Download Central mechanisms regulating coordinated cardiovascular and

Am J Physiol Regul Integr Comp Physiol 309: R429 –R443, 2015.
First published June 3, 2015; doi:10.1152/ajpregu.00051.2015.
Review
2013 CARL LUDWIG DISTINGUISHED LECTURESHIP OF THE APS NEURAL CONTROL AND
AUTONOMIC REGULATION SECTION
Central mechanisms regulating coordinated cardiovascular and respiratory
function during stress and arousal
Roger A. L. Dampney
School of Medical Sciences (Physiology) and Bosch Institute, University of Sydney, New South Wales, Australia
Submitted 12 February 2015; accepted in final form 28 May 2015
defensive behavior; sympathetic activity; respiratory activity; hypothalamus; midbrain; sympathetic premotor nuclei
AN ANIMAL’S SURVIVAL
is dependent on being able to respond
appropriately to stressors, which can be categorized into two
different groups: interoceptive (also-called physical) stressors and exteroceptive (also-called psychological) stressors
(44, 133). Physical stressors are those that directly threaten
homeostasis, such as hypoxia, hemorrhage, or infection,
whereas psychological stressors can be defined as actual or
perceived threats in the external environment. Psychological
stressors can be further subdivided into conditioned stressors (i.e., ones that are normally innocuous but which are
perceived as threatening because of previous experiences)
or unconditioned stressors (i.e., ones that are intrinsically
Address for reprint requests and other correspondence: R. A. L. Dampney,
School of Medical Sciences (Physiology) and Bosch Institute, The Univ. of
Sydney, NSW 2006, Australia (e-mail: [email protected]).
http://www.ajpregu.org
threatening, such as the sight, sound, or odor of a predator).
Physical and psychological stressors activate different populations of neurons in the brain (44, 63, 102). Similarly,
there is evidence that the autonomic responses to conditioned and unconditioned psychological stressors are also
mediated by different pathways in the brain (62). In this
review, which is based on my 2013 Carl Ludwig Distinguished Lecture to the American Physiological Society, I
consider the brain mechanisms that coordinate the physiological
responses to unconditioned psychological stressors, which may
range in intensity from mild alerting stimuli to extreme stimuli
that may be life-threatening. Such stressors evoke a wide range of
physiological responses including autonomic, hormonal, and behavioral responses. I focus particularly on the brain mechanisms
that generate coordinated cardiovascular and respiratory changes
that support behavioral responses to psychological stress and
arousal.
0363-6119/15 Copyright © 2015 the American Physiological Society
R429
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Dampney RA. Central mechanisms regulating coordinated cardiovascular
and respiratory function during stress and arousal. Am J Physiol Regul Integr
Comp Physiol 309: R429 –R443, 2015. First published June 3, 2015;
doi:10.1152/ajpregu.00051.2015.—Actual or potentially threatening stimuli in the
external environment (i.e., psychological stressors) trigger highly coordinated
defensive behavioral responses that are accompanied by appropriate autonomic and
respiratory changes. As discussed in this review, several brain regions and pathways have major roles in subserving the cardiovascular and respiratory responses
to threatening stimuli, which may vary from relatively mild acute arousing stimuli
to more prolonged life-threatening stimuli. One key region is the dorsomedial
hypothalamus, which receives inputs from the cortex, amygdala, and other forebrain regions and which is critical for generating autonomic, respiratory, and
neuroendocrine responses to psychological stressors. Recent studies suggest that
the dorsomedial hypothalamus also receives an input from the dorsolateral column
in the midbrain periaqueductal gray, which is another key region involved in the
integration of stress-evoked cardiorespiratory responses. In addition, it has recently
been shown that neurons in the midbrain colliculi can generate highly synchronized
autonomic, respiratory, and somatomotor responses to visual, auditory, and
somatosensory inputs. These collicular neurons may be part of a subcortical
defense system that also includes the basal ganglia and which is well adapted
to responding to threats that require an immediate stereotyped response that
does not involve the cortex. The basal ganglia/colliculi system is phylogenetically ancient. In contrast, the defense system that includes the dorsomedial
hypothalamus and cortex evolved at a later time, and appears to be better
adapted to generating appropriate responses to more sustained threatening
stimuli that involve cognitive appraisal.
Review
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BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
Pattern of Cardiovascular and Respiratory Responses to
Stress and Arousal
∆MAP
(mmHg)
10
0
30
∆HR
(bpm)
20
10
0
10
∆Renal
conductance
(% baseline)
0
-10
-20
-30
10
∆Mesenteric
conductance
(% baseline)
0
-10
-20
-30
150
∆Forearm
conductance
(% baseline)
100
50
0
B
1
2
3
4
5
R
Mental stress (min)
Fig. 1. Changes (means ⫾ SE) in mean arterial pressure (MAP), heart rate
(HR), and conductance in the renal, mesenteric, and forearm vascular beds
during a 5-min period of mental stress (mental arithmetic) in normal subjects
lying supine compared with the baseline (B) values measured before the onset
of the mental stress. The values during the recovery (R) period are also shown.
From Kuipers et al. (95, Figs. 1– 4).
trical stimulation of sites within the classic hypothalamic
“defense area” inhibits the depressor response normally evoked
by baroreceptor stimulation (38, 108). It is now clear, however,
that during naturally evoked psychological stress, the baroreflex control of sympathetic vasomotor activity is not inhibited
but instead is reset, such that both the arterial pressure and
sympathetic vasomotor activity is regulated over a higher
operating range, without any decrease in reflex gain, both in
normotensive and hypertensive animals (20, 85).
Increases in respiratory rate are evoked by either brief
alerting stimuli or more prolonged psychological stressors in
both humans and animals (16 –18, 84, 145). During more
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In animals, brief alerting stimuli such as an unexpected noise
or light will evoke immediate autonomic and respiratory responses, characterized by strong cutaneous vasoconstriction
and respiratory activation (17, 18, 84, 109, 161). In contrast,
such nonnoxious brief stimuli evoke only small and transient
increases in arterial pressure and little or no changes in blood
flow to the mesenteric, renal, and hindlimb vascular beds (109,
162), indicating that the sympathetic outflow to the cutaneous
vascular bed is rather selectively activated by mild alerting
stimuli. Consistent with this, alerting stimuli in humans reliably increase cutaneous sympathetic activity (156). Brief alerting stimuli also evoke variable and often biphasic changes in
heart rate (1, 8, 33, 161) due to the fact that there is coactivation of cardiac sympathetic and vagal parasympathetic activity
(1, 8, 33, 123).
