification of sympathetic
premotor neurons controlling different thermoregulatory and metabolic
tissues remains to be accomplished. Although neither the role of
raphe-spinal neurons in thermoregulation in the cat nor the functional
specificity of cat raphe sympathetic premotor neurons has been examined
(although see Ref. 12), the finding of raphe neurons with
projections to the IML, with strong baroreceptor modulation
(129, 130) and with a role in the 10-Hz rhythm in sympathetic nerve activity (11), suggests that a
cardiovascular regulatory function is represented within the population
of raphe sympathetic premotor neurons in this species.
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Fig. 4.
Activation of brown adipose sympathetic nerve activity
(BAT SNA) from raphe pallidus (RPa) after inhibition of neurons in
RVLM. Left: integrated and raw phrenic nerve activity (PHR),
arterial pressure (AP), splanchnic nerve activity (SPL SNA), and BAT
SNA under normothermic, control conditions. Middle: same
variables after bilateral microinjections of muscimol (MUSC) into the
RVLM to inhibit local neuronal discharge. Note the marked reduction in
SPL SNA and AP. Right: same variables after disinhibition of
RPa neurons following a microinjection of bicuculline (BIC). The large
increase in BAT SNA suggests that RPa, rather than RVLM, contains
sympathetic premotor neurons regulating BAT SNA. [From Morrison
(127).]
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Summary.
Current physiological data provide strong support for the existence of
tissue-specific populations of sympathetic premotor neurons as an
important structural and functional basis for the ability of the
central nervous system to generate autonomic responses at selective
sites in the body and to orchestrate complex autonomic patterns
involving differential changes in the amplitudes of the sympathetic
outflows to relevant targets. Although only two of the several
anatomically segregated groups of sympathetic premotor neurons have
been studied from a functional perspective, the results suggest an
organizational model in which the basis for the anatomic clustering of
different subpopulations of premotor neurons resides in the larger
homeostatic function to which the regulation of their target tissues
contributes. Thus RVLM premotor neurons regulate cardiovascular target
tissues to control arterial pressure at an appropriate level to
maintain nutritive tissue blood flow, whereas a population of rostral
raphe-spinal sympathetic premotor neurons may selectively control
sympathetic outputs involved in thermoregulatory and metabolic control.
Within this model, it is expected not only that certain supraspinal
loci will comprise unique sites for premotor neurons regulating
particular tissues but also that some populations of SPNs will receive
premotor inputs from more than one source. For instance, the increase
in heart rate during exercise may arise from activation of cardiac
sympathetic premotor neurons in the RVLM, whereas that occurring during
brown adipose tissue thermogenesis may involve stimulation of premotor neurons in the rostral raphe that project to the same population of
cardiac preganglionic neurons (30).
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HIERARCHICAL ORGANIZATION OF DIFFERENTIAL SYMPATHETIC REGULATION |
Given the evidence described above that sympathetic premotor
neurons are functionally "dedicated" by virtue of their axonal projection pattern, one might ask whether the selective control of
tissue-specific autonomic outflow is maintained at any organizational level that is central to the premotor neurons? Specifically, are neurons antecedent to premotor neurons functionally specific or are
their axonal branches distributed to provide mechanisms for linking
sympathetic premotor output channels to effect simultaneous changes in
different target tissues? Although these questions do pose a potential,
albeit simplistic, framework for the neural substrates underlying
patterned autonomic responses, a number of factors combines to
complicate the experimental testing of such hypotheses. As with all
such studies, there are significant limitations set by the number of
outputs that can be simultaneously monitored and by the difficulty in
distinguishing whether simultaneous activation of multiple outputs
arises from stimulating 1) separate populations of neurons
controlling each output or 2) a single group of neurons with
axons that branch to innervate multiple, functionally specific efferent
pathways. Regions containing sympathetic premotor neurons receive
inputs from multiple sources, which may themselves be interconnected.
Additionally, considerable evidence supports the existence of
individual "oscillator" circuits that drive target-specific
populations of premotor neurons (63) to generate the
bursting activity characteristic of each sympathetic outflow. The
interaction of inputs from more rostral sites with such brain stem
oscillator circuits, the potential for coupling among oscillators for
different outputs, and the presence of a significant inhibitory input
to premotor neurons (71, 132) represent further
complexities of the central autonomic networks.
Stimulation of the hypothalamus.
