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date: 17 December 2017

Central Mechanisms Regulating Coordinated Cardiovascular and Respiratory Function

Summary and Keywords

In response to changes in metabolic demand, the cardiovascular and respiratory systems are regulated in a highly coordinated fashion, such that both ventilation and cardiac output increase in a parallel fashion, thus maintaining a relatively constant level of arterial blood PO2, PCO2, and pH. In addition, external alerting stimuli that trigger defensive or orienting behavioral responses also trigger coordinated cardiorespiratory changes that are appropriate for the particular behavior. Furthermore, environmental challenges such as hypoxia or submersion evoke complex cardiovascular and respiratory response that have the effect of increasing oxygen uptake and/or conserving the available oxygen.

The brain mechanisms that are responsible for generating coordinated cardiorespiratory responses can be divided into reflex mechanisms and feedforward (central command) mechanisms. Reflexes that regulate cardiorespiratory function arise from a wide variety of internal receptors, and include those that signal changes in blood pressure, the level of blood oxygenation, respiratory activity, and metabolic activity. In most cases more than one reflex is activated, so that the ultimate cardiorespiratory response depends upon the interaction between different reflexes. The essential central pathways that subserve these reflexes are largely located within the brainstem and spinal cord, although they can be powerfully modulated by descending inputs arising from higher levels of the brain. The brain defense mechanisms that regulate the cardiorespiratory responses to external threatening stimuli (e.g., the sight, sound, or odor of a predator) are highly complex, and include both subcortical and cortical systems. The subcortical system, which includes the basal ganglia and midbrain colliculi as essential components, is phylogenetically ancient and generates immediate coordinated cardiorespiratory and motor responses to external stimuli. In contrast, the defense system that includes the cortex, hypothalamus, and limbic system evolved at a later time, and is better adapted to generating coordinated responses to external stimuli that involve cognitive appraisal.

Keywords: cardiorespiratory regulation, homeostasis, defensive behavior, chemoreceptor reflex, central respiratory neurons, hypothalamus, basal ganglia, medulla oblongata

Introduction

Homeostasis requires highly coordinated cardiovascular and respiratory regulatory mechanisms to ensure that the delivery of oxygen to all regions of the body is sufficient to match the metabolic demands of each region. This is especially important in the case of the heart and skeletal muscles, whose metabolic activity can vary greatly. For example, during maximal exercise in humans, the oxygen delivery to exercising skeletal muscles can increase to levels 20- to 50-fold greater than resting levels (Sarelius & Pohl, 2010). This is achieved by a combination of local, autonomic, and respiratory mechanisms, as shown in Fig. 1. Local mechanisms, which include metabolic, endothelial, and myogenic components (Sarelius & Pohl, 2010) result in vasodilation in metabolically active skeletal muscle vascular beds, which increases the blood flow to the metabolically active region provided the arterial pressure is maintained. The arterial pressure in maintained as a consequence of (1) an increase in cardiac output, which results from a sympathetically mediated increase in heart rate and ventricular contractility; and (2) increases in sympathetic vasoconstrictor activity in regions where metabolic activity has not increased, such as the kidneys, gut. and resting skeletal muscles.

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Figure 1. Flow diagram showing how cardiovascular and respiratory regulatory mechanisms, together with local mechanisms, operate together to match the oxygen supply to a particular region (skeletal muscle in this case) to the metabolic demand of that region.

From Dampney (2016), with permission.

An increase in oxygen delivery to match an increase in oxygen consumption in a particular region also requires, apart from increased blood flow, maintenance of the oxygen content of the blood supply to the region. This is achieved by increasing respiratory rate and depth such that the increase in alveolar ventilation is sufficient to ensure that the pulmonary venous blood (and thus systemic arterial blood) is fully saturated with oxygen, despite the large increase in blood flow to the lungs (i.e., cardiac output) that occurs during exercise. It is remarkable that the arterial blood oxygen partial pressure (PaO2) remains little changed from resting levels, even during heavy exercise (Asmussen & Nielsen, 1960). The cardiovascular and respiratory regulatory mechanisms therefore achieve a close matching of cardiac output, ventilation, and oxygen consumption over a wide range of exercise intensities.

Respiratory and cardiovascular function is also regulated in a highly coordinated fashion in other circumstances, such as in association with behavioral responses that are critical for survival, for example, escape from a predator or pursuit of a prey. In addition, environmental challenges, such as hypoxia or heat stress, also require coordinated cardiovascular and respiratory responses to maintain homeostasis. Finally, such coordinated regulation is also evident even under resting conditions, as shown for example by respiratory-related variations in heart rate (respiratory sinus arrhythmia) or in the activity of sympathetic vasomotor nerves. In this article the central mechanisms that subserve coordinated cardiovascular and respiratory regulation under resting conditions will first be discussed. This will be followed by a discussion of the regulatory mechanisms that help to maintain homeostasis in response to the environmental challenges of hypoxia and heat stress, and then finally the central mechanisms regulating the cardiovascular and respiratory changes associated with defensive behavior.