Casto et al. (32) suggested that the initial response to a novel
alerting stimuli is an orienting reflex, which may lead to what
has been termed a “defense reaction” or “visceral alerting
reaction” (74) if the stimulus is prolonged or more threatening.
Consistent with this view, Yu and Blessing (161) proposed that
the cutaneous vasoconstriction that is initially evoked is associated with cerebral vasodilation, such that cerebral blood flow
is increased at a time when the salience of the stimulus needs
to be assessed. Regardless of the physiological significance of
the initial orienting reflex, however, it has long been known
that more prolonged threatening stimuli typically elicit a more
complex autonomic response, which is characterized by an
increase in arterial blood pressure, cardiac output, and heart
rate, together with marked vasoconstriction in renal and mesenteric vascular beds and usually also vasodilation in skeletal
muscle beds, in both humans (6, 14, 27, 34, 60, 68, 75, 95, 99,
119, 157) (Fig. 1) and animals (24, 65, 106, 155). These
cardiovascular changes are accompanied by a marked increase
in total norepinephrine spillover in humans, indicative of an
overall increase in sympathetic activity (158).
In humans direct measurements of the activity of sympathetic nerves innervating blood vessels in arm and leg skeletal
muscle shows variable changes, including increases, decreases,
or no change, during psychological stress (mental arithmetic)
(27–29, 55, 75, 95). Thus the vasodilation in skeletal muscle
and consequent increase in skeletal muscle blood flow evoked
by psychological stress is due to nonneurogenic factors, which
are believed to be primarily an increase in the level of circulating epinephrine as well as the effects of endothelial nitric
oxide (99). Consistent with observations in humans, the activity of lumbar sympathetic nerves (which supply mainly skeletal
muscle) is little altered during psychological stress in rats,
whereas renal sympathetic nerve activity is greatly increased
under these conditions (160). In summary, studies in both
humans and animals indicate that psychological stress evokes
a differentiated pattern of sympathetic responses, with marked
increases in the activity of sympathetic nerves supplying the
heart, skin, renal and mesenteric beds, and adrenal medulla, but
with highly variable effects on skeletal muscle sympathetic
activity.
It is often assumed that the increase in arterial pressure
during psychological stress is associated with inhibition of the
baroreceptor reflex, based on early studies showing that elec-
20
Review
BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
PAG
PVN
NTS
KF/PB
MeA/BLA
DMH/PeF/LH
**
Forebrain/midbrain
**
60
*
40
**
*
20
**
**
*
** **
Fos-positive
cells/section
40
PA
G
lP
AG
vl
dl
PA
G
LH
dm
*
Pons/medulla
30
*
**
20
PA
G
F
H
Pe
A
M
D
eA
BL
M
eA
C
PV
N
0
control
*
Premotor Nuclei Driving Stress-Evoked Sympathetic Activity
**
10
*
stress
**
*
M
M
VL
C
RV
M
M
RP
a
RV
L
l
c
TS
m
TS
N
N
A5
TS
N
PB
KF
0
LC
(DMH), perifornical area (PeF), midbrain periaqueductal gray
(PAG), parabrachial region, nucleus tractus solitarius (NTS),
and the ventrolateral medulla. Such studies, however, do not
clearly identify the particular neurons and pathways that mediate stress-evoked increases in arterial pressure, sympathetic
activity, and respiratory activity. Furthermore, c-Fos expression occurs only after sustained stimulation of neurons and so
this method cannot be used to identify cell populations activated by brief alerting stimuli. Nevertheless, even though many
questions remain unanswered, recent studies have provided
much new information concerning the central pathways and
mechanisms that generate coordinated sympathetic and respiratory responses during psychological stress and arousal.
In this review I propose that there are essentially two
different systems in the brain that generate defensive behavioral responses associated with appropriate autonomic and
respiratory changes. One of these defense systems includes the
DMH and dorsolateral PAG as key components and is dependent on inputs to these regions from the amygdala, cortex, and
other forebrain regions. The second system is subcortical and
includes the basal ganglia and midbrain colliculi. This system
is phylogenetically ancient and is well adapted to responding to
threats that require an immediate stereotyped response that
does not involve the cortex. Before discussing the mechanisms
by which these two defense systems generate autonomic and
respiratory responses to external threatening stimuli, however,
I will first consider which sympathetic premotor neurons in the
brain drive increased sympathetic activity during psychological
stress.
Fig. 2. Top: sagittal section of the rat brain showing location of different
brain regions that were examined for c-Fos expression after a period of
air-puff stress in rats. Bottom: histograms showing numbers of c-Fospositive cells per section (means ⫾ SE) in the different brain regions under
control conditions (n ⫽ 4) and during air-puff stress (n ⫽ 5). BLA,
basolateral amygdala; c, commissural; CeA, central nucleus of the amygdala; CVLM, caudal ventrolateral medulla; dl, dorsolateral; dm, dorsomedial;
DMH, dorsomedial hypothalamus; KF, Kölliker-Fuse nucleus; l, lateral;
LC, locus coeruleus; LH, lateral hypothalamus; m, medial; MeA, medial
amygdala; PAG, periaqueductal gray; PeF, perifornical area; PVN, paraventricular nucleus; RPa, raphe pallidus; RVLM, rostral ventrolateral
medulla; RVMM, rostral ventromedial medulla; vl, ventrolateral. **P ⬍
0.01, *P ⬍ 0.05 vs. control. From Furlong et al. (64).
prolonged stress, the ventilation is also increased as demonstrated by a decreased end-tidal CO2 (145). Hyperventilation is
also a characteristic feature of panic disorder in humans (136),
which is an extreme type of psychological stress.
Brain Regions Activated During Acute Psychological Stress
Many previous studies have identified brain regions that are
activated during unconditioned psychological stress, as indicated by c-Fos expression (e.g., 44 – 46, 64, 101, 121, 138, 139,
151) (Fig. 2). Many of these regions also play an important role
in sympathetic and/or respiratory regulation, such as the paraventricular nucleus (PVN), dorsomedial hypothalamus
Sympathetic premotor neurons within the rostral ventrolateral medulla (RVLM), many of which are epinephrine-synthesizing neurons of the C1 group, are known to have a critical
role in the tonic and reflex control of sympathetic vasomotor
activity and blood pressure (41, 70). It is often assumed that
these neurons would be strongly activated and thus drive
increased sympathetic vasomotor activity in response to psychological stress. In a recent study from our laboratory (64),
however, we found that air-puff stress, an unconditioned psychological stressor of moderate intensity (138, 139, 149) that
elicits significant increases in arterial pressure, resulted in only
a small increase in c-Fos expression in neurons within the
RVLM sympathetic premotor region (Figs. 2 and 3A) and
virtually no c-Fos expression in C1 cells (Fig. 3C). In response
to baroreceptor unloading, however, which reflexly activates
RVLM sympathetic premotor neurons (41, 70), there was a
large increase in c-Fos expression in the RVLM, including C1
cells (Fig. 3, B and D). Similarly, Dayas et al. (44) found that
another psychological stressor, noise stress, evoked c-Fos expression in only 4% of C1 cells, although there was substantial
c-Fos expression in other brain regions that are known to be
activated by psychological stress, including the PVN, medial
amygdala, and A1 cell group in the caudal ventrolateral medulla.