A variety of differential autonomic responses has been documented from
activation of the hypothalamus. The varied use of electrical vs.
chemical stimuli; the activation of relatively large, functionally heterogeneous populations of neurons; and the existence of
intrahypothalamic connections as well as descending pathways to the
periaqueductal gray (PAG), the RVLM, and the spinal cord allow few
conclusions on the pathways or, in some cases, the functional
significance for these responses. Nonetheless, in the best light, the
differential nature of the evoked responses does indicate a degree of
separate regulation of the outputs being monitored, although likely
reflecting only a portion of an organized homeostatic response
involving an unknown number of additional efferents.
Sampling of plasma catecholamines during systematic stimulation through
the cat hypothalamus revealed that markedly different ratios of adrenal
epinephrine and norepinephrine secretion could be evoked, even from
neighboring sites (56, 145). Although these data reveal
little of the organization of hypothalamic networks influencing adrenal
medullary function, they are consistent with the existence of separate
descending pathways to the two groups of adrenal sympathetic premotor
neurons controlling epinephrine- vs. norepinephrine-secreting
chromaffin cells (128). In this regard, different
hypothalamic regions contribute to the autonomic response to
hypoglycemia and to hypothermia, which elicit differential release of
adrenal catecholamines (163). Opposite responses can also
be evoked in cardiac sympathetic nerve activity and muscle vasoconstrictor outflow in cat and in cardiac and renal sympathetic nerve activities in the rabbit by stimulation at certain hypothalamic sites (97, 140). Stimulation within neighboring sites in
the lateral hypothalamus evoked differential responses in cardiac and
in vasoconstrictor efferents to neck or to pharyngeal muscles (21). Although these responses resemble portions of the
response to arterial chemoreceptor activation, it will remain for
future investigation to identify the behavioral or reflex context for many of these data.
Historically, the hypothalamically evoked defense response, also
referred to as the fight-or-flight or visceral alerting response, has
often been described as a behavior involving differential control of
sympathetic outflow (1, 76, 77). This view seems to have
arisen from the finding that the cardiac stimulation, widespread
visceral vasoconstriction, piloerection, and pupillary dilatation
observed during the defense response are accompanied by a
characteristic increase in skeletal muscle blood flow
(43). However, the evoked increase in muscle blood flow is
mediated by activation of a cholinergic (atropine sensitive)
vasodilator pathway, with little evidence for a marked inhibition of
adrenergic muscle vasoconstrictors (43, 81). Although the
utility of studies examining the defense response in anesthetized
animals has been questioned (18) and the prominence of a
cholinergic vasodilator pathway is unclear in species other than the
cat, experiments to identify the descending pathways for the
hypothalamic defense response were a significant motivation for
examining the role of the PAG in the organization of patterned
autonomic responses (40).
Stimulation of the PAG.
Detailed stimulation studies have delineated an organizational
structure based on longitudinal columns within the PAG for circuits
that are capable of coordinating a variety of complex autonomic, motor,
and sensory modulating commands mimicking the fight-or-flight response
(dorsal and lateral columns, Fig.
5A) as well as those seen
during recovery from stress, activation of antinociception, or the
vasovagal syncope that can accompany deep pain (ventrolateral columns)
(7, 35, 109). The portions of the PAG columns from which
autonomic responses are evoked have extensive, viscerotopically
organized, descending projections to sympathetic premotor neurons in
the RVLM (36, 37, 39). Differential activation of these
pathways is likely to mediate the vasoconstrictor and tachycardic
components of "active emotional coping" evoked from the dorsal and
lateral columns of PAG and the vasodepressor and bradycardic responses
of "passive coping" strategies mimicked by stimulation of
ventrolateral PAG (5, 6, 38). These response patterns
suggest that PAG neurons, by virtue of the topography of their inputs
to the RVLM, provide a substrate for the parallel activation or
inhibition of premotor neurons controlling an extensive array of
cardiovascular targets.
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Fig. 5.
Differential blood flow and sympathetic nerve responses
elicited from activation of the defense region in lateral
periaqueductal gray (PAG). A: activation of neurons in PAG
with microinjection of D,L homocysteic acid (DLH; arrow)
produces a simultaneous increase in iliac flow and a reduction in renal
blood flow, as well as an increase in AP and defensive behaviors.
[Reprinted from Brain Res, Vol 483, Carrive et al., Somatic
and autonomic integration in the midbrain of the unanesthetized
decerebrate cat: a distinctive pattern evoked by excitation of neurones
in the subtentorial portion of the midbrain periaqueductal grey, p.