Resting Conditions

Respiratory-Related Changes in Heart Rate

Variations in heart rate associated with the respiratory cycle (respiratory sinus arrhythmia) occur in many vertebrate species, from fish to mammals (Yasuma & Hayano, 2004). Typically the heart rate increases during inspiration and decreases during expiration (Ben-Tal et al., 2014; Eckberg, 2009; Yasuma & Hayano, 2004). The heart rate changes are due almost entirely to variations in cardiac vagal activity, and the magnitude of heart rate changes in respiratory sinus arrhythmia is sometimes used as a surrogate measure for cardiac vagal activity (Yasuma & Hayano, 2004). There is evidence from studies in both humans and animals that respiratory sinus arrhythmia improves the efficiency of pulmonary gas exchange by better matching of perfusion to ventilation in each respiratory cycle (Giardino, Glenny, Borson, & Chan, 2003; Hayano, Yasuma, Okado, Mukai, & Fujinami, 1996). In addition, it has also been proposed that respiratory sinus arrhythmia reduces the work of the heart while maintaining the same cardiac output and physiological levels of arterial carbon dioxide (Ben-Tal et al., 2014).

It is generally recognized that there are two major mechanisms that are responsible for the respiratory-related variations in cardiac vagal activity. First, cardiac vagal activity is inhibited during the inspiratory and late expiratory phase, as a consequence of inhibitory inputs to cardiac vagal preganglionic neurons in the nucleus ambiguus arising from central respiratory neurons (Gilbey, Jordan, Richter, & Spyer,1984; Silvani, Calandra-Buonara, Dampney, & Cortelli, 2016; Yasuma & Hayano, 2004). These inhibitory inputs have the effect of gating excitatory inputs to cardiac vagal preganglionic neurons arising from baroreceptors, chemoreceptors, and nasopharyngeal receptors (Davidson, Goldner, & McCloskey, 1976; Gandevia, McCloskey, & Potter, 1978; Gilbey et al., 1984; Haymet & McCloskey, 1975). Secondly, lung inflation during inspiration activates pulmonary stretch receptors innervated by C-fibers, leading to a reflex inhibition of cardiac vagal activity (Daly & Scott, 1958; Yasuma & Hayano, 2004).

It has been argued, however, that respiratory sinus arrhythmia, at least in humans, is due mainly to inputs from arterial baroreceptors, whose activity fluctuates with respiration as a consequence of respiratory-related changes in arterial pressure (Karemaker, 2009). While there is no doubt that respiration affects venous return and consequently cardiac output and arterial pressure, there are several reasons why the respiratory sinus arrhythmia observed in humans cannot be explained as a consequence of baroreceptor reflex effects, as discussed by Eckberg (2009). In particular, mechanical artificial ventilation that suppresses the activity of central respiratory neurons, but increases respiratory-related fluctuations in arterial pressure, greatly reduces respiratory sinus arrhythmia (Koh, Brown, Beightol, & Eckberg, 1998). Secondly, as shown in Fig. 2, when the magnitude of respiratory sinus arrhythmia is increased by slow deep breathing the heart rate increases before, not after, the increase in arterial pressure.

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Figure 2. Recording of arterial pressure, respiration, and heart rate in a conscious subject, showing respiratory sinus arrhythmia. Note that the magnitude of the respiratory sinus arrhythmia increases during slow deep breathing, and also that the onset of the increased heart rate at this time precedes the changes in arterial pressure. Thus the change in heart rate is not a baroreflex response to changes in arterial pressure. Unpublished data (Dampney, 2007).

The precise source(s) of the inhibitory input(s) to cardiac vagal preganglionic neurons during inspiration is not known. There appear, however, to be at least two classes of inputs, which release GABA and glycine, respectively (Neff, Wang, Baxi, Evans, & Mendelowitz, 2003). The Bötzinger region within the ventral respiratory group in the medulla oblongata contains glycinergic neurons that are active during inspiration (Morgado-Valle, Baca, & Feldman, 2010), and so these could be the source of the glycinergic inhibitory input to cardiac vagal preganglionic neurons. The origin of the GABAergic inhibitory input to these neurons, however, is unknown.

Respiratory-Related Changes in Sympathetic Vasomotor Activity

The activity of virtually all sympathetic nerves innervating blood vessels displays respiratory-related fluctuations, although the precise pattern of respiratory modulation (i.e., whether firing is maximal during the inspiratory period or some other phase of the respiratory cycle) varies according to the vascular region, species of animal, and experimental conditions (Guyenet, 2011; Malpas, 1998). Sympathetic vasomotor nerves, with the exception of those innervating cutaneous blood vessels, also show a cardiac rhythm that is due to their reflex responsiveness to baroreceptor inputs that also have a cardiac pulsatile activity (Guyenet, 2011; Malpas, 1998). It has been suggested that the physiological advantage of the bursting pattern of firing in sympathetic nerves, whether it is related to the cardiac or respiratory cycle, is that it facilitates neuroeffector transmission, such that stronger vasomotor responses are elicited than would be the case if sympathetic nerves did not fire in bursts (Malpas, 1998).

