Adv Physiol Educ 40: 283–296, 2016;
doi:10.1152/advan.00027.2016.
Central neural control of the cardiovascular system: current perspectives
Roger A. L. Dampney
School of Medical Sciences (Physiology) and Bosch Institute, The University of Sydney, Sydney, New South Wales, Australia
Submitted 3 February 2016; accepted in final form 23 May 2016
Dampney RA. Central neural control of the cardiovascular system:
current perspectives. Adv Physiol Educ 40: 283–296, 2016;
doi:10.1152/advan.00027.2016.—This brief review, which is based
on a lecture presented at the American Physiological Society Teach-
ing Refresher Course on the Brain and Systems Control as part of the
Experimental Biology meeting in 2015, aims to summarize current
concepts of the principal mechanisms in the brain that regulate the
autonomic outflow to the cardiovascular system. Such cardiovascular
regulatory mechanisms do not operate in isolation but are closely
coordinated with respiratory and other regulatory mechanisms to
maintain homeostasis. The brain regulates the cardiovascular system
by two general means: 1) feedforward regulation, often referred to as
“central command,” and 2) feedback or reflex regulation. In most
situations (e.g., during exercise, defensive behavior, sleep, etc.), both
of these general mechanisms contribute to overall cardiovascular
homeostasis. The review first describes the mechanisms and central
circuitry subserving the baroreceptor, chemoreceptor, and other re-
flexes that work together to regulate an appropriate level of blood
pressure and blood oxygenation and then considers the brain mecha-
nisms that defend the body against more complex environmental
challenges, using dehydration and cold and heat stress as examples.
The last section of the review considers the central mechanisms
regulating cardiovascular function associated with different behaviors,
with a specific focus on defensive behavior and exercise.
cardiovascular reflexes; central command; autonomic nervous system;
hypothalamus; brain stem
HOMEOSTASIS can be defined as the maintenance of the physical
and chemical properties of the extracellular fluid in all body
tissues. It is dependent, among other things, on effective
cardiovascular and respiratory regulatory mechanisms that en-
sure that the delivery of O2 to all regions of the body is
sufficient to match the metabolic demands of each region. This
is particularly critical in the case of the heart and skeletal
muscles, whose metabolic activity can vary greatly in different
circumstances. For example, during maximal exercise in hu-
mans, O2 demand can increase to a level up to 50-fold greater
than resting levels (49). This is achieved by an enormous
increase in blood flow (up to 20-fold) together with a 2- to
3-fold increase in O2 extraction from the blood (49). These
effects are produced by a combination of local and neural
mechanisms, as shown in Fig. 1. Local mechanisms, which
include metabolic, endothelial, and myogenic components
(49), result in vasodilation in metabolically active skeletal
muscle vascular beds, leading to large increases in local blood
flow provided the perfusion pressure (arterial pressure) is
maintained or increased. Similarly, the increase in O2 extrac-
tion from the blood also depends on both local factors (e.g.,
local acidosis, which shifts the hemoglobin-oxygen saturation
Address for reprint requests and other correspondence: R. A. L. Damp-
ney, School of Medical Sciences (Physiology) and Bosch Institute, The
Univ. of Sydney, Sydney, NSW 2006, Australia (e-mail: roger.dampney
@sydney.edu.au).
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Refresher Course
curve to the right) (49) as well as central regulatory mecha-
nisms that maintain the arterial blood PO2 (PaO2) despite large
changes in metabolic activity (1).
Apart from physical exercise, coordinated cardiovascular
and respiratory mechanisms regulate the O2 supply to all tissue
during other behaviors, such as defensive behavior or sleep. In
addition, such regulatory mechanisms are also required to
maintain homeostasis in the face of challenges such as hyp-
oxia, dehydration, or changes in ambient temperature. In this
review, I shall focus primarily on the central neural mecha-
nisms that regulate cardiovascular function, although I shall
also discuss, where relevant, how these mechanisms are coor-
dinated with respiratory regulatory mechanisms.
As shown in Fig. 1, arterial blood pressure is regulated by
autonomic nerves, consisting of sympathetic nerves that inner-
vate the heart and blood vessels, and vagal parasympathetic
nerves, which innervate the heart. Sympathetic outflow, in turn,
is regulated by sympathetic premotor neurons located in the
lower brain stem and hypothalamus, whereas vagal cardiac
outflow originates primarily from the nucleus ambiguus in the
medulla oblongata. The activity of the sympathetic premotor
neurons and cardiac vagal neurons is controlled by two general
mechanisms: 1) reflex effects arising from stimulation of a
wide variety of peripheral receptors and 2) feedforward con-
trol, or “central command,” from descending inputs arising
from higher centers in the brain (Fig. 1).
One of the most important cardiovascular reflexes is the
baroreceptor reflex, and an example of its operation is shown in
Fig. 2A. In this example, recordings were made of mean
arterial pressure, heart rate, and renal sympathetic nerve activ-
ity in a conscious rat during treadmill exercise (35). Changes in
arterial pressure were induced by systemic injection of a
vasoconstrictor (phenylephrine) and a vasodilator (sodium ni-
troprusside), resulting in reflex changes in heart rate and renal
sympathetic nerve activity.
In contrast to reflex or feedback control, feedforward control
(central command) does not require inputs from peripheral
receptors. A classic example of such control is shown in Fig.
2B. Recordings of arterial pressure and heart rate were made in
a paralyzed, mechanically ventilated, but conscious, human
subject, who was asked to attempt to contract leg muscles (18).
The numbers indicate the effort as a percentage of the maxi-
mum. Note that there were graded increases in arterial pressure
and heart rate according to the degree of effort, despite the lack
of any afferent feedback from the paralyzed muscles.
These two general mechanisms of feedback and feedforward
control are not, however, entirely independent. In particular, as
shall be described in more detail below, cardiovascular reflexes
such as the baroreceptor reflex can be powerfully modulated by
central command signals arising from the forebrain or mid-
brain.
283
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284 THE BRAIN AND THE CARDIOVASCULAR SYSTEM

Extrinsic inputs (e.g. Forebrain & midbrain and reflex changes in the output (e.g., renal sympathetic
sight, sound, odor) Other intrinsic inputs activity or heart rate) are then measured. The sigmoidal
Central command (from chemoreceptors, curve that best fits the relationship between the input and
skeletal muscle
Motor outflow to receptors etc.) output is then determined (e.g., Fig. 4B).
Lower brainstem
respiratory muscles The precise characteristics of the sigmoidal baroreflex func-
tion curve are defined by 1) the maximum and minimum values
Symp outflow to Symp outflow to Vagal outflow of the reflexly controlled output; 2) the maximum gain or
Respiratory skeletal muscle other vascular to the heart sensitivity of the reflex, i.e., where the slope of the curve is
activity vascular bed beds & heart
maximal; and 3) the operating range of the reflex, which is
Baroreceptor
inputs defined as the range of mean arterial pressure over which
Metabolic,
myogenic &
Skeletal muscle changes in pressure can produce significant reflex changes in
vascular Arterial pressure
endothelial
resistance the output (Fig. 4A) (30).
factors
The baroreceptor reflex is operational at all times, although
the functional properties of the reflex can vary under different
Blood flow to
skeletal muscle
behavioral conditions. For example, the maximum gain of the
Arterial blood PO2 baroreceptor-sympathetic reflex is increased both during exer-
O2 supply

Fig. 1. Flow diagram illustrating how feedforward (central command) and A 180
feedback (reflex) mechanisms operate together to regulate the O2 supply to
MAP
particular regions (skeletal muscle in this example) to match the metabolic
(mmHg) 140
demands of that region and thus maintain homeostasis.