In contrast, air-puff stress, but not baroreceptor unloading,
evoked a large increase in c-Fos expression in the region
medial to the RVLM that has been termed the rostral ventromedial medulla (RVMM) (39, 144) (Figs. 2 and 3). Similar to
our results, Carrive and Gorissen (26) found that another
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Fos-positive
cells/section
100
80
CVLM
RVLM/
RVMM
120
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BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
A
Air puff stress
B
Hypotension
-12.0
NTS
NTS
Sp5
Sp5
NA
RVLM
NA
GiV
RVLM
LPG
-13.0
NTS
Sp5
D
12N
NA
LPG
C
GiV
-12.0
*
*
*
*
*
*
*
*
*
*
psychological stressor (conditioned fear) also evokes c-Fos
expression in the RVMM but not in the RVLM. The RVMM,
like the RVLM, contains sympathetic premotor neurons, some
of which synthesize serotonin (144), but their precise function
in cardiovascular regulation is not known. It is interesting to
note, however, that Cox and Brody (39) showed over 20 years
ago that inhibition of neurons in the RVMM, but not the
RVLM, greatly reduced responses evoked by stimulation of the
hypothalamus. It is therefore possible that sympathetic premotor neurons in the RVMM (including serotonin neurons) are
one of the main drivers of stress-evoked sympathetic hyperactivity (Fig. 4).
A study using retrograde transport of viral tracers showed
that the neurons that regulate the sympathetic outflow to the
*
*
*
*
*
*
kidney are located within the RVMM of the rat at a level just
caudal to the facial nucleus (134), consistent with the fact that
psychological stress increases renal sympathetic activity (85,
160). The more rostral part of the RVMM, at the level of the
facial nucleus, contains premotor neurons that regulate the
sympathetic outflow to the stellate ganglion (82) which contains sympathetic postganglionic neurons innervating sweat
glands (2). Consistent with this, glutamate microinjections into
this rostral part of the RVMM evokes sweating in the paw of
the cat but has no effect on arterial pressure (135). Sweating in
the paw of the cat or rat may be analogous to sweating in the
human hand, which is typically evoked by psychological
stress (100). Furthermore, a brain imaging study in humans
has shown that psychogenic sweating is associated with
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Fig. 3. Data from the study by Furlong et al.
(64) showing the distribution of c-Fos-positive
cells in the rostral ventral medulla following
air-puff stress (A, combined data from three
rats), and following hypotension (B, example
from one rat). The numbers above each section
indicate the level caudal (⫺) to the bregma
(mm). The RVLM and RVMM were defined
as the regions ventral to the nucleus ambiguus
(NA), separated by a vertical line placed 0.2
mm medial to the medial edge of the NA and
extending from ⬃12.0 to 13.2 mm caudal to
bregma. The RVMM region included the ventral part of the gigantocellular reticular nucleus
(GiV) and medial parts of the lateral paragigantocellular nucleus (LPG). C and D: examples of cells labeled for tyrosine hydroxylase
(TH), a marker of C1 cells (brown-stained
cytoplasm) immunoreactivity and c-Fos
(black-stained nuclei) within the RVLM following air-puff stress and hypotension, respectively. Note the lack of double-labeled
c-Fos/TH cells following air-puff stress (C) in
contrast to the large number of double-labeled
cells (indicated by *) following hypotension
(D). 12N, hypoglossal nucleus; Sp5, spinal
trigeminal nucleus. For other abbreviations see
Fig. 2. From Fig. 3 in Furlong et al. (64).
GiV
LPG
Review
BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
mPFC
PAG
PVN
DMH/PeF
NTS
Amy
Acute
psychological
stressor
Baroreceptor
inputs
RVMM
via mPFC &
amygdala
PVN
DMH/PeF
Baroreflex
resetting
Premotor
nucleus
(RVMM?)
Raphe
pallidus
Sympathetic
outflow
Sympathetic
outflow
Central
respiratory
nuclei
NTS
CVLM
RVLM
Visceral
vasoconstriction
Heart rate
Cutaneous
vasoconstriction
BAT activity
Phrenic
nucleus
Respiratory
activity
Fig. 4. Top: sagittal section of the rat brain showing location of different brain
regions referred to in the diagram below. Bottom: schematic diagram showing
input and output connections of the DMH/PeF that subserve the sympathetic,
respiratory and neuroendocrine responses to psychological stress. The unbroken lines indicate known connections (which may be monosynaptic or
polysynaptic), whereas the dashed lines indicate postulated connections
that have not yet been defined. ACTH, adrenocorticotropic hormone; AVP,
arginine vasopressin; mPFC, medial prefrontal cortex. For other abbreviations see Fig. 2.
activation of a region in the rostral medulla that is homologous to the rostral RVMM region described above (56).
Thus, taking all of these observations together, I suggest that
psychological stress activates different groups of sympathetic premotor neurons in the RVMM that, as first suggested by Shafton and McAllen (135), are topographically
organized such that premotor neurons regulating the renal
and other vasomotor outflows are located more caudally,
while those regulating the sudomotor outflow are located
more rostrally.
As mentioned above, the baroreceptor-sympathetic reflex is
reset during psychological stress. Thus, although RVLM sympathetic premotor neurons may not be primary drivers of
stress-evoked increases in sympathetic activity, they would
still play a major indirect role by regulating sympathetic
activity and arterial pressure within an increased operating
range (Fig. 4).
The raphe pallidus in the midline medulla also contains
sympathetic premotor neurons, particularly those that regulate
the sympathetic outflow to the heart, cutaneous vasculature,
and brown adipose tissue (BAT) (112). Neurons within the
raphe pallidus mediate stress-evoked tachycardia (54), cutaneous vasoconstriction (120), and activation of the sympathetic
outflow to BAT, leading to thermogenesis and an increased
body temperature (86) (Fig. 4). Many of the sympathetic
premotor neurons within the raphe pallidus contain serotonin
and also express inhibitory 5-HT1A receptors (72). In conscious rabbits activation of 5-HT1A receptors in the raphe
pallidus greatly reduces the tachycardia evoked by psychological stress (116). Similarly, in anesthetized rats activation of
5-HT1A receptors in the raphe pallidus reduces leptin-evoked
increases in BAT thermogenesis (111). Because activation of
5-HT1A autoreceptors inhibits serotonergic neurons, these observations suggest that the tachycardia and BAT thermogenesis
in response to psychological as well as physical stressors are
mediated to a substantial degree by serotonergic neurons
within the raphe pallidus.