The activity of sympathetic vasomotor nerves is driven largely by spinally projecting neurons in the rostral ventrolateral medulla (RVLM) (Dampney et al., 2003; Guyenet, 2006). These neurons, which consist of both adrenaline-synthesizing (C1) and non-C1 neurons (Dampney et al., 2003; Guyenet, 2006), include subsets of neurons that preferentially or exclusively project to sympathetic preganglionic neurons that regulate blood vessels in particular regions, such as the skin, skeletal muscle, or kidney (Dampney & McAllen, 1988; McAllen, May, & Campos, 1997). Furthermore, RVLM sympathetic premotor neurons display different patterns of respiratory-related activity, which are similar to those recorded in the sympathetic outflows to particular vascular beds (Guyenet, 2006). It therefore seems likely that the respiratory modulation of the activity of different sympathetic vasomotor nerves derives from their antecedent premotor neurons in the RVLM.

RVLM sympathetic premotor neurons receive both excitatory and inhibitory inputs from a variety of sources (Dampney et al., 2003; Guyenet, 2006). One of the major inhibitory inputs originates from GABAergic neurons within the caudal ventrolateral medulla (CVLM), and is a critical link in the central pathways mediating the baroreceptor reflex (Dampney et al., 2003; Guyenet, 2006). Neurons in the CVLM display a variety of respiratory patterns, some of which are opposite to those observed in RVLM sympathetic premotor neurons (Mandel & Schreihofer, 2006). Thus, the inputs from CVLM inhibitory neurons can account for the different patterns of respiratory modulation of RVLM neurons. The sources of inputs to the CVLM neurons that produce their respiratory modulation is unknown, but as pointed out by Guyenet (2011) they lie in close proximity to the pre-Bötzinger complex and adjacent rostral ventral respiratory group, both of which are key components of the central respiratory pattern generator.

Homeostatic Reflex Responses

Homeostasis is dependent, among other things, on reflexes that produce appropriate physiological responses to environmental challenges. In this section I shall consider particularly the central mechanisms that generate coordinated cardiovascular and respiratory reflex responses to such challenges, using hypoxia and heat stress as examples.

Hypoxia

In arterial blood, over 95% of hemoglobin molecules are bound to oxygen, forming oxyhemoglobin, provided the arterial blood PO2 (PaO2) is greater than 90 mmHg. A decrease in arterial blood PO2 can occur when the atmospheric PO2 is reduced (e.g., at high altitudes), or when normal breathing is prevented, such as during submersion in diving animals or when a noxious substance (e.g., smoke) is encountered in the ambient air. The principal defense mechanism against hypoxia is the arterial chemoreceptor reflex, which when stimulated increases breathing (where that is possible) and simultaneously conserves the available oxygen. The chemoreceptors are located in the carotid and aortic bodies, and are activated primarily by a decrease in PaO2 and to a lesser extent by an increase in PaCO2 or a decrease in pH (Biscoe, Purves, & Sampson, 1970; Kumar & Prabahker, 2012).

As shown in Fig. 3, the reflex effects of hypoxic stimulation of the chemoreceptors are an increase in ventilation, due to increases in both the rate and depth of breathing, and cardiovascular effects, consisting of sympathetically mediated vasoconstriction in many vascular beds combined with vagally mediated bradycardia. The increase in ventilation allows oxygen uptake in the lungs to increase, while the reflexly evoked cardiovascular changes (vasoconstriction in skeletal muscle and visceral beds and bradycardia) tends to conserve the available oxygen.

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Figure 3. Flow diagram showing the primary reflex effects of chemoreceptor stimulation by arterial hypoxia, leading to an increase in ventilation as well as cardiovascular reflex changes that tend to conserve the available oxygen.

Modified from Dampney (2016), with permission.

It must be emphasized, however, that the chemoreceptor reflex is rarely, if ever, activated in isolation. For example, when hypoxia occurs under conditions where respiratory activity can increase, such as exposure to a high altitude, ventilation is reflexly increased, which in turn activates pulmonary stretch receptors, innervated by vagal afferent fibers. The pulmonary stretch receptor reflex tends to increase heart rate and decrease vascular resistance, thus opposing the primary cardiovascular reflex effects of chemoreceptor stimulation (Coleridge & Coleridge, 1994; Daly, Ward, & Wood, 1986). In contrast, when hypoxia occurs under conditions when respiratory activity cannot increase (such as during submersion or on exposure to a noxious substance), the primary reflex response to chemoreceptor stimulation is not opposed by secondary effects arising from pulmonary stretch receptor activation (Fig. 4). Instead, under such conditions, nasopharyngeal receptors may be stimulated, triggering the diving reflex. This reflex exists in all air-breathing vertebrates, but is particularly powerful in diving animals (Panneton, Gan, & Juric, 2010). Activation of the diving or nasopharyngeal reflex results in apnea, intense widespread peripheral vasoconstriction (except in the brain and heart), and a profound vagally mediated bradycardia (Fig. 4). The cardiovascular reflex effects conserve the available oxygen, which is thus preferentially provided to the brain and heart, two critical regions that cannot sustain an oxygen debt. In addition, the arterial hypoxia resulting from the reflexly evoked apnea will stimulate the arterial chemoreceptor reflex, thus reinforcing the vasoconstriction and bradycardia and further enhancing conservation of the available oxygen (Fig. 4).