Central Mechanisms Subserving Homeostatic Reflexes 100

HR 700
To maintain cardiovascular homeostasis, several key phys-
iological variables must be regulated: arterial blood pressure, (bpm) 550
the O2 content of the blood, blood volume, and body temper- 400
ature. The following sections will briefly describe the reflex
250
mechanisms that regulate these variables. RSNA
Blood pressure. The baroreceptor reflex is the principal ( V) 0
mechanism regulating arterial pressure, at least in the short -250
term. For example, a decrease in arterial pressure is sensed by
2 min
baroreceptors located in the walls of the carotid sinus and PE SNP
aortic arch (Fig. 3A). The baroreceptors are stretch receptors
located on the terminal arborizations of afferent fibers, so a B
decrease in arterial pressure results in a decreased firing rate of 150

baroreceptor afferent fibers. Inputs from baroreceptor afferent HR 130

fibers reflexly inhibit the sympathetic outflow to the heart and (bpm)
blood vessels and reflexly excite the cardiac vagal outflow via 110
central pathways in the brain stem and spinal cord (described 200
in more detail below). Therefore, a decrease in baroreceptor
firing rate results in a reflex increase in sympathetic vasomotor
150
activity, which increases total vascular resistance, and an Arterial
increase in sympathetic cardiac activity together with a reflex pressure 100
decrease in cardiac vagal activity, which together results in an (mmHg)
increase in heart rate and cardiac contractility, and thus cardiac
output (Fig. 3A). The reflex increases in total peripheral 50 100% 50% 25% 0%
resistance and cardiac output together help to restore arterial (Numbers indicate %maximum effort)
pressure (Fig. 3A). The most important component of the 0
0 100 200 300 400 500
reflex response is the reflex change in total peripheral
resistance, which accounts for ⬃80% of the reflex change in Time (s)
arterial pressure at rest and virtually 100% during exercise Fig. 2. A: example of baroreflex control of the cardiovascular system. Changes
(Fig. 3B) (44). in mean arterial pressure (MAP) were induced in a conscious exercising rat by
The functional properties of the baroreceptor reflex in any systemic injection of the vasoconstrictor phenylephrine (PE) or the vasodilator
sodium nitroprusside (SNP), resulting in reflex changes in heart rate (HR) and
particular situation can be represented by a sigmoidal curve renal sympathetic nerve activity (RSNA). [Modified from Miki et al. (35) with
that shows the input-output relationship for the reflex, where permission.] B: example of central command. Recordings of arterial pressure
the input is the mean arterial pressure and the output is the and HR [in beats/min (bpm)] were made in a paralyzed, mechanically venti-
reflexly controlled variable, e.g., renal sympathetic activity lated, but conscious human subject, who was asked to attempt to contract leg
muscles. The numbers indicate the effort as a percentage of the maximum.
or heart rate (Fig. 4). To determine this curve, changes in Note that there were graded increases in arterial pressure and HR according to
mean arterial pressure are induced (e.g., by infusing a the degree of effort, despite the lack of any afferent feedback from the
vasodilator or vasoconstrictor drug, as shown in Fig. 2A), paralyzed muscle. [Modified from Gandevia et al. (18) with permission.]

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THE BRAIN AND THE CARDIOVASCULAR SYSTEM 285

A Arterial pressure
B Contribution (% total) of
cardiac output (CO) and total
peripheral resistance (TPR)
to reflex changes in
Baroreceptor firing rate arterial pressure

TPR
Fig. 3. A: flow diagram showing the sequence of
Brainstem centers CO events after a decrease in arterial pressure, leading
to a reflex compensatory restoration of arterial pres-
100
Sympathetic Sympathetic sure. B: histogram showing that the reflex increase
Vagal cardiac
vasomotor cardiac in total peripheral resistance (TPR) is the major
activity
activity activity factor contributing to the reflex response both at rest
and during exercise. CO, cardiac output. [Modified
50
from Raven et al. (44) with permission.]
Vascular Cardiac Heart rate
resistance contractility

0
Cardiac At During
Arterial pressure output rest exercise

cise (Fig. 5A) and psychological stress (Fig. 5B). Furthermore,
the reflex is reset so that it operates over a higher range of mean
arterial pressure and sympathetic activity during exercise and
stress (Fig. 5, A and B) (25, 35). Similarly, the baroreceptor-
heart rate reflex is reset to a higher operating range of both
mean arterial pressure and heart rate during exercise (Fig. 5C),
with little change in gain (41). The effect of such baroreflex
resetting is that during behaviors where an increase in arterial
pressure is physiologically advantageous (e.g., exercise or
defensive behavior), the baroreflex continues to be highly
effective in regulating arterial pressure at this increased level.
It is well known that mean arterial pressure and heart rate
show parallel diurnal variations, such that, in humans, both of
these variables tend to be minimal during the early hours of the
morning (i.e., during the sleep phase) and maximal after
waking during the morning period (54). These variations in
arterial pressure and heart rate can be explained as a continuous
modulation or resetting of the baroreflex, which thus serves to
regulate arterial pressure at a level that is optimal for each
phase of the sleep-wake or activity cycle.
Studies over the last 35 yr have identified the essential
central pathways that mediate the baroreceptor reflex (13, 19),
and these are shown in Fig. 6. Primary afferent fibers from
arterial baroreceptors located in the carotid sinus and aortic
arch, which run in the glossopharyngeal nerve (cranial nerve
IX) and vagus nerve (cranial nerve X), respectively, terminate
in the nucleus tractus solitarius (NTS) in the dorsomedial
medulla. From the NTS, second-order neurons project directly
to cardiac vagal motoneurons in the nucleus ambiguus or to
interneurons in the caudal ventrolateral medulla (CVLM). The

A Operating range
B
150
RSNA (% baseline)