It is well known that neurons in the hypothalamic PVN
regulate neuroendocrine responses to psychological stress (9)
(Fig. 4). The PVN also contains sympathetic premotor neurons
as well as neurons that project indirectly to the spinal sympathetic outflow via the RVLM (9), but a study in conscious rats
showed that inhibition of the PVN had no effect on the pressor
response and tachycardia evoked by air jet stress, although it
blocked the stress-evoked neuroendocrine response (142).
Therefore, sympathoexcitatory neurons in the PVN are not a
critical component of the central pathways mediating sympathetic responses to unconditioned psychological stress, although such neurons are activated by physical stressors such as
an immune challenge or hypovolemia (3, 19). At the same
time, PVN sympathoexcitatory neurons may also contribute to
sympathetic responses evoked by unconditioned psychological
stress, because it has been shown that ⬃10% of spinally
projecting PVN neurons are activated by a conditioned stressor
(conditioned fear) (26). In addition, a small proportion (⬃7%)
of PVN neurons projecting to the NTS are activated by air-puff
stress in rats (64). Therefore, PVN neurons projecting to the
NTS, and/or those projecting to the RVLM and spinal cord,
may contribute to resetting of the baroreceptor-sympathetic
reflex during psychological stress (Fig. 4).
Role of DMH and PeF in Integrating Stress-Evoked
Responses
Several observations clearly demonstrate the critical importance of the DMH in mediating stress-evoked cardiovascular
and respiratory responses. In landmark studies, DiMicco and
co-workers (142, 143) first demonstrated that inhibition of
neurons within the DMH greatly reduced the pressor response
and tachycardia evoked by air jet stress, whereas, as mentioned
above, inhibition of neurons in the PVN had no effect. This
finding was later confirmed by others (101, 110). Similarly,
inhibition of the DMH almost completely abolishes the neuroendocrine and respiratory responses to psychological stressors (17, 53, 142), whereas blockade of NMDA receptors in the
DMH reduces the increases in arterial pressure, heart rate, and
respiratory rate evoked by lactate infusion in a rat model of
panic disorder (83). In addition, activation of neurons in the
DMH evokes a pattern of autonomic and respiratory effects,
including a resetting of the baroreceptor reflex, which are very
similar to naturally evoked stress responses (23, 52, 53, 59, 76,
103, 104, 146). Finally, psychological stress evokes a marked
increase in c-Fos expression in the DMH (64, 101, 132, 138)
(Fig. 2).
It is well known that central respiratory activity can influence sympathetic activity via connections from respiratory
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ACTH, AVP
secretion
RP
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BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
neurons activated by psychological stress may increase respiratory activity via connections with Pef neurons that project to
brain stem respiratory neurons.
Inputs to the DMH mediating stress-evoked cardiovascular
and respiratory responses. The majority of inputs to the DMH
arise from other hypothalamic nuclei. In fact, virtually every
major hypothalamic nucleus provides an input to the DMH
(148). In addition, there are major inputs from the bed nucleus
of the stria terminalis (BNST), amygdaloid nuclei, and medial
prefrontal cortex (35, 78, 148, 153). In contrast, direct inputs
from brain stem nuclei are sparse, except for a substantial input
from the parabrachial nucleus (148). Given the fact that the
DMH subserves many different functions, including ingestive
behavior, thermoregulation, and circadian rhythms in addition
to stress responses (12, 54, 148), and the fact that the inputs to
the DMH arise from many different sources, it is difficult to
identify specifically the inputs that generate stress-evoked
cardiovascular and respiratory responses.
Nevertheless, some information is available. The classic
study by Klüver and Bucy (91) first demonstrated that lesions
of the tremporal lobes (including the amygdaloid complex)
abolished fear responses normally elicited by threatening stimuli. Later, Blanchard and Blanchard (15) showed that this was
due specifically to lesions of the amygdaloid complex. More
recently, it has been shown that inhibition of neurons in the
amygdaloid nuclei by microinjection of muscimol greatly reduces both the cutaneous vasoconstrictor and respiratory responses evoked by brief alerting stimuli such as noise or light
(18, 109, 162). Furthermore, lesions of the amygdaloid complex also reduce the hindlimb vasodilation and mesenteric
vasoconstriction that are evoked by a more prolonged threatening stimulus (65). Psychological stress activates neurons in
the medial and basolateral amygdala (44, 64), both of which
project to the DMH both directly and indirectly via the BNST
(35, 93, 148). In addition, disinhibition of both the basolateral
amygdala and BNST evokes increases in arterial pressure and
respiratory activity, similar to those evoked by psychological
stress (165), and these effects appear to be mediated by
excitatory amino acid receptors in the DMH (137). Taken
together, these observations indicate that neurons in the medial
and basolateral amygdala that are activated by threatening
stimuli activate neurons in the DMH via both direct and
indirect pathways (Fig. 4).
There is also a major input to the DMH from the infralimbic
cortex in the medial prefrontal cortex (78, 153), which is
believed to have a role in regulating autonomic functions
associated with stress (40, 117). Activation of neurons in the
infralimbic cortex reduces the pressor and tachycardic response evoked by psychological stress (115), while inhibition of the ventral part of the medial prefrontal cortex that
includes the infralimbic cortex results in increased c-Fos
expression in the DMH and also the medial amygdala (101).
These findings suggest that the input from the infralimbic
cortex acts to reduce stress-evoked autonomic (and possibly
also respiratory) activation via an inhibitory action on DMH
neurons or on neurons in the medial amygdala which, as
discussed above, provide an excitatory input to the DMH.
In summary, the DMH is a critical region for integrating
autonomic and respiratory responses to psychological stress
and arousal. The DMH is immediately medial to the PeF,
however, and it is not clear whether the neurons that are critical
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neurons to sympathetic premotor neurons within the brain stem
(57). In response to disinhibition of DMH neurons, however,
McDowall et al. (103) found that there was no consistent
change in the amplitude of the respiratory-related variations in
renal sympathetic nerve activity, despite the marked increase in
the amplitude and frequency of phrenic nerve activity bursts
that occur under those conditions. This indicates that the
marked increase in sympathetic vasomotor activity in response
to disinhibition of the DMH is not simply a consequence of the
increased central respiratory drive. Similarly, Tanaka and
McAllen (146) found that there was little correlation between
increases in cutaneous sympathetic activity and phrenic
nerve activity in response to activation of different sites
within the DMH. It is therefore likely that the increased
sympathetic and respiratory activities that are evoked by
activation of DMH neurons are mediated by separate independent descending pathways (Fig. 4).