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Figure 4. 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 respiratory activity can increase, the reflex decrease in heart rate and reflex increase in vascular resistance (in skeletal muscle and visceral beds) is opposed by the secondary reflex effects arising from activation of pulmonary stretch receptors, thus increasing oxygen uptake. In contrast, when hypoxia occurs under conditions when respiratory activity cannot increase, such as during submersion or exposure to a noxious substance in the ambient environment, the primary reflex response to chemoreceptor stimulation is reinforced by reflex effects arising from the nasopharyngeal reflex, leading to a greater degree of oxygen conservation.

From Dampney (2008), with permission.

In summary, the net effect of arterial hypoxia on cardiovascular and respiratory function depends upon interactions between several reflexes. The effect of such interactions between reflexes is that the pattern of reflexly evoked cardiovascular and respiratory responses is most appropriate for the particular environmental challenge.

The essential central pathways mediating the chemoreceptor reflex are shown in Fig 5. The chemoreceptor primary afferent fibers arising from the carotid and aortic bodies, which run in cranial nerves IX and X respectively, terminate on secondary interneurons in the nucleus of the tractus solitaries (NTS), primarily in the commissural and medial subnuclei (Finley & Katz, 1992). The primary chemoreceptor afferent fibers are probably glutamatergic (Guyenet, 2014; Vardhan, Kachroo, & Sapru, 1993) although it has been suggested that ATP may also have a role (Braga et al., 2007). The second-order neurons in the NTS that receive inputs from chemoreceptor afferent fibers do not receive inputs from baroreceptor or other types of sensory inputs; that is, there is little or no convergence of inputs from different receptor types to second-order NTS neurons (McDougall, Peters, & Andresen, 2009). There are direct projections from hypoxia-sensitive neurons in the commissural NTS to the RVLM (Hirooka, Polson, Potts, & Dampney, 1997) and also to the Kölliker-Fuse nucleus and lateral parabrachial nuclei in the dorsolateral pons (Song, Wang, Macdonald, & Poon, 2011). In addition, hypoxia-sensitive neurons in the Kölliker-Fuse nucleus project directly to the RVLM (Hirooka et al., 1997) (Fig. 5). Thus, signals from peripheral chemoreceptors may excite RVLM sympathetic premotor neurons by both direct and indirect routes from NTS neurons (Fig. 5). The hypoxia-sensitive neurons in the NTS that project directly to the RVLM, and those that project to the dorsolateral pons may arise from the same population of second-order chemosensitive neurons, which use glutamate as a neurotransmitter (Guyenet, 2014).

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Figure 5. Schematic diagram showing the essential pathways within the lower brainstem that subserve the chemoreflex control of the sympathetic outflow to the heart and blood vessels. The unbroken lines from the nucleus tractus solitaries (NTS) to the rostral ventrolateral medulla (RVLM) indicate a direct connection that generates tonic chemoreflex excitation, while the broken lines may be direct or indirect. There is a direct projection from chemosensitive neurons in the NTS to the Kölliker-Fuse nucleus and lateral parabrachial nuclei within the dorsolateral pons. The descending projections from the dorsolateral pons to the RVLM subserve the component of the chemoreflex sympathoexcitation that is modulated by the respiratory cycle, at least in part via connections with neurons in the ventral respiratory group (VRG) and caudal ventrolateral medulla (not shown in this diagram). Neurons in the RVLM then project directly to the intermediolateral cell column (IML).

Modified from Dampney et al. (2002), with permission.

The increased sympathetic activity evoked by chemoreceptor stimulation occurs in respiratory-related bursts (Dick, Baekey, Paton, Lindsey, & Morris, 2009; Guyenet, 2014; Koshiya & Guyenet, 1996). After pontomedullary transection or blockade of central respiratory activity by inhibition of neurons in the ventral respiratory group, the bursting pattern of chemoreceptor-evoked sympathoexcitation is abolished but is replaced by tonic activation (Dick et al., 2009; Guyenet, 2014; Koshiya & Guyenet, 1996). Thus, it appears that tonic chemoreceptor-induced sympathoexcitation is mediated by the direct projection from NTS to RVLM sympathetic premotor neurons (Fig. 5), while the bursting pattern is mediated by the indirect pathway that includes neurons in the dorsolateral pons and ventrolateral medulla that are part of the central respiratory generator (Dick et al., 2009; Guyenet, 2014; Koshiya & Guyenet, 1996) (Fig. 5). It has been proposed that neurons in the central respiratory generator impose their respiratory-related bursting pattern on RVLM sympathetic premotor neurons via CVLM GABAergic neurons (Guyenet, 2014).