100
Y value

Point of 50
maximum
gain

0
X value 60 80 100 120 140 160
Thr Sat
MAP (mmHg)
Fig. 4. A: the standard sigmoidal curve that is used to represent the input-output relationship for the baroreceptor reflex. The curve represents the following
function: Y ⫽ A1/{1 ⫹ exp[A2(X ⫺ A3)]} ⫹ A4, where X is the input (typically MAP) and Y is the output (e.g., sympathetic activity or HR) and A1, A2, A3, and
A4 are the parameters that define the specific curve in any particular situation. The gain or sensitivity of the reflex at any value of X is represented by the slope
of the curve and is maximal at the midpoint of the Y range (i.e., between the maximum and minimum values of Y). The threshold (Thr) value of X is the point
at which the value of Y is 5% of the Y range below the maximum value of Y, and the saturation (Sat) value of X is the point at which the value of Y is 5% of
the Y range above the minimum value of Y. The operating range of X lies between the Thr and Sat values and is thus the range of X over which changes in X
evoke significant reflex changes in Y. [Modified from McDowall et al. (30).] B: example of a baroreflex sigmoidal function curve that best fits the reflex
relationship between MAP and RSNA. In this experiment, changes in MAP were induced by injections of vasoconstrictor and vasodilator drugs, and the
corresponding reflex changes in RSNA were measured (solid circles). [Modified from McDowall et al. (31).]

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286 THE BRAIN AND THE CARDIOVASCULAR SYSTEM

sympathetic premotor neurons under resting conditions also

A 500
permits both reflex decreases and increases in sympathetic
activity in response to altered input from the arterial barore-
400
ceptors.
Some of the neurons within the baroreflex circuitry shown in
(% baseline)

300 Fig. 6 receive inputs from nuclei at higher levels of the brain,
RSNA

including the midbrain periaqueductal gray (PAG), dorsome-

exercise
dial and paraventricular nuclei in the hypothalamus, central
200
nucleus of the amygdala, medial prefrontal cortex, and insular
cortex (13, 53). Although the precise functions of these inputs
100 rest has not been determined, it is likely that they include inputs
that reset the baroreceptor reflex during different behaviors.
Blood O2 level. Nearly all O2 in the blood is attached to
0
60 80 100 120 140 160 180
hemoglobin. In arterial blood, ⬎95% of hemoglobin molecules
are bound to O2, forming oxyhemoglobin, provided the PaO2 is
MAP (mmHg)
B 500 ⬎90 mmHg. The principal mechanism that helps to maintain
PaO2 under hypoxic conditions (e.g., when atmospheric PO2 is
400 reduced at high altitudes or when normal breathing is pre-
(% baseline)

vented, such as during submersion in diving animals) is the

arterial chemoreceptor reflex. Chemoreceptors located in the
RSNA

300 carotid and aortic bodies are activated primarily by a decrease

stress in PaO2 (Fig. 7A) (4). The main reflex effects of chemoreceptor
200 activation are 1) an increase in respiratory rate and depth that
rest increases alveolar ventilation and 2) cardiovascular effects that
reduce blood flow to peripheral tissues and that also decrease
100
heart rate and thus cardiac work, thus conserving the available
O2 (Fig. 7B).
0 Under resting conditions, carotid body chemoreceptor activ-
60 80 100 120 140 160 180 ity and the reflex ventilatory response do not start to increase
MAP (mmHg) markedly until PaO2 decreases to ⬃60 mmHg (Fig. 7, A and C).
90 This corresponds to the point at which the percentage of
C hemoglobin binding O2 also starts to decrease rapidly (23), so
80
the result is that the chemoreflex ventilatory response reflects
exercise
HR (bpm)

70

60
rest
carotid sinus
50
60 80 100 120 140 160 180
MAP (mmHg)
IX
Fig. 5. A: baroreflex function curves showing the relationship between MAP
and RSNA in conscious rats at rest and during exercise. Note that the
maximum gain is increased and the operating range is shifted to higher values NTS
of MAP during exercise. [Modified from Miki et al. (35) with permission.] B:
baroreflex function curves showing the relationship between MAP and RSNA IML
in conscious rats at rest and during psychological stress (air jet stress). Note
that the maximum gain is increased and the operating range is shifted to higher
values of MAP during psychological stress, similar to the changes observed in
exercise. [Modified from Kanbar et al. (25).] C: baroreflex function curves X
showing the relationship between MAP and HR in human subjects at rest and NA
during exercise. Note that the operating range of the reflex is shifted to higher CVLM
values of MAP during exercise but with little change in the maximum gain of RVLM
the reflex. [Modified from Ogoh et al. (41) with permission.]
heart and heart excitatory synapse
blood vessels inhibitory (GABAergic) synapse
latter group are GABAergic neurons, which project to and
inhibit sympathetic premotor neurons in the rostral ventrolat- Fig. 6. Schematic diagram showing the essential pathways within the lower
eral medulla (RVLM). RVLM sympathetic premotor neurons brain stem that subserve the baroreflex control of the sympathetic outflow to
the heart and blood vessels and of the vagal parasympathetic outflow to the
are tonically active, and their tonic activity is critical in heart. CVLM, caudal ventrolateral medulla; IML, imtermediolateral cell col-
maintaining sympathetic vasomotor tone and resting arterial umn; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; RVLM, rostral
pressure (13, 19). Furthermore, the tonic activity of RVLM ventrolateral medulla; X, vagus nerve. [Modified from Dampney et al. (11).]

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THE BRAIN AND THE CARDIOVASCULAR SYSTEM 287

100
A B
Hypoxia
75
Chemoreceptor
Activity (units)

50 Chemoreceptor
afferent activity Fig. 7. A: curve showing the relationship be-
tween the arterial blood PO2 (PaO2) and the
25 activity of a single carotid body chemorecep-
tor afferent fiber. [Modified from Biscoe et al.
(4) with permission.] B: flow diagram show-
0 Respiratory Sympathetic Cardiac ing the reflex effects of chemoreceptor stim-
0 40 80 120 activity vasomotor vagal activity ulation by arterial hypoxia, leading to an in-
PaO2 (mmHg) activity crease in ventilation (provided that respiratory
C 40 activity can increase, as during exposure to
high altitude) as well as cardiovascular reflex
Vaso- Heart rate & changes that tend to conserve the available
30 Ventilation constriction O2. C: curve showing the chemoreflex rela-
cardiac work
(liters/min)
Ventilation

tionship between PaO2 and alveolar ventila-

tion at rest and exercise in human subjects.
20 Note that the reflex effects on ventilation are
Moderate exercise
enhanced during exercise. [Modified from
Weil et al. (56).]
10 Rest Oxygen uptake Oxygen conservation