Output pathways from the DMH mediating stress-evoked
cardiovascular and respiratory responses. Since there is no
direct projection from the DMH to the spinal cord (147), DMH
neurons can only generate autonomic and respiratory responses
via premotor supraspinal nuclei. There are direct descending
projections from neurons in the DMH to the raphe pallidus in
the midline medulla (86, 122, 132, 147, 150), and there is
substantial evidence that these projections mediate the stressinduced tachycardia, cutaneous vasoconstriction, and activation of the sympathetic outflow to BAT (86, 132, 150), which
as discussed above is dependent on activation of the raphe
pallidus (Fig. 4).
Apart from the pathway to the raphe pallidus, however,
descending direct projections from the DMH to the lower brain
stem are relatively sparse (122, 147). Therefore, the question
remains: what are the output pathways from the DMH mediating stress-evoked increases in sympathetic vasomotor activity and respiration? The DMH projects very heavily to other
hypothalamic regions, including the PVN and PeF (147), both
of which project to the spinal sympathetic outflow directly or
via premotor nuclei in the medulla. As discussed above, there
is little evidence that PVN neurons make a major contribution
to the increased sympathetic vasomotor activity evoked by
unconditioned psychological stress, although PVN neurons
projecting to the NTS may contribute to the stress-evoked
baroreflex resetting. On the other hand, several lines of evidence suggest that the PeF may be a major source of sympathetic vasomotor drive during arousal or psychological stress.
First, unlike the PVN (67), there is a strong direct connection
from the PeF to the RVMM (122), which as discussed above
may be a major driver of stress-evoked sympathetic activation. Second, there is also a projection from the PeF to the
spinal cord, and the results of a combined c-Fos/retrograde
labeling study suggests that the PeF-spinal pathway is one
of the main sources of increased sympathetic activity during
the conditioned fear response (26). In addition, there is a
projection from the PeF to the NTS which, like the projection from PVN to NTS, may contribute to stress-evoked
baroreflex resetting (Fig. 4) (64).
There are also significant projections from PeF neurons to
brain stem regions that contain respiratory neurons, including
the dorsomedial medulla and Kölliker-Fuse nucleus (125, 163),
and disinhibition of PeF neurons can powerfully increase
respiratory activity (80). It is therefore possible that DMH
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BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
shown that the excitatory actions of orexin on BAT sympathoexcitatory neurons in the RVMM are dependent on the presence of ongoing activity in those neurons (150), whereas a
study at the cellular level has shown that orexin can act
presynaptically to modulate the release of glutamate from
nerve terminals (58).
Role of Midbrain PAG in Integrating Stress-Evoked
Responses
There is a very extensive literature that has clearly documented the role of the midbrain PAG in the production of
coordinated somatomotor and autonomic responses to a wide
variety of stressors, both physical and psychological (for reviews see Refs. 4, 5, 25, 88, 154). The PAG consists of four
longitudinal columns referred to as the dorsomedial (dmPAG),
dorsolateral (dlPAG), lateral (lPAG), and ventrolateral (vlPAG) subdivisions, which differ with respect to their functional properties, anatomical connections and chemical properties (4, 5, 25, 42, 88, 154). The findings of functional and
Psychological stressors
Auditory
Visual
Olfactory
Perceived
emotional
stressor
auditory
cortex
visual
cortex
amygdala
Medial PFC
DMH
Physical
stressors
somatic receptors
dlPAG
spinal cord
& brainstem
PBsl
lPAG
CnF
medulla
Sympathetic
activity
Respiratory
activity
Fig. 5. Schematic diagram showing major inputs to the dlPAG and the
proposed output pathways subserving the coordinated changes in sympathetic
vasomotor and respiratory activity regulated by the dlPAG. The lines with
arrows indicate projections, which include both direct (monosynaptic) or
indirect (polysynaptic) projections. In contrast to the dlPAG, the lPAG is
activated primarily by physical stressors and regulates sympathetic and respiratory activity via direct descending projections to medullary nuclei. CnF,
cuneiform nucleus; PBsl, superior lateral parabrachial nucleus. For other
abbreviations see Fig. 2. From Dampney et al. (Fig. 5, 42).
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for the expression of these responses are essentially confined
within the DMH or whether they extend into the PeF. Although
microinjections of muscimol centered on the DMH greatly
reduce stress-evoked cardiovascular and respiratory responses
(see Role of DMH and PeF in Integrating Stress-Evoked
Responses), the effects of muscimol microinjections centered
on the adjacent PeF have not been performed. It has been
shown, however, that neurotoxic lesions centered on the PeF
largely abolish the cardiovascular response associated with
conditioned fear (62). As discussed above, there are extensive
interconnections between the DMH and PeF (147, 148), and it
is therefore possible that DMH neurons may regulate autonomic and respiratory activity via projections to PeF neurons.
The precise functional relationship between DMH and PeF
neurons in regulating stress-evoked responses is an important
question that will need to be addressed in future studies.
Role of orexin neurons in regulating stress-evoked cardiovascular and respiratory responses. Neurons containing orexin
(also known as hypocretin) are located within the DMH, PeF,
and lateral hypothalamus (125). It is believed that orexin
neurons located in the PeF and DMH are primarily involved in
arousal and stress, whereas those located more laterally in the
lateral hypothalamus are primarily involved in reward processing (71). In orexin knockout mice, the cardiovascular and
respiratory responses evoked by disinhibition of the DMH/PeF
are greatly reduced compared with responses in wild-type mice
(87, 164). Similarly, systemic administration of the dual orexin
receptor antagonist Almorexant reduces the cardiovascular
responses associated with arousal and psychological stress but
not those associated with cold stress, a physical stressor (63).
In addition, the increases in arterial pressure, heart rate, renal
sympathetic nerve activity, and respiratory rate evoked by
disinhibition of neurons in the PeF and DMH are reduced by
about 50% after systemic administration of Almorexant (80).
Consistent with these observations, arousal and psychological
stress activates orexin neurons in the PeF and DMH, but not
those in the lateral hypothalamus (63).