Chemoreceptor stimulation reflexly causes a vagally mediated bradycardia in the absence of secondary effects arising from increased respiratory activity, or when the stimulation is sufficiently intense so as to override secondary effects (McAllen, Salo, Paton, & Pickering, 2011). Such activity shows a respiratory modulation, such that it occurs primarily during the post-inspiratory and expiratory phase (McAllen et al., 2011). The reduced activity during the inspiratory phase is explained by respiratory gating as discussed above (see section Respiratory-Related Changes in Heart Rate), such that inputs to cardiac vagal preganglionic neurons in the nucleus ambiguus arising from chemoreceptors (and other peripheral receptors) are inhibited by inputs either from central respiratory neurons or from pulmonary stretch receptors (Davidson, Goldner, & McCloskey, 1976; Gandevia, McCloskey, & Potter, 1978). The site at which such gating occurs, at least in the case of inputs from pulmonary stretch receptors, is unlikely to be in the NTS, because as mentioned above, inputs from chemoreceptor and pulmonary stretch receptor afferents synapse with different neurons in the NTS. It is more likely that gating occurs in the nucleus ambiguus itself, because this nucleus receives direct inputs from the medial subnucleus of the NTS (Stuesse & Fish, 1984), one of the main sites of termination of primary chemoreceptor afferent fibers (Finley & Katz, 1992), as well as respiratory-related inputs (McAllen et al., 2011). The chemoreceptor-evoked excitation of cardiac vagal preganglionic neurons that occurs during the post-inspiratory and expiratory phase is presumably driven by the direct input from the medial NTS.

The receptors triggering the diving or nasopharyngeal reflex are innervated by trigeminal nerve afferents that terminate in the spinal trigeminal nucleus (Panneton, 2013), which in turn projects to various targets including the medial NTS, RVLM, and Kölliker-Fuse nucleus in the dorsolateral pons (Panneton et al., 2010). The medial NTS, which projects directly to the RVLM, is critical for the expression of the sympathoexcitatory component of the response (Dutschmann & Herbert, 1998b). In contrast, the Kölliker-Fuse nucleus is essential for the expression of the reflex apnea and bradycardia but not sympathoexcitation (Dutschmann & Herbert, 1998a). Thus, descending pathways from the Kölliker-Fuse nucleus to medullary respiratory neurons and cardiac vagal preganglionic neurons may mediate the reflex apnea and bradycardia, respectively. Alternatively, as suggested by Guyenet (2011), it is possible that the reflex bradycardia is secondary to the apnea, that is, it is caused by removal of the inhibition of cardiac vagal preganglionic neurons by central respiratory neurons that are responsible for respiratory sinus arrhythmia (see section on Respiratory-Related Changes in Heart Rate). In any case, it is clear that the inhibitory influence of the Kölliker-Fuse nucleus on respiration is sufficiently powerful to completely suppress respiratory activity during diving, even though the resultant arterial hypoxia would activate peripheral chemoreceptors.

Heat Stress

Maintenance of a core body temperature within narrow limits is essential for survival in mammals, and highly effective regulatory mechanisms have evolved that enable mammals to conserve and generate heat in response to cold stress, and increase heat loss in response to heat stress. The compensatory response to heat stress, in particular, requires a close coordination of cardiovascular and respiratory reflex responses.

An increase in ambient temperature is detected by warm receptors in the skin, and leads to cutaneous vasodilation, due to inhibition of sympathetic vasoconstrictor activity and excitation of sympathetic vasodilator activity (Kellogg, 2006; Morrison & Nakamura, 2011; Rowell, 1974). In humans and other mammals with sweat glands, sympathetic sudomotor activity is reflexly increased, causing increased sweat production and consequent increased evaporative heat loss from the skin. In mammals that lack sweat glands, evaporative cooling is achieved primarily by panting, which is characterized by rapid shallow breathing (Morrison & Nakamura, 2011). Even in non-panting animals such as humans, respiratory activity is altered, most typically by an increase in tidal volume (Saxton, 1975).

Afferent fibers conveying signals from warm receptors terminate in the dorsal column of the spinal cord, from which an ascending pathway conveys warm signals to the median preoptic nucleus (MnPO) in the hypothalamus, via a relay in the dorsolateral subnucleus of the lateral parabrachial nucleus (dlPB) (Fig. 6). The neurons in the MnPO that receive these inputs project to and excite neurons in the median preoptic nucleus (MPO) that inhibit the sympathetic premotor neurons in the raphe pallidus (RP) in the midline medulla that produce skin vasoconstriction and thermogenesis in brown adipose tissue, both directly and via the DMH (Fig. 6) (McKinley et al., 2015).

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Figure 6. Diagram showing the brain pathways that mediate defense mechanisms in response to skin warming. Red lines indicate excitatory neural pathways, blue lines indicate inhibitory neural pathways. The unbroken lines indicate defined connections, while the unbroken lines indicate undefined polysynaptic connections. dLPB, dorsal subnucleus of the lateral parabrachial nucleus; DMH, dorsomedial hypothalamus; MnPO, median preoptic nucleus; MPO, medial preoptic nucleus; RP, raphe pallidus nucleus.