0
40 80 120
PaO2 (mmHg)

the degree of hypoxia of arterial blood. The reflex ventilatory fibers arising from the carotid and aortic bodies, which run in
response to chemoreceptor stimulation is not constant but is cranial nerves IX and X, respectively, terminate on secondary
enhanced during exercise (Fig. 7C), as a consequence of interneurons in the NTS (13, 19, 20). The secondary interneu-
increased peripheral chemosensitivity (56). This is a further rons, in turn, project to a number of targets, including respira-
example of reflex operating properties being altered according tory neurons that drive the ventilatory response as well as
to the behavioral state. sympathetic premotor neurons in the RVLM that drive the
The essential central pathways mediating the chemoreceptor sympathetic component of the reflex (13, 19, 20). In regard to
reflex are shown in Fig. 8. Chemoreceptor primary afferent the latter, there is now strong evidence that chemoreflex
sympathoexcitation is mediated by both a direct input from the
NTS to sympathetic premotor neurons in the RVLM as well as
by indirect inputs via neurons within the central respiratory
network, including respiratory neurons in the preBötzinger
complex and dorsolateral pons (Fig. 8) [for a detailed review,
carotid body see Guyenet (20)].
Apart from the chemoreceptor reflex, all air-breathing ver-
tebrates have a diving reflex (also called nasopharyngeal re-
flex), which is another reflex that acts to conserve the available
O2 (42). This reflex is particularly powerful in diving animals
NTS (Fig. 9A). The reflex is triggered by activation of nasopharyn-
IML geal receptors, which leads to a reflex apnea, intense wide-
Dorsolateral spread peripheral vasoconstriction (except in the brain and
pons heart), and a profound bradycardia (Fig. 9B). The cardiovas-
cular reflex effects conserve the available O2, which is thus
preferentially provided to the brain and heart, two critical
regions that cannot sustain an O2 debt. The same pattern of
PreB reflex respiratory and cardiovascular effects is also evoked in
A5 cell group
RVLM nondiving animals, in response to stimulation of nasopharyn-
heart and
blood vessels geal receptors by a noxious substance, such as smoke (57).
excitatory synapse Under those circumstances, cessation of ventilation combined
inhibitory synapse with O2 conservation will also increase the probability of
Fig. 8. Schematic diagram showing the essential pathways within the lower survival.
brain stem that subserve the chemoreflex control of the sympathetic outflow to Interactions between reflexes. In most situations, more than
the heart and blood vessels. The solid lines indicate direct connections that
have been clearly identified, whereas the dashed lines may be direct or indirect.
one reflex is activated in response to a particular challenge, and
PreB, pre-Bötzinger cell group. For other abbreviations, see Fig. 6. [Modified hypoxia is a good example of this. For example, in diving
from Dampney et al. (11).] animals, the first effect of submersion is the activation of

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288 THE BRAIN AND THE CARDIOVASCULAR SYSTEM

reflex cardiovascular and respiratory responses is optimal for

A the particular environmental challenge faced by the animal.
160
As shown in Fig. 11, the NTS and RVLM are key compo-
Arterial pressure

nents of the central pathways mediating the nasopharyngeal

reflex as well as baroreceptor and chemoreceptor reflexes (see
(mmHg)

120 above) (42). Furthermore, inputs from a wide range of recep-

tors that reflexly affect cardiovascular function also project to
the NTS, either directly or indirectly via other relay nuclei (Fig.
11). These receptors include cardiopulmonary receptors (that
80 5s respond primarily to changes in blood volume), vestibular
Diving period receptors that are critical for othostatic reflexes, receptors in
skeletal muscle that are activated during exercise (sometimes
called “ergoreceptors”), and skin nociceptors (11, 13). In
addition, inputs from some of these receptors also project to the
B RVLM via other pathways that bypass the RVLM (Fig. 11)
Submersion (38, 42, 59). Ultimately, however, all of the inputs from the
receptors shown in Fig. 11 converge on sympathetic premotor
neurons in the RVLM. Thus, the RVLM is a major site at
Nasopharyngeal which interactions between different inputs regulating sympa-
receptor activity thetic activity occurs. In addition, it is a likely site, together
with the NTS, at which inputs from higher centers modulate
baroreceptor, chemoreceptor, and other cardiovascular reflexes
(Fig. 11) (13, 19).
Apnea Sympathetic Cardiac The reflex effects of activation of these various inputs on the
vasomotor vagal activity sympathetic outflow are not uniform (Fig. 12). For example,
activity baroreceptor stimulation results in reflex vasodilation in skel-
etal muscle vascular beds and a modest vasodilator effect on
the skin blood vessels, whereas chemoreceptor stimulation has
Intense peripheral Heart rate & a similar effect on skin blood vessels, but evokes a powerful
vasoconstriction (except cardiac work vasoconstrictor effect on skeletal muscle vascular beds (24).
in brain & heart)

Oxygen conservation

Fig. 9. A: example of the extreme bradycardia evoked during voluntary diving

in a rat. Note that despite the extreme bradycardia (decrease in HR of ⬃80%),
the arterial pressure is maintained, due to intense vasoconstriction. [Modified
from Panneton et al. (42).] B: flow diagram showing the reflex effects of
nasopharyngeal stimulation submersion, leading to cardiovascular reflex
changes that conserve the available O2.

nasopharyngeal receptors that then trigger the diving reflex,

including apnea as well as the cardiovascular effects described
above. The resultant hypoxia, in turn, triggers the chemorecep-
tor reflex (Fig. 10). The interaction between the two reflexes
reinforces the vasoconstriction and bradycardia, but the normal
ventilatory response to chemoreceptor stimulation is sup-
pressed by inputs from nasopharyngeal receptors (Fig. 10).
In contrast, under conditions where hypoxia occurs without
activation of nasopharyngeal receptors, (e.g., high altitude),
chemoreceptor activation does reflexly increase ventilation,
which then activates another reflex arising from pulmonary
stretch receptors, innervated by afferent vagal fibers. The
pulmonary stretch receptor reflex tends to increase heart rate
and decrease vascular resistance, opposing the primary effects
of chemoreceptor stimulation (Fig. 10). Thus, the net effect on
cardiovascular and respiratory function depends on interactions
between a number of reflexes, which ensures that the pattern of
Fig. 10. Flow diagram illustrating the interaction between reflexes arising
from inputs from arterial chemoreceptors, pulmonary stretch receptors, and
nasopharyngeal receptors. When hypoxia occurs under conditions where re-
spiratory activity can increase (e.g., exposure to a high altitude), the reflex
decrease in HR and the reflex increase in vascular resistance (in skeletal
muscle and visceral beds) is opposed by the secondary reflex effects arising
from the activation of pulmonary stretch receptors, which tends to increase O2
uptake. In contrast, when hypoxia occurs under conditions when respiratory
activity cannot increase (e.g., during submersion), the primary reflex response
to chemoreceptor stimulation is not opposed by these secondary effects.
Furthermore, under such conditions, nasopharyngeal receptors may be
stimulated, triggering reflex effects that reinforce the primary effects of
chemoreceptor stimulation, leading to greater reflex bradycardia and pe-
ripheral vasoconstriction and thus a greater degree of O2 conservation.
[From Dampney (11).]