Orexin neurons in the PeF and DMH project to multiple
targets in the brain stem, including regions that have an
autonomic and/or respiratory function, such as the midbrain
PAG, parabrachial and Kölliker-Fuse nuclei, NTS, RVLM, and
RVMM (125, 131). It might be suggested, therefore, that
orexin neurons in the DMH and PeF projecting to autonomic
and respiratory centers in the brain stem generate the cardiorespiratory responses to psychological stress. Double-labeling
studies indicate, however, that orexin neurons constitute only a
minority of the projection neurons from the PeF and DMH. For
example, only ⬃20% of PeF neurons projecting to the NTS
and RVMM contain orexin (150, 166). Although it is possible
that 20% of projection neurons from the DMH and PeF could
be sufficient to mediate stress-evoked cardiovascular and respiratory responses, other evidence indicates that orexin neurons primarily act to modulate responses mediated by nonorexinergic neurons, rather than being the prime mediators of these
responses. In particular, as reviewed by Kuwaki and Zhang
(96), the firing rate of orexin neurons is altered greatly during
a variety of behaviors, including the different phases of sleep,
exercise, and psychological stress, leading to the conclusion
that their principal function is state-dependent modulation of
physiological responses. Supporting the view that orexinergic
inputs act to amplify the actions of other inputs, it has been
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BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
dlPAG that converge on cardiovascular and respiratory neurons in the lower brain stem. In that case, it is conceivable that
cardiovascular and respiratory responses would only be evoked
by activation of the dlPAG if the descending pathway from the
DMH were also active. Although there are no direct descending projections from the dlPAG to the lower brain stem (42),
there is, as mentioned above, a projection from the dlPAG to
the cuneiform nucleus, which has descending projections to
cardiovascular and respiratory nuclei in the lower brain stem
and is believed to be involved in stress-evoked cardiovascular
responses (92, 152) (Fig. 5). Future studies will be required,
however, to determine the precise functional relationship between the DMH and dlPAG in generating stress-evoked response.
Role of Midbrain Colliculi in Integrating Stress-Evoked
Responses
The superior colliculus (SC) receives inputs arising from
visual, auditory, and somatosensory stimuli and can generate
appropriate highly coordinated orienting, defensive, or escape
behavioral responses to stimuli that require immediate action
(36, 47, 66). Similarly, the inferior colliculus (IC), which
receives convergent signals from brain stem auditory nuclei,
can also generate appropriate behavioral responses to auditory
signals via projections to the SC (30). In a recent study in
anesthetized rats, my colleagues and I (114) found that natural
auditory, visual, and somatosensory stimuli could evoke highly
synchronized increases in sympathetic, respiratory, and somatomotor activity, but only after disinhibition (by microinjection of the GABA receptor antagonists picrotoxin or bicuculline) of certain sites within the SC or IC (Fig. 6). Although
the evoked responses were highly synchronized, the onsets of
the evoked increases in respiratory and somatomotor activity
slightly preceded the onset of the evoked increases in sympathetic activity (114) (Fig. 6, B and C). These differences in
onset times are consistent with the hypothesis that the sympathetic, respiratory, and somatomotor responses are driven by a
common population of “command neurons” within the colliculi, as shown in Fig. 6D, because the conduction velocity of
unmyelinated sympathetic postganglionic axons is much
slower than that of myelinated phrenic and sciatic motor
pathways (81, 126) (Fig. 6D). Many neurons within the deep
layers of the SC receive convergent visual, auditory, and
somatosensory inputs and also have descending projections to
the brain stem (107). Such multisensory neurons could therefore conceivably act as command neurons driving synchronized changes in sympathetic, respiratory, and somatomotor
output in response to multisensory inputs.
Fig. 6. Cardiovascular, respiratory, and somatomotor responses evoked by different stimuli after microinjection of picrotoxin into the midbrain colliculi. A:
example in which auditory (clap), visual (light), and somatosensory (pinch) stimuli all evoked responses in splanchnic nerve activity (SpSNA), phrenic nerve
activity (PNA), and sciatic nerve activity (ScNA) after, but not before, picrotoxin (GABA receptor antagonist) microinjection. B: cycle-triggered average of 10
responses evoked by single claps following picrotoxin microinjection into one site in the colliculi, where the trigger was the onset of the evoked SpSNA burst.
C: portion of the averaged response (indicated by shaded portion in B) showing that the onsets of the bursts of PNA and ScNA occurred slightly before the onset
of the burst of SpSNA. The time of onset in each case is indicated by the vertical dashed line. These differences in onset time are consistent with activation of
sympathetic, respiratory, and somatomotot outputs by a single population of collicular neurons (as shown schematically in D), given the relatively slow
conduction velocity of sympathetic efferent pathways compared with that of phrenic and sciatic motor pathways (114). From Müller-Ribeiro et al. (Figs. 2 and
3, 114).
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anatomical studies have led to the proposal, first put forward by
Bandler and co-workers (4, 5), that the dlPAG has a major role
in generating the behavioral and autonomic changes associated
with defensive responses evoked by unconditioned threatening
psychological stimuli. The evidence for this hypothesis has
been discussed in detail in previous reviews (see Refs. 4 or 42)
but can be briefly summarized as follows: 1) the dlPAG is the
only PAG subregion that receives inputs related to visual,
auditory, and olfactory signals (10, 113, 118) (Fig. 5); 2)
auditory, visual, or olfactory threatening stimuli (e.g., ultrasound application, the sight or odor of a cat) that are known to
trigger defensive behavior in rats also evoke strong c-Fos
expression in the dlPAG but much less expression in other
PAG regions (21, 50, 89, 113); 3) lesions of the dorsal PAG
that include the dlPAG reduce the behavioral and cardiovascular response to the sight or odor of a cat (51); and 4)
activation of neurons in the dlPAG, but not other PAG subregions, evoke increases in sympathetic activity and respiratory
rate that closely resemble responses naturally evoked by psychological stressors (79). In contrast to the dlPAG, the lPAG
receives afferent inputs arising from somatic receptors and
generates increases in sympathetic activity in response to
physical stressors (e.g., cutaneous pain) via direct descending
projections to the medulla (42, 88) (Fig. 5).
Functional relationship between the PAG and DMH. If both
the dlPAG and DMH have important roles in integrating the
cardiovascular and respiratory responses to psychological
stressors, then what is the relationship between these key
regions? It has previously been suggested that the dlPAG is a
component of the descending pathway mediating cardiovascular responses evoked by activation of DMH neurons (43), but
a recent study has shown that inhibition of neurons in the
dlPAG has no effect on cardiovascular and respiratory responses evoked from the DMH (77). In contrast, however, the
increases in arterial pressure, heart rate, renal sympathetic
nerve activity, and respiratory activity evoked by stimulation
of dlPAG neurons are virtually abolished by inhibition of
neurons in the DMH in both conscious and anesthetized rats
(48, 77). There are two possible explanations for this observation. The simplest explanation is that there is an ascending
pathway from the dlPAG that activates DMH neurons that in
turn generate the cardiovascular and respiratory responses, as
illustrated in Figs. 4 and 8. There is only a minor direct
projection from the dlPAG to the DMH (148), but there are
much stronger projections to the cuneiform nucleus (11, 127)
and superior lateral parabrachial nucleus (94), both of which
project to the DMH and other hypothalamic nuclei (13, 61, 97)
(Fig. 5).