In animals such as dogs that normally pant in response to heat stress, localized heating in the preoptic area in the hypothalamus that includes the MnPO results in panting (Boulant, 1981; Kronert & Pleschka, 1976). Furthermore, the onset of panting in dogs is accompanied by a large increase in lingual blood flow, whether induced by increased ambient temperature or localized heating of the preoptic area (Kronert & Pleschka, 1976). The combination of panting and increased lingual blood flow greatly increases evaporative heat loss, and the fact that they occur simultaneously suggests that both are driven by a common central mechanism within the preoptic area. In contrast to the cardiovascular responses to heat stress, however, very little is known about the central pathways that mediate the respiratory responses, apart from the fact that in both cases the MnPO plays a critical role (Fig. 6).

Central Cardiovascular and Respiratory Regulation Associated With Defensive Behavior

The ability of an animal to respond rapidly and appropriately to threatening or potentially threatening stimuli in its environment is critical for survival. In the case of predators, the ability to respond appropriately to the presence of prey is equally critical. An appropriate response includes both behavioral responses (e.g., escape or pursuit) supported by cardiovascular and respiratory changes that meet the metabolic demands associated with the particular behavior. In this section the coordinated cardiovascular and respiratory changes that are triggered by alerting or potentially threatening stimuli will be summarized first, followed by a discussion of the brain mechanisms that subserve these responses.

Brief alerting stimuli such as an unexpected noise evokes immediate autonomic and respiratory responses, characterized by strong cutaneous vasoconstriction and respiratory activation, but without significant effects on the mesenteric, renal, and hindlimb vascular beds (Bondarenko, Averell, Hodgson, & Nalivaiko, 2013; Mohammed, Kulasekera, de Menezes, Ootsuka, & Blessing, 2013; Yu & Blessing, 2011). This initial response to a novel alerting stimuli may lead to what is often called a defense reaction if the stimulus is prolonged or more threatening (Casto et al., 1989). More prolonged threatening stimuli typically elicit a more complex autonomic response, which is characterized by a differentiated pattern of sympathetic responses, with increases in arterial pressure, heart rate, adrenaline release, and sympathetically mediated vasoconstriction in skin, renal, and mesenteric beds, but with highly variable effects on skeletal muscle sympathetic activity (for a more detailed discussion see Dampney (2015)). During naturally evoked psychological stress the baroreflex control of sympathetic vasomotor activity is reset, such that both the arterial pressure and sympathetic vasomotor activity are regulated over a higher operating range, without any decrease in reflex gain (Kanbar, Orea, Varres, & Julien, 2007). These autonomic responses are accompanied by an increased respiratory rate and ventilation (Bondarenko, Beig, Hodgson, Braga, & Nalivaiko, 2015; Bondarenko, Hodgson, & Nalivaiko, 2014; Suess, Alexander, Smith, Sweeney, & Marion, 1980).

All levels of the brain, from the medulla oblongata to the cortex, play a role in generating cardiovascular and respiratory responses to alerting or threatening stimuli. In regard to the mechanisms that produce highly synchronized and coordinated cardiovascular and respiratory responses, there is clear evidence that three regions have a pivotal role: the dorsomedial hypothalamus (DMH) and adjacent perifornical area (PeF), the midbrain periaqueductal gray (PAG), and midbrain colliculi. The DMH/PeF receives inputs from several forebrain regions, including the cortex and amygdala, and is well adapted to generating appropriate responses to sustained threatening stimuli that involve cognitive appraisal (Dampney, 2015). In contrast, the midbrain colliculi is part of a subcortical defense system that also includes the basal ganglia and which produces immediate stereotyped response to alerting stimuli (that may be visual, auditory, or somatosensory) (Müller-Ribeiro, Goodchild, McMullan, Fontes, & Dampney, 2016). The basal ganglia/colliculi system is phylogenetically ancient, going back to the beginning of vertebrate evolution 560 million years ago (Grillner & Robertson, 2015). In the following sections the mechanisms by which each of these different defense systems produce coordinated cardiovascular and respiratory responses will be discussed separately.

The Basal Ganglia/Colliculi Defense System

As shown in Fig. 7, the superior colliculus (also called the optic tectum in non-mammalian vertebrates) receives inputs arising from visual, auditory, and somatosensory stimuli, and can generate different patterns of highly coordinated behavioral responses, including orienting, defensive, or escape responses, via their descending projections to the brainstem and spinal cord (Dean, Redgrave, & Westby, 1989).