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THE BRAIN AND THE CARDIOVASCULAR SYSTEM
Direct projections
Direct and indirect Higher brain
projections regions
Arterial
baroreceptors
Arterial Nucleus of solitary
chemoreceptors tract (NTS)
Cardiopulmonary
receptors Rostral
ventrolateral
Medullary medulla (RVLM)
Nasopharyngeal
receptors trigeminal (V)
Sympathetic outflow
nucleus
Vestibular Medullary Heart
receptors vestibular (VIII)
nucleus Skin blood
vessels
Skeletal muscle
Renal blood
receptors Dorsal horn of vessels
spinal cord
Skin nociceptors Skeletal muscle
blood vessels
Fig. 11. Schematic diagram summarizing the essential central connections
within the brain stem of different reflexes regulating the sympathetic vasomo-
tor outflow. Note that there are direct inputs from all receptors to the NTS and
that the RVLM is also a site of convergence of signals from all receptors,
which are conveyed by direct inputs or indirect inputs via the NTS. There are
also inputs to the NTS and RVLM from higher brain regions, which can
modify the reflex responses arising from the various peripheral receptors.
Finally, note that there are separate descending outputs from the RVLM, each
of which exclusively or preferentially regulates the sympathetic outflow to
blood vessels in different regions. This allows for a differentiated control of the
sympathetic outflow according to the pattern of inputs from peripheral recep-
tors and higher brain regions.
Such differentiated effects on the sympathetic outflows to
different vascular beds reflect the fact that there are subgroups
of sympathetic premotor neurons in the RVLM that preferen-
tially or exclusively control different sympathetic outflows
(Fig. 11) (13, 29).
Blood volume. The essential central pathways subserving the
reflexes described above are contained within the lower brain
stem, although they can be powerfully modulated by descend-
ing inputs from higher brain regions. In contrast, the central
regulatory mechanisms defending the body against a decrease
in blood volume (e.g., as a result of hemorrhage or dehydra-
tion) are located in the forebrain as well as the lower brain stem
and include neural, hormonal, and behavioral components. The
signals that activate compensatory responses to a decrease in
blood volume are also complex, including those that are an
immediate consequence of the hypovolemia as well as second-
ary effects that result from the hypovolemia (15).
For example, hypovolemia caused by dehydration results in
increased blood osmolarity as well as reduced atrial and arterial
pressures (as a consequence of the reduced blood volume and
venous return) (Fig. 13). Apart from the reflex changes in
sympathetic activity resulting from unloading of cardiopulmo-
nary and arterial baroreceptors (11, 13), the reduced arterial
pressure also activates the renin-angiotensin system (Fig. 13).
The increased levels of osmolarity and ANG II in the blood act
on receptors on neurons in the circumventricular organs in the
anterior wall of the third ventricle [especially the organum
vasculosum lamina terminalis (OVLT) and subfornical organ
(SFO)] (21, 32, 33, 50, 52). These neurons in the OVLT and
SFO have direct and indirect (via the median preoptic nucleus)
connections to the hypothalamic supraoptic nucleus (SON) and
paraventricular nucleus (PVN), and thus activation of these
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Refresher Course
289
neurons leads to increased sympathetic activity and vasopres-
sin release from the pituitary (Fig. 13) (10, 15, 32, 33, 50, 52).
In addition, these signals also trigger an increase in drinking
(32, 33) (Fig. 13). The combined effect of all these compen-
satory responses is to minimize fluid loss and increase fluid
intake, thus restoring fluid homeostasis.
Apart from ANG II and Na⫹, other circulating substances
(e.g., relaxin, leptin, and cytokines) can also activate OVLT
and/or SFO neurons, and there is now strong evidence that both
these circumventricular organs, together with the median pre-
optic nucleus, are critical sites at which these circulating
substances can affect cardiovascular function. For example,
circulating relaxin acts on receptors in the OVLT and SFO to
stimulate vasopressin release (32). Second, infusion of leptin, a
hormone derived from adipose tissue, induces an increase in
renal sympathetic nerve activity, whereas blockade of leptin
receptors in the SFO prevents this effect (60). Third, circulat-
ing proinflammatory cytokines act on the brain to increase
blood pressure, heart rate, and sympathetic activity, and these
effects are blocked by lesions of the SFO (55). It should be
noted, however, that these results do not necessarily imply that
circulating leptin or cytokines exert their effects exclusively
via the SFO. For example, blockade of leptin receptors in the
hypothalamic arcuate nucleus also prevents the increase in
renal sympathetic nerve activity evoked by circulating leptin
(22), whereas Yu et al. (61) found that circulating proinflam-
matory cytokines can also increase sympathetic activity via
increases in prostaglandin production in perivascular macro-
phages located in hypothalamic regions outside the circumven-
tricular organs.
Taken together, however, the results of many studies over
many years have led to the conclusion that the OVLT, SFO,
and median preoptic nucleus, which collectively is referred to
as the lamina terminalis, have a pivotal role in cardiovascular
regulation (for reviews, see Refs. 32, 33, and 50). This region
also plays an important role in maintaining increased sym-
pathetic activity in at least some forms of experimental
hypertension, as first shown by the pioneering work of
Buggy et al. (7).
Body temperature. Maintenance of body core temperature
within narrow limits is critical for survival in mammals (37).
Ambient temperature is sensed by receptors in the skin,
whereas body core temperature is sensed by receptors in the
hypothalamic preoptic area, spinal cord, and abdomen (33, 37,
39). The afferent signals from all these receptors contribute to
thermoregulation, although it has been proposed that signals
from body core thermoreceptors are important mainly in more
extreme situations where the responses to inputs from periph-
Receptor Muscle Skin Cardiac
activated vasoconstrictor vasoconstrictor sympathetic
Baroreceptors
Chemoreceptors
Fig. 12. Examples of the different patters of reflex activation of the sympa-
thetic outflow to different vascular beds in response to stimulation of arterial
baroreceptors and chemoreceptors.
Refresher Course
290 THE BRAIN AND THE CARDIOVASCULAR SYSTEM