The alternative possibility, as suggested previously (42), is
that there are separate descending pathways from the DMH and
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BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
A
Arterial
pressure
(mmHg)
SpSNA
(units)
Before picrotoxin
After picrotoxin
180
120
60
1
0
-1
1
PNA
(units)
0
0.5
Integrated
PNA
(units)
0.5
Integrated
ScNA
(units)
0
1
0
1
0.5
0
5s
clap
B
clap
Cycle-triggered averaging
Averaged
integrated
SpSNA
(units)
1
light on
C
Averaged
integrated
SpSNA
(units)
0.5
Averaged
integrated
ScNA
(units)
1
0.5
0
0
Averaged
integrated
PNA
(units)
pinch
1
Averaged
integrated
PNA
(units)
0.5
0
1
Averaged
integrated
ScNA
(units)
0.5
0
1s
1
0.5
0
1
0.5
200 ms
0
clap
Command neuron
(colliculus)
D
Premotor nuclei
(pons/medulla)
Motor nuclei
(spinal cord)
visual
auditory
somatosensory
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Sympathetic
activity
Phrenic nerve
activity
Sciatic nerve
activity
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-1
1
Integrated
SpSNA
(units)
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BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
SC
ILN
Str
SNpr
Amy
Visual, auditory &
somatosensory inputs
Inputs from
cortex &
amygdala
Thalamus
Superior
colliculus
Rostral
intralaminar n.
Superficial
layers
Caudal
intralaminar n.
Deep
layers
Striatum
Substantia
nigra pars
reticulata
Somatomotor &
autonomic
outputs
Coordinated
behavioral &
autonomic response
Fig. 7. Schematic diagram showing the subcortical loop involving the superior
colliculus (SC) and basal ganglia. The deep layers of the SC receive topographically organized visual, auditory, and somatosensory inputs, whereas
superficial layers receive only visual inputs. There are multiple parallel
projections from the deep layers of the SC to the striatum, relayed via
intralaminar nuclei in the thalamus. The striatum also receives inputs from the
cortex and may act as an “action selector,” comparing inputs from the SC with
those from the cortex, so that the most appropriate action can be selected for
a particular set of inputs. This is done by disinhibition of the particular output
neurons in the SC that regulate the appropriate coordinated somatomotor/
autonomic response, by inhibiting neurons in the substantia nigra pars reticulata, which in turn are inhibitory to specific neurons within the deep layers of
SC. The red lines indicate an excitatory projection, whereas the blue lines
indicate an inhibitory projection. From McHaffie et al. (Fig. 2, 105).
creased) (114). It therefore seems unlikely that the observed
sympathetic-respiratory synchronization is simply a consequence of sympathetic premotor neurons receiving a modulatory input from central respiratory neurons that in turn are
activated by inputs from the colliculi.
In summary, these observations support the hypothesis that
there are neurons within the SC or IC that are capable of
generating immediate behavioral responses to external stimuli,
supported by cardiovascular and respiratory changes that are
appropriate for the particular behavior. Such neurons are normally inhibited by tonic GABAergic inputs, which arise from
the substantia nigra pars reticulata (31, 37). The substantia
nigra pars reticulata itself receives inhibitory inputs from the
striatum that in turn receives inputs from the deep layers of the
SC relayed via the thalamus as well as from the cortex and
amygdala (31, 69, 105) (Fig. 7). The substantia nigra pars
reticulata and striatum are components of the basal ganglia,
and it has been proposed that this subcortical loop involving
the basal ganglia and SC allows selection of an appropriate
response to competing inputs, including those that arise from
the cortex (105). The inputs to the SC from visual, auditory,
and somatosensory inputs, as well as all the connections within
this subcortical loop, are highly topographically organized, so
that the pattern of inputs to the striatum are highly specific for
a particular stimulus (47, 105). Similarly, the inputs to the
striatum from the cortex are also highly topographically organized (105). Thus it has been suggested (105) that the striatum
may act as an “action selector,” comparing inputs from the SC
with those from the cortex, so that the most appropriate action
can be selected for a particular set of inputs, by withdrawing
inhibition from the particular output neurons in the SC that
regulate the appropriate coordinated somatomotor/autonomic
response. For example, visual or auditory inputs signaling the
presence of a predator may via this loop result in disinhibition
of collicular neurons that trigger escape behavior accompanied
by appropriate cardiovascular and respiratory activation, while
other alternative behavioral responses continue to be inhibited.
The functional relationship between the dlPAG and the basal
ganglia-colliculi system is not known, although as pointed out
in a previous review (42), they share certain anatomical and
functional properties. In particular, both the dlPAG and deep
layers of the SC receive inputs from several nuclei in the
cortex, hypothalamus, and medulla (10, 22, 90, 159). In addition, the pattern of sympathetic and respiratory changes evoked
by stimulation of neurons in the dlPAG is similar to that
evoked from the deep layers of the SC (79). Furthermore, the
dlPAG (but not other PAG subregions) receives a direct input
from the deep layers of the SC (129). At the same time, there
are significant differences in the connections of the dlPAG and
deep layers of SC; for example, there is a dense projection
from the medial prefrontal cortex to the dlPAG but not to the
adjacent SC (4) and a descending projection to the pontomedullary reticular formation from the deep layers of SC but not
from the dlPAG (42, 128). Furthermore, cardiovascular and
respiratory responses evoked from the dlPAG, but not those
evoked from the SC, are dependent on the activation of the
DMH (48, 77, 114). Thus, although the dlPAG and deep layers
of the SC have some features in common, they appear to be
essentially distinct defense systems.
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The projection targets of the putative collicular command
neurons are unknown. It is proposed, as depicted in Fig. 6D,
that such neurons provide collateral inputs to premotor sympathetic, respiratory, and somatomotor neurons in the brain
stem. Alternatively, with regard to the synchronized sympathetic and respiratory responses, it could be argued that such
neurons project to respiratory neurons in the brain stem that in
turn provide an input to sympathetic premotor neurons. As
mentioned above, central respiratory activity can modulate
sympathetic activity via connections from respiratory neurons
in the lower brain stem to sympathetic premotor neurons (57).