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Figure 7. Top: sagittal section of the rat brainstem showing the location of brain regions referred to in the flow diagram below. Bottom: schematic diagram showing the subcortical loop involving the superior colliculus (SC) and basal ganglia, based on a scheme proposed by McHaffie et al. (2005). 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 (Str), relayed via the intralaminar nuclei (ILN) in the thalamus. The striatum also receives inputs from the cortex and amygdala (Amy) and acts as an action selector, generating different patterns of behavioral responses accompanied by appropriate cardiovascular and respiratory changes, via inputs to the substantia nigra pars reticulata (SNpr), which in turn project to projection neurons in the SC. For further details see the text. The red lines indicate excitatory projections, whereas the blue lines indicate inhibitory projections.

Modified from Dampney (2015), with permission.

The collicular neurons that generate such coordinated responses are normally inhibited by tonic GABAergic inputs, which arise from the substantia nigra pars reticulata (Coimbra & Brandao, 1993) (Fig. 7). The substantia nigra pars reticulata itself receives inhibitory inputs from the striatum that in turn receives inputs from the thalamus as well as from the cortex and amygdala (McHaffie, Stanford, Stein, Coizet, & Redgrave, 2005) (Fig. 7). There are also projections back from the superior colliculus to the striatum, relayed via the thalamus (Fig. 7). The substantia nigra pars reticulata and striatum are components of the basal ganglia, and it has been proposed that this loop involving the basal ganglia and superior colliculus allows selection of an appropriate response to competing inputs, including those that arise from the cortex (McHaffie et al., 2005). In other words, the striatum acts as an “action selector,” so that the most appropriate behavioral response can be selected, according to the inputs into the striatum. Such selection is achieved by withdrawing inhibition from the particular output neurons in the superior colliculus that regulate the appropriate behavioral response.

It should be emphasized that although there are inputs to the striatum from the cortex and amygdala (Fig. 7), highly coordinated behavioral responses to external stimuli can still be elicited even when such inputs are removed (Grillner & Robertson, 2015). That is, the basal ganglia/colliculi system is sufficient to produce complex behaviors, consistent with the fact that this system evolved very early in vertebrate evolution, before the development of the cerebral cortex.

Most studies of the role of the basal ganglia/colliculi system in generating behavioral responses have focused on the somatomotor components of such responses. Recently, however, it has been shown that in anesthetized rats natural auditory, visual, and somatosensory stimuli could evoke, in addition to somatomotor responses, increases in sympathetic and respiratory activity, but only after disinhibition (by microinjection of the GABA receptor antagonists picrotoxin or bicuculline) of certain sites within the midbrain colliculi (Müller-Ribeiro, Dampney, McMullan, Fontes, & Goodchild, 2014) (Fig. 8A). These effects were still observed after removal of the cerebral cortex and amygdala, and thus were independent of inputs from the cortex and amygdala (Müller-Ribeiro et al., 2014). Taken together with previous studies of the role of the basal ganglia/colliculi system in somatomotor control and behavior, these findings suggest that this system generates appropriate cardiovascular and respiratory responses to support the stereotyped behavioral responses evoked by auditory, visual, and somatosensory stimuli inputs to the colliculi (Fig. 7).

A remarkable feature of the sympathetic, respiratory, and somatomotor responses evoked by visual, auditory, and somatosensory stimuli following disinhibition of sites within the colliculi is that the responses are highly synchronized (e.g., Fig. 8A), suggesting the hypothesis that all these responses are driven by a common population of command neurons that are activated by these different inputs, as shown in Fig. 8B (Müller-Ribeiro et al., 2014). Consistent with this hypothesis, many neurons within the deep layers of the superior colliculus receive convergent visual, auditory, and somatosensory inputs, and also have descending projections to the brain stem (Meredith & Stein, 1986).

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Figure 8. A, Changes in arterial pressure, splanchnic sympathetic nerve activity (SpSNA) and phrenic nerve activity (PNA) evoked in an anesthetized rat by touching the whiskers, after microinjection of picrotoxin into the colliculus. Note the highly synchronized bursting patterns of SpSNA and SNA. Modified from Müller-Ribeiro et al. (2016), with permission. B, Schematic diagram showing the proposed pathways by which different types of sensory inputs converge on to command neurons in the colliculi, which then drive cardiovascular, respiratory, and somatomotor responses that are appropriate for the particular pattern of inputs.

From Dampney (2015), with permission.

An alternative hypothesis to explain the synchrony between respiratory and sympathetic responses generated from the colliculi is that the collicular neurons project to respiratory neurons in the brain stem that in turn provide an input to sympathetic premotor neurons. In fact, such coupling does occur at the level of the brain stem (see Respiratory-Related Changes in Sympathetic Vasomotor Activity). This alternative hypothesis is highly unlikely, however, because the pattern of respiratory modulation of sympathetic activity that occurs at the level of the brain stem is distinctly different from that evoked by activation of collicular neurons. In particular, under resting conditions splanchnic sympathetic activity is increased during the expiratory phase (Dick, Hsieh, Morrison, Coles, & Prabhakar, 2004), whereas after collicular disinhibition the increase in splanchnic sympathetic activity evoked by auditory, visual, or somatosensory stimuli occurs primarily during the inspiratory phase of respiration (i.e., when phrenic nerve activity is increased) (Müller-Ribeiro et al., 2014) (Fig. 8A). It therefore seems more likely that the synchronized sympathetic and respiratory responses that can be evoked after collicular disinhibition are driven by the same population of collicular neurons. It is conceivable that these same neurons may also generate stereotyped behavioral responses from the colliculi, such as orienting or escape. In that case, the simultaneously evoked cardiovascular and respiratory effects are presumably appropriate for the particular behavioral response.