A B
Cardiac Arterial
Dehydration output pressure
Fig. 13. A: flow diagram showing the se-
quence of events following dehydration,
which leads ultimately to compensatory car- SFO
MnPO
diovascular, hormonal, and behavioral re- Blood osmolarity Renin release PVN
sponses that restore fluid balance. The sub- OVLT
SON
fornical organ (SFO) and organum vasculo-
sum lamina terminalis (OVLT) are key SFO & OVLT Angiotensin II
components of these central mechanisms via level
their projections to the paraventricular nu- C
cleus (PVN), median preoptic nucleus c-Fos expression
Higher
(MnPO), and supraoptic nucleus (SON) in the SON MnPO PVN Control Hyperosmotic
integrative
hypothalamus. B: sagittal section of the rat
centers
brain indicating the locations of the nuclei SON
referred to in A. C: examples of increased Sympathetic nerve
neural activity, indicated by c-Fos expres- Vasopressin activity
sion, within the SON and PVN induced in a release Drinking
rat after dehydration compared with a control
Arterial
rat. [Modified from Ho et al. (21).] PVN
pressure
Reabsorption of Restoration of
water in kidneys fluid balance

eral thermoreceptors are not adequate to maintain body core
temperature (39).
The central mechanisms that have evolved to maintain body
core temperature are complex and include autonomic (both
cardiovascular and noncardiovascular) and somatomotor com-
ponents. For example, a decrease in ambient temperature is
detected by skin cold receptors, leading to reflex increases in
the activity of sympathetic nerves innervating skin blood ves-
sels and skin piloerector muscle, causing skin vasoconstriction
and an increase in skin insulation, both of which reduce heat
loss and thus conserve heat (Fig. 14). In addition, it is now
known that, like many other species, both newborn and adult
humans have a significant amount of brown adipose tissue
(BAT), which is innervated by sympathetic nerves (48). An
increase in BAT sympathetic activity increases BAT metabolic
activity and thus heat production (Fig. 14). The somatomotor
component of the reflex response to ambient cold temperature
is an increase in the activity of nerves supplying skeletal
muscle, resulting in increased metabolic activity, which, to-
gether with increased BAT metabolic activity, also aids heat
production (Fig. 13) (37).
An increase in ambient temperature is detected by warmth
receptors in the skin and leads to autonomic and somatomotor
effects that are opposite to those described above (i.e., cutane-
ous vasodilation due to inhibition of sympathetic vasoconstric-
tor activity and excitation of sympathetic vasodilator activity,
together with inhibition of BAT thermogenesis and shivering)
(27, 37, 39, 46). In addition, in humans and other mammals
with sweat glands, sympathetic sudomotor activity is reflexly
increased, causing increased sweat production and conse-
quently increased evaporative heat loss from the skin. In
mammals that lack sweat glands, panting is the most common
means of evaporative cooling (33, 39).

Cold ambient temperature

AUTONOMIC SOMATOMOTOR
Skin cold receptor activity

Sympathetic Sympathetic activity Sympathetic activity Skeletal muscle

activity to skin to piloerector to brown adipose motoneuron activity
Fig. 14. Flow diagram showing the auto- blood vessels muscle tissue (BAT)
nomic and somatomotor responses evoked by
cold stress, leading to an increase in heat
conservation as well as heat production.
Shivering
Vaso- Skin
constriction insulation
Metabolic
activity

Heat conservation
Heat production

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THE BRAIN AND THE CARDIOVASCULAR SYSTEM 291

Fig. 15. Diagram showing the brain path-

ways that mediate cold and warm defense
mechanisms in response to skin cooling (A)
DMH and skin warming (B). Red lines indicate
MnPO eLPB
excitatory neural pathways; blue lines indi-
PO cate inhibitory neural pathways. As dis-
RP
cussed in the text, both an inhibition of skin
vasoconstrictor activity as well as excitation
Skin sc of skin vasodilator activity contribute to the
B skin vasodilation reflexly evoked by warm-
BAT, shivering ing. The central pathways mediating excita-
thermogenesis tion of skin vasodilator nerves, however,
have not been defined. dLPB, dorsal subnu-
cold skin cleus of the lateral parabrachial nucleus;
DMH, dorsomedial hypothalamus; eLPB,
MnPO DMH dLPB external subnucleus of the lateral parabra-
warm skin
chial nucleus; PO, preoptic region; RP, raphe
PO
RP pallidus nucleus; sc, spinal cord. [Modified
from McKinley et al. (33) with permission.]
sc
Skin vasoconstriction inhibited
Skin shivering thermogenesis inhibited

Figure 15A shows the neural pathways that mediate the ward control. Such cardiovascular responses are components
physiological responses to cold stress. Afferent fibers convey- of more complex and highly coordinated responses, which
ing signals from cold receptors terminate in the dorsal column typically include appropriate respiratory and behavioral com-
of the spinal cord, from which an ascending pathway conveys ponents.
cold signals to the median preoptic nucleus (MnPO) in the Defensive behavior. The ability to respond rapidly and
hypothalamus via a relay in the external subnucleus of the appropriately to a threat in the external environment is critical
lateral parabrachial nucleus (eLPB) (33, 37). From the MnPO, for survival, and so it is not surprising that highly complex
there are direct and indirect descending projections to the raphe brain systems have evolved that subserve such defensive re-
pallidus in the midline medulla, synapsing with sympathetic sponses. Such responses may be triggered by a wide variety of
premotor neurons that produce skin vasoconstriction and BAT stimuli, which may be either unconditioned salient stimuli
thermogenesis, as well as premotor neurons that control shiv- arising from the external environment (e.g., sight, sound, or
ering thermogenesis (33, 37). The indirect descending path- odor of a predator or prey) or else conditioned stimuli (e.g.,
ways include synapses in the preoptic area and dorsomedial stimuli that are normally innocuous but which an animal has
hypothalamus (DMH), which are also thus important compo-
nents of central thermoregulatory mechanisms (33, 37). In
response to a heat stress, the signals arising from warm recep- CORTICAL cortex
tors in the skin are also conveyed to the MnPO, but via a
separate ascending pathway that includes a relay in the dorso-
Conditioned
lateral subnucleus of the lateral parabrachial nucleus (dlPB) stimulus
(Fig. 15B). The neurons in the MnPO that receive these inputs SUB-CORTICAL
project to and excite neurons in the preoptic area that inhibit amygdala
the sympathetic premotor neurons that produce skin vasocon- hippocampus
striction and BAT thermogenesis, both directly and via the thalamus
DMH (Fig. 15B) (33).
The MnPO thus plays a central role in thermoregulation as
well as in the regulation of blood volume, as discussed above. External midbrain hypothalamus
Furthermore, it has become clear that the MnPO is also a salient
stimulus
critical region for other homeostatic functions, including the Hormone
BRAINSTEM pons/
regulation of salt balance and sleep (33). medulla release

Central Mechanisms Coordinating Cardiovascular

Responses With Different Behaviors: Central Command Sympathetic Respiratory Motor activity
activity activity (e.g. freezing)
The above examples of central cardiovascular mechanisms
Fig. 16. Flow diagram showing the major central connections at cortical,
all involve reflexes with feedback from peripheral receptors. subcortical, and brain stem levels that subserve the autonomic, respiratory, and
As stated in the Introduction, the other general mechanism of somatomotor responses to both conditioned and unconditioned stimuli that
central cardiovascular control is central command, or feedfor- signal a real or potential threat in the external environment.