Such coupling occurs under resting conditions and is exaggerated during hypoxia when both respiratory activity and sympathetic activity is increased (49). The pattern of such modulation, however, is distinctly different from that observed
following activation of collicular neurons that drive synchronized increases in sympathetic and respiratory activity. In
particular, under both resting conditions and hypoxia, splanchnic sympathetic activity (spSNA) is increased during the expiratory phase (49). In contrast, as illustrated in Fig. 6C, in
response to auditory, visual, or somatosensory stimulation
following disinhibition of certain sites in the colliculi, the
increase in spSNA occurs primarily during the inspiratory
phase of respiration (i.e., when phrenic nerve activity is in-
Review
BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
Perspectives and Significance
Psychological stressor
(e.g. sight/sound/odor of
predator, or perceived threat)
Alerting stimulus
(sight, sound, touch)
DMH
via cortex and
hypothalamus
Basal ganglia/
colliculi system
dIPAG
IPAG
component of a system that includes the cortex, amygdala, and
midbrain PAG. Threatening stimuli (i.e., the sight, sound, or
odor of a predator) activate neurons in the DMH/PeF via inputs
from the cortex, amygdala and/or PAG, whereas output neurons in the DMH/PeF convey descending signals to premotor
nuclei in the pons and medulla that generate appropriate
cardiovascular and respiratory responses. These premotor nuclei have not been definitively identified, except for the midline
medullary raphe nuclei that mediates the stress-evoked increased activity of the sympathetic outflow to the heart, cutaneous blood vessels, and BAT. With regard to stress-evoked
sympathetically mediated visceral vasoconstriction, it is proposed that sympathetic premotor neurons in the RVMM are
one of the main drivers of this activity (Fig. 4), whereas the
sympathetic premotor neurons in the RVLM play a critical role
in subserving the baroreflex control of sympathetic vasomotor
activity, which is reset to a higher operating range via descending inputs to the NTS (Fig. 4). The output neurons in the
DMH/PeF include orexin neurons, whose principal role may be
to amplify increases in sympathetic and respiratory activity via
their projections to sympathetic and respiratory premotor nuclei in the pons and medulla (96).
The general scheme shown in Fig. 8 is highly simplified and
incomplete and is very likely to be greatly modified and added
to as new knowledge is gained from future studies. Many
important questions remain unanswered. For example, locomotion is associated with coordinated cardiovascular and respiratory changes, but the extent to which brain pathways
regulating exercise-induced cardiorespiratory responses overlap with those regulating stress-evoked cardiorespiratory responses is not known. Another major general issue concerns
the role of noradrenergic neurons in the locus coeruleus and
serotonergic neurons in the dorsal raphe, both of which are
activated during stress and arousal and have widespread projections to many parts of the brain, including key nuclei
involved in cardiovascular and respiratory regulation (7, 98,
124). Furthermore, the nucleus incertus in the pons and lateral
habenula in the midbrain have recently been shown to contain
neurons that are strongly activated by stress and which also
project very widely throughout the brain (73, 130). There is a
large body of evidence indicating that all of these neuronal
systems can modify stress-evoked responses (98, 124, 130) but
their precise role in stress-evoked cardiorespiratory responses
remain unclear and will need to be defined in future studies.
ACKNOWLEDGEMENTS
via spinal cord
and brainstem
Somatosensory stressor
(e.g. painful stimulus)
Pons/medulla
Cardiovascular
response
Behavioral
response
Respiratory
response
Fig. 8. Schematic diagram showing a general hypothesis of the systems
subserving cardiovascular, respiratory, and behavioral responses to psychological stressors or alerting stimuli. It is proposed that the pathways subserving the
DMH/cortical system are essentially separate to those of the basal gangliacolliculi system, although it is possible that both activate the same premotor
nuclei in the pons and medulla. Also shown in the diagram are inputs to the
lPAG arising from somatosensory inputs. For further details of the connections
of the DMH, the dlPAG, and the basal ganglia/colliculi see Figs. 4, 5, and 7,
respectively.
I am very grateful to the following colleagues (in alphabetical order) who
worked with me at the University of Sydney and at Macquarie University on
our studies that are discussed in this review: Marco Fontes, Teri Furlong, Ann
Goodchild, Jouji Horiuchi, Kamon Iigaya, Suzanne Killinger, Lachlan McDowall, Simon McMullan, Flavia Müller-Ribeiro, and Jaimie Polson. I also
have benefitted from many discussions with other colleagues, particularly
Robin McAllen, Pascal Carrive, and Bill Blessing. I thank Howard Schultz and
the Neural Control and Regulation Section of the American Physiological
Society for giving me the privilege of presenting the Carl Ludwig Lecture.
GRANTS
Studies described in this review that were performed in my laboratory were
supported by the National Health and Medical Research Council of Australia,
the Australian Research Council, and the National Heart Foundation of
Australia.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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It is clear that several different brain regions and pathways
play major roles in subserving the cardiovascular and respiratory responses to threatening stimuli. As discussed earlier,
these stimuli may vary from relatively mild acute alerting
stimuli to more prolonged life-threatening stimuli. It is likely
that in the course of vertebrate evolution different defense
systems have developed that subserve different functions.
The basal ganglia and colliculi are phylogenetically ancient
and highly conserved (140, 141), whereas the defense system
that includes the DMH and cortex evolved at a later time. The
basal ganglia-colliculi system is well adapted to responding to
threats that require an immediate but highly stereotyped action
that does not require cognitive appraisal of the stimulus. In
particular, it is able to elicit different types of coordinated
behaviors (e.g., orienting, pursuit, escape) depending on the
pattern of inputs (visual, auditory, and/or somatosensory) that
trigger the behavior (47, 105). These behaviors are accompanied by appropriate autonomic and respiratory responses (47).
In contrast to the basal ganglia-colliculi defense system, the
hypothalamic defense system appears to be better adapted to
generating appropriate responses to more sustained threatening
stimuli, that presumably involve cognitive appraisal and/or
recollection of memories, via inputs arising from the cortex
and/or amgydaloid complex.
A common feature of these different defense systems is that
they all produce highly coordinated behavioral, cardiovascular,
and respiratory responses. Even though much is still unknown
about the precise brain circuits that subserve these coordinated
responses, it is possible to put forward a working hypothesis of
these circuits, as shown in Fig. 8. It is proposed that the basal
ganglia-colliculi subcortical system evokes immediate defensive responses to alerting stimuli, while the DMH is a critical
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BRAIN DEFENSE SYSTEMS INTEGRATING AUTONOMIC RESPONSES
AUTHOR CONTRIBUTIONS
Author contributions: R.A.D. drafted manuscript; R.A.D. edited and revised
manuscript; R.A.D. approved final version of manuscript.
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