The DMH/PeF Defense System

As shown in Fig. 9, the DMH/PeF receives inputs from neurons in the prefrontal cortex, amygdala, and PAG, and projects directly and indirectly to other nuclei that regulate ACTH and vasopressin release, and cardiovascular and respiratory activity. The critical importance of this region in mediating stress-evoked cardiovascular and respiratory responses is well-established. First, inhibition of neurons within the DMH/PeF greatly reduces the cardiovascular, neuroendocrine, and respiratory responses to psychological stressors (Bondarenko et al., 2015; DiMicco, Samuels, Zaretskaia, & Zaretsky, 2002). Second, activation of neurons in the DMH/PeF evokes cardiovascular and respiratory responses that are very similar to naturally evoked stress responses (DiMicco et al., 2002; Fontes, Tagawa, Polson, Cavanagh, & Dampney, 2001; Horiuchi et al., 2004; McDowall, Horiuchi, & Dampney, 2007; McDowall, Horiuchi, Killinger, & Dampney, 2006). Finally, psychological stress evokes a marked increase in c-Fos expression in the DMH/PeF (Furlong, McDowall, Horiuchi, Polson, & Dampney, 2014; Spencer & Day, 2004).

The fact that cardiovascular and respiratory changes are evoked by activation of DMH/PeF neurons raises the question as to whether both responses are driven from the same population of neurons. There is little correlation, however, between the magnitude of respiratory responses (measured as changes in phrenic nerve activity) or cardiovascular responses (measured as changes in renal or cutaneous sympathetic activity) when different sites in the DMH/PeF are activated (McDowall et al., 2007; Tanaka & McAllen, 2008). It therefore can be concluded that the increased sympathetic and respiratory activities that are evoked by activation of DMH/PeF neurons are mediated by separate descending pathways (Fig. 9). These descending pathways, however, have not been clearly defined, except for a direct projection from the DMH to the raphe pallidus in the midline medulla that regulates heart rate (Fig. 9) (Dampney, 2015).

Central Mechanisms Regulating Coordinated Cardiovascular and Respiratory FunctionClick to view larger

Figure 9. Top: sagittal section of the rat brainstem showing the location of brain regions referred to in the flow diagram below. Bottom: flow diagram showing the major pathways that subserve the cardiovascular, respiratory, and neuroendocrine responses to an acute psychological stressor. The DMH and perifornical area (PeF) are key components of these pathways, and receive inputs from the cortex, amygdala, and midbrain periaqueductal gray (PAG) that signal the real or perceived threatening stimulus. The unbroken lines indicate direct connections that have been clearly identified, while the broken lines may be direct or indirect. mPFC, medial prefrontal cortex; PAG,. For other abbreviations see legends to previous figures.

From Dampney (2015), with permission.

Lesions or inhibition of neurons in the amygdala reduce both the cardiovascular and respiratory responses to psychological stress (Bondarenko et al., 2014; McDougall, Widdop, & Lawrence, 2005). The amygdala is also the source of one of the major inputs to the DMH/PeF (Dampney, 2015) (Fig. 9), and so it seems likely that the input from the amygdala is a major component of the central pathways driving cardiovascular and respiratory responses to psychological stress. An additional input to the DMH/PeF that also may also contribute to these responses arises from the dorsolateral part of the PAG (Horiuchi, McDowall, & Dampney, 2009).

Conclusions

Survival of an animal depends on regulating the delivery of oxygen to all regions of the body so as to match the metabolic requirements of each region. That in turn depends upon a close coordination of central cardiovascular and respiratory mechanisms. Such coordination results from three general mechanisms: (1) reflexes that simultaneously regulate both cardiovascular and respiratory function in response to inputs from peripheral receptors, such as chemoreceptors, nasopharyngeal receptors, or warm receptors; (2) central connections between neurons regulating respiratory activity and those regulating cardiovascular function; and (3) central command, whereby neurons at higher levels of the brain have collateral projections to both cardiovascular and respiratory neurons within the brain stem. In many cases two or more of these mechanisms may contribute to the coordination of cardiovascular and respiratory function, together with local mechanisms that are also required to ensure that blood flow to particular regions, especially the skeletal muscles and heart, matches the metabolic demands of those regions.

While much progress has been in identifying and unraveling the central cardiovascular and respiratory mechanisms, there is still much that is not understood. For example, while it is generally agreed that central command has a critical role in regulating cardiovascular and respiratory function in exercise (Forster, Haouzi, & Dempsey, 2012; Williamson, Fadel, & Mitchell, 2006), very little is known about the central pathways that subserve central command in exercise. Future studies will be needed to address these important unanswered questions.

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