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Refresher Course
292 THE BRAIN AND THE CARDIOVASCULAR SYSTEM

mPFC PAG

PVN
NTS
DMH
Fig. 17. Flow diagram showing the major pathways that PeF
subserve the cardiovascular and respiratory responses to
Amy
an acute psychological stressor. Note that the DMH and
perifornical area (PeF) are key components of these RVLM
pathways, and they receive inputs from the cortex,
amygdala, and brain stem that signal the real or perceived
threatening stimulus. Note also that the sympathetically Acute
via cortex, amygdala & brainstem
mediated vasoconstriction is dependent on two mecha- psychological
nisms: 1) central command subserved by sympathetic stressor
premotor neurons located outside the RVLM, possibly in
the rostral ventromedial medulla (RVMM), and 2) baro- DMH/PeF
reflex resetting, mediated by descending inputs from the
Baroreflex
DMH/PeF. The solid lines indicate direct connections
that have been clearly identified, whereas the dashed lines resetting
may be direct or indirect. Amy, amygdala; mPFC, medial
prefrontal cortex; PAG, periaqueductal gray. For other Baroreceptor Central
Premotor Medullary
abbreviations, see previous figures. inputs respiratory
nucleus raphe
(RVMM?) nuclei
NTS

CVLM Sympathetic Sympathetic Phrenic

RVLM outflow outflow nucleus

Heart rate
Visceral Skin Respiratory
vasoconstriction vasoconstriction activity
BAT activity

learned is indicative of a threat or other stimulus that requires Fig. 16. Signals relating to the stimulus (e.g., sight, sound, or
immediate action). touch) reach the cortex, amygdala, and hippocampus via tha-
A general scheme illustrating the brain regions that are lamic relay nuclei. The amygdala also receives inputs from the
involved in generating these coordinated responses is shown in cortex and hippocampus. The amygdala, which consists of

Flight or freezing
BP and HR
Visceral vasoconstriction PAG
Hindlimb vasodilation&

Fig. 18. Schematic diagram showing the longitudi-

nal columns within the midbrain PAG that mediate
different types of defensive responses. Neurons in
the lateral (l) and dorsolateral (dl) columns generate
active coping responses, characterized by flight or Dorsolateral (dl)
freezing and increases in blood pressure (BP) and
Lateral (l)
HR, whereas neurons in the ventrolateral (vl) col-
umn generate passive coping responses, character- Active coping strategies evoked
ized by quiescence and decreases in BP and HR. Ventrolateral (vl) from lPAG and dlPAG
[Modified from Bandler et al. (2) with permission.] Passive coping strategies
evoked from vlPAG
Quiescence
BP and HR
Sympathetic
activity&

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 Refresher Course
THE BRAIN AND THE CARDIOVASCULAR SYSTEM 293

several interconnected nuclei (43), plays a critical role in ated with decreases in blood pressure and heart rate as well as
generating cardiovascular and respiratory responses to uncon- sympathoinhibition (2, 8, 26) (Fig. 18).
ditioned and conditioned alerting stimuli (6, 36). The input to The precise pattern of responses generated by the PAG
the amygdala from the hippocampus (Fig. 16) is essential for naturally depends on the pattern of inputs to the PAG. For
the expression of physiological responses to conditioned stim- example, inputs from visceral nociceptors trigger passive cop-
uli but not unconditioned stimuli (43). Inputs arising from ing responses, whereas inputs from somatic nociceptors (e.g., a
unconditioned salient stimuli that project to the thalamus then painful stimulus to the skin) trigger active coping responses (2,
project to the amygdala directly or indirectly via the cortex 26). It is also important to note that active coping responses
(Fig. 16). The direct input from the thalamus is believed to triggered by physical stimuli (such as the above example of a
generate rapid responses to simple external stimuli (e.g., a painful stimulus to the skin) are generated by activation of
sudden loud noise), whereas more complex stimuli require
neurons within the lateral PAG, whereas those triggered by
cortical processing (43).
emotional or psychological stressors (e.g., sight, sound, or
The output pathways from the amygdala to cardiovascular,
respiratory, and somatomotor nuclei in the lower brain stem odor of a predator or a perceived emotional stressor) gen-
responses include synapses in hypothalamic and midbrain erate a similar pattern of behavioral, cardiovascular, and
regions (Fig. 16) (12). One of these regions is the DMH and respiratory responses but via activation of the dorsolateral
adjacent perifornical area (PeF), which, like the amygdala, PAG (Fig. 19) (14).
have a critical role in generating cardiovascular and respiratory
responses to alerting or stressful stimuli (5, 12, 16, 51). Apart
from the amygdala, there are also inputs to the DMH/PeF from
the cortex and brain stem (Fig. 17) that also may signal alerting
or stressful stimuli. The output pathways from the DMH/PeF
have not been completely identified but include direct descend-
ing projections to sympathetic premotor neurons in the med-
ullary raphe pallidus that regulate the sympathetic outflows to
the heart, skin blood vessels, and BAT. These sympathetic
outflows are activated in response to alerting or stressful
stimuli (12) as well as in response to a cold stress, as discussed
above. In addition, there are output pathways from the DMH/
PeF to other sympathetic premotor neurons that regulate the
sympathetic outflow to renal, splanchnic, and other visceral
blood vessels. These premotor neurons are not within the
RVLM, but there is evidence that they are located more
medially, within the rostral ventromedial medulla (RVMM)
(12). Thus, in summary, the sympathetic premotor neurons that
drive the sympathetic outflow during arousal or defensive
behavior appear to be distinct from the sympathetic premotor
neurons within the RVLM that mediate the baroreceptor,
chemoreceptor, and other homeostatic cardiovascular reflexes,
as described above (see Central Mechanisms Subserving Ho-
meostatic Reflexes).
As also discussed above, however, the baroreceptor reflex is
reset during defensive behaviors, such that the sympathetic
outflow continues to be regulated but within a higher operating
range of arterial blood pressure and sympathetic activity. The
DMH/PeF contains neurons that, when activated, reset the
baroreceptor-sympathetic reflex in this way (31), probably via
descending pathways to the NTS (Fig. 17) (12, 34).
It is well established that the PAG in the midbrain is another
brain region that can coordinate a wide variety of behavioral
responses associated with appropriate cardiovascular and re- Fig. 19. Schematic diagram showing major inputs to the dlPAG and lPAG
spiratory changes (2, 8, 26). The PAG is organized into and the proposed output pathways subserving the coordinated changes in
longitudinal columns, including dorsolateral, lateral, and ven- sympathetic vasomotor and respiratory activity regulated by the dlPAG and
trolateral columns. The dorsolateral PAG and lateral PAG lPAG. The lines with arrows indicate connections that are either direct
(monosynaptic) or indirect (polysynaptic). Neurons in the dlPAG are
columns regulate what has been termed an active coping activated primarily by inputs related to psychological stressors, whereas
strategy (26), consisting of freezing and/or flight, associated those in the lPAG are activated primarily by inputs related to physical
with increases in blood pressure and heart rate, visceral vaso- stressors. Note that the dlPAG projects to the DMH via both direct and
constriction, skeletal muscle vasodilation, and increased ven- indirect [via the superior lateral parabrachial nucleus (PBsl) or cuneiform
nucleus (CnF)]. The cardiovascular and respiratory responses generated
tilation (Fig. 18) (2, 8, 26). Conversely, the ventrolateral PAG from the dlPAG are dependent on its connections with the DMH, whereas
column regulates what has been termed a passive coping the responses generated from the lPAG are mediated by direct descending
strategy (2, 26), consisting of behavioral quiescence, associ- projections to the medulla. [From Dampney (12).]