251-258, 1989, with permission from Elsevier Science.]
B: electrical stimulation in PAG evokes a simultaneous
decrease in vertebral nerve (VN) activity to muscle and increases in
renal (RN) and cardiac (CN) nerve activities. [From Gebber et al.
(64).]
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Recent studies have also provided evidence that activation of sites in
the defense region of PAG can evoke differential changes in visceral
vs. skeletal muscle sympathetic outflows (64, 65). Under
conditions allowing 10-Hz rhythms in these nerves, PAG stimuli that
elicited increases in cardiac and renal sympathetic nerve activities
produced a prompt inhibition of vertebral nerve activity (Fig.
5B) and a prolongation of the phase angle between them. These findings have led to the proposal of a novel mechanism by which
differential responses may be produced in functionally specific sympathetic outflows: if an input (such as that from PAG) to a network
of coupled oscillators (in this case involving populations of premotor
neurons in RVLM) shifts the phase relationship between the oscillators
generating the bursts in different sympathetic nerves, then, by virtue
of their coupling, the reduced synchrony could result in a decrease in
the burst amplitude of one output relative to the other, including a
complete inhibition if the shift in phase is of sufficient magnitude
(62).
| |
CONCLUSIONS |
The demonstration that sympathetic outflows to different targets
can be differentially affected by central stimulation and during reflex
and behavioral responses reflects a much more complex structure to the
central autonomic network than that necessary to affect the relatively
simple global changes in sympathetic discharge that were the focus of
early investigators. Anatomic and functional studies have indicated a
structural foundation for differential sympathetic responses in the
target specificity of the projections of ganglion cell axons and those
of their preganglionic inputs. Although it has been more difficult to
obtain direct evidence for dedicated, tissue-specific populations of
sympathetic premotor neurons, the ability to elicit differential
responses in different sympathetic outflows from stimulations at
stereotyped sites within a single locus of premotor neurons (such as
RVLM) or at sites within anatomically separate loci of premotor neurons
(such as RVLM and raphe) is strongly supportive of such a model.
Similarly, differential sympathetic responses to activation of a number
of reflexes that involve changes in sympathetic premotor neuronal discharge are most easily explained through differential inputs to
populations of functionally dedicated premotor neurons. The functional
fingerprints of the sympathetic outflows to different tissues could
provide the information needed for a response-based differentiation
among premotor neurons controlling different tissues. Although current
evidence is still sparse, the clustering of different populations of
tissue-specific premotor neurons at a particular anatomic site may
relate to a similarity in the overall function of the outputs being
regulated by those groups of premotor neurons. Within the framework of
this hypothesis, the premotor neurons located in the RVLM appear to be
primarily involved in regulating cardiovascular target tissues involved
in maintaining organ perfusion pressure and nutritive blood flow, in
contrast to those in the rostral raphe nuclei that influence targets
with thermoregulatory and metabolic functions. Will this model be
supported by the differential nature of the responses evoked from other
sources of premotor input to preganglionic neurons, such as the A5
region and the paraventricular nucleus of the hypothalamus?
Determining the substrate for tissue specificity within central
autonomic pathways represents not only a significant advance in our
understanding of the functional organization of sympathetic control
networks, but also a stepping stone to identifying the mechanisms
through which multiple, tissue-dedicated output systems are engaged to
produce the constellation of changes in individual effector outflows
that comprises a complete autonomic response or behavior component. On
this threshold, we are challenged to put the information derived from
patterns of differential, stimulation-evoked responses into functional
contexts that will yield insight into the underlying organizational
structure, operating principles, and response dynamics of the central
autonomic network.
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ACKNOWLEDGEMENTS |
I thank Dr. J. B. Young for insightful discussions related to
this review and the American Physiological Society for its support of a
symposium related to this subject at the Experimental Biology 2000 meeting.
| |
FOOTNOTES |
Portions of the research described in this review were supported by
grants from the National Heart, Lung, and Blood Institute (HL-56365)
and the National Institute of Diabetes and Digestive and Kidney
Diseases (DK-20378).
Address for reprint requests and other correspondence: S. F. Morrison, Dept. of Physiology (M211), Northwestern Univ. Medical School, 303 E. Chicago Ave., Chicago, IL 60611 (E-mail:
s-morrison2{at}northwestern.edu).
| |
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TOP
ABSTRACT
INTRODUCTION