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294 THE BRAIN AND THE CARDIOVASCULAR SYSTEM
These differences in inputs to the lateral PAG and dorsolat-
eral PAG are also reflected in differences in outputs (Fig. 19).
Whereas neurons in the lateral PAG descend directly to the
medulla where they synapse with neurons regulating somato-
motor, cardiovascular, and respiratory responses, there are no
direct descending projections to the medulla from the dorso-
lateral PAG (Fig. 19) (14). There are, however, ascending
projections from the dorsolateral PAG to the DMH (Fig. 19),
and this projection is essential for the expression of cardiovas-
cular and respiratory responses generated from the dorsolateral
PAG (12, 14). Thus, the DMH is a site of convergence of
inputs related to psychological stressors that are relayed via the
dorsolateral PAG as well as those from the cortex and
amygdala, as discussed above.
A further component of the brain mechanisms that subserve
the cardiovascular and respiratory responses associated with
defensive behavior is the basal ganglia/colliculi system [for a
more detailed review of this system, see Müller-Ribeiro et al.
(40)]. The basal ganglia/colliculi system is phylogenetically
ancient and independent of the cortex and DMH/PeF and is
capable of responding to threats that require immediate stereo-
typed responses (17, 40). In contrast, the defense systems
described above that include the DMH/PeF and cortex as
important components appear to be better adapted to integrat-
ing responses to more sustained threats that require cognitive
appraisal.
Exercise. The cardiovascular and respiratory changes asso-
ciated with exercise have been well described, both in animals
and humans (9, 16, 34, 45, 47). It is well established that
central command plays a major role in generating these re-
sponses (Fig. 2B) (58), but reflexes also have an important role
(16, 34, 58).
There are many similarities in the pattern of cardiovascular
and respiratory changes associated with exercise and psycho-
logical stress (e.g., in both cases, there are increases in blood
pressure, heart rate, and cardiac output, vasoconstriction in the
renal and splanchnic beds, and vasodilation in skeletal muscle
beds) (16). In addition, in both exercise and psychological
stress, the baroreflex is reset in a similar way, as described
above (e.g., Fig. 5). This naturally raises the question as to
whether the cardiovascular and respiratory responses to exer-
cise and those to stress are driven, at least in large part, by the
same central mechanisms. Relatively little is known about the
brain regions responsible for central command during exercise
(58), although studies in animals have indicated that the DMH
and immediately adjacent regions are activated during exercise
(3), as is the case in psychological stress (12). Furthermore,
neurons that contain the peptide orexin (also called hypocretin)
in the DMH/PeF are activated during both exercise and stress,
and it is thought that orexin neurons facilitate cardiorespiratory
responses in both exercise and psychological stress (28).
In summary, the studies to date are consistent with the
hypothesis that the cardiovascular and respiratory responses
associated with exercise and psychological stress are driven by
common central mechanisms, at least in part.
Conclusions and Key Points
This article has attempted to highlight some of the key
pathways and mechanisms in the brain that are responsible for
regulating the autonomic outflow to the cardiovascular system.
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I have emphasized that cardiovascular regulatory mechanisms
do not operate in isolation but are closely coordinated with
respiratory and other regulatory mechanisms to maintain ho-
meostasis. The key points can be summarized as follows:
• The brain regulates the cardiovascular system by two gen-
eral means: 1) feedforward regulation (central command)
and 2) feedback regulation (reflex control).
• The baroreceptor and chemoreceptor reflexes are the pri-
mary homeostatic reflexes.
• The baroreceptor reflex regulates blood pressure not at a
constant fixed level but at a level appropriate for each
particular behavioral state (e.g., rest, exercise, or sleep).
• The chemoreceptor reflex maintains oxygenation of the
arterial blood but in cases of O2 deficiency also conserves
O2, often in concert with other reflexes (e.g., pulmonary
reflexes or the diving reflex).
• Other critical reflexes maintain body temperature and salt
and water balance.
• The brain also can generate patterned changes in autonomic,
respiratory, and neuroendocrine activity during different
behaviors (e.g., exercise, defense, feeding, sexual activity, or
sleep).
• The essential circuitry for baroreceptor and chemoreceptor
reflexes is in the lower brain stem but can be modified by
inputs from higher centers or other peripheral inputs.
• The lamina terminalis in the forebrain (OVLT, SFO, and
median preoptic nucleus) is critical for the regulation of salt
and water balance and in the long-term regulation of sym-
pathetic activity and blood pressure.
• The brain mechanisms regulating cardiovascular and respi-
ratory changes during defensive behavior are complex, but
the prefrontal cortex, amygdala, hypothalamus, midbrain
PAG, and colliculi play key roles.
• During arousal and defensive behavior, orexin (hypocretin)
neurons in the hypothalamus are activated, and this has the
effect of facilitating the cardiovascular and respiratory re-
sponses associated with these behaviors.
ACKNOWLEDGMENTS
The author thanks the organizers of the American Physiological Society
2015 Teaching Refresher Course on the Brain and Systems Control, and
particularly Dr. Catharine Young, for the opportunity to participate in the
session on which this article is based.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
R.A.D. prepared figures; R.A.D. drafted manuscript; R.A.D. edited and
revised manuscript; R.A.D. approved final version of manuscript.
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