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Central Mechanisms Generating Cardiovascular and Respiratory Responses to Emotional Stress
C H A P T E R
28 Central Mechanisms Generating Cardiovascular and Respiratory Responses to Emotional Stress R.A.L. Dampney School of Medical Sciences (Physiology) and Bosch Institute, University of Sydney, Camperdown, NSW, Australia
O U T L I N E Introduction
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Amygdaloid Complex Midbrain PAG Medial Prefrontal Cortex
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Summary and Conclusions
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References
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Pattern of Cardiovascular and Respiratory Responses Associated With Emotional Stress 392 Key Brain Regions Activated by Emotional Stress DMH/PeF Region
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INTRODUCTION Animals, including humans, have evolved different types of stereotyped defensive behaviors that are triggered by real or perceived threatening stimuli in their external environments. These stimuli may be either unconditioned (i.e., stimuli that are innately threatening, such as the sight, sound, or odor of a predator) or conditioned (i.e., stimuli that are normally innocuous but which are perceived as threatening because of past experience). These stimuli can be referred to collectively as emotional stressors. In general,
Stress: Physiology, Biochemistry, and Pathology https://doi.org/10.1016/B978-0-12-813146-6.00028-X
the behavioral responses to emotional stressors can be classified as either active or passive. Active responses are usually evoked if the threat is escapable (e.g., presence of a predator or conspecific), while passive responses are usually evoked if the threat is inescapable (such as deep pain). Active responses are characterized by increased somatomotor activity, increased vigilance, and hyperreactivity, while passive responses are characterized by reduced somatomotor activity, decreased vigilance, and hyporeactivity.1 Each of these patterns of behavioral responses is accompanied by autonomic
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Copyright © 2019 Elsevier Inc. All rights reserved.
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and respiratory changes that support the particular behavior.
KEY POINTS • Emotional stress is triggered by real or perceived external threats. • This stress triggers defensive behavioral responses accompanied by appropriate neuroendocrine, autonomic, and respiratory responses. • Different pathways in the brain subserve different components of the response. • The amygdaloid complex and dorsomedial hypothalamus/perifornical region (DMH/PeF) are essential for the expression of the cardiorespiratory response to emotional stress. • Descending pathways from the DMH/PeF region to the brainstem and spinal cord subserve the cardiorespiratory response. • Other brain regions, including the medial prefrontal cortex and midbrain periaqueductal gray, also contribute to the cardiorespiratory response, via inputs to the amygdaloid complex and/or DMH/ PeF region. • Cognitive processing of the threatening stimulus occurs within the medial prefrontal cortex.
Many studies have focused on the brain mechanisms that mediate behavioral and neuroendocrine responses to emotional stress, as summarized in recent reviews.2e4 Less attention has been paid to the brain mechanisms subserving the autonomic and respiratory changes that accompany these behavioral and neuroendocrine responses. In this review I shall first describe the pattern of the evoked cardiovascular and respiratory responses that accompany active defensive behaviors. This will be followed by a description of the key brain regions that subserve these responses and the brain pathways and mechanisms that generate these responses.
PATTERN OF CARDIOVASCULAR AND RESPIRATORY RESPONSES ASSOCIATED WITH EMOTIONAL STRESS Brief alerting stimuli (e.g., a sudden noise) in animals evoke an immediate orienting response, typically characterized by cutaneous vasoconstriction and respiratory activation.5e8 Similarly, such stimuli in humans evoke an increase in cutaneous sympathetic and respiratory activity.9,10 There is usually little change in arterial pressure or blood flow to other vascular beds,8 but often biphasic changes in heart rate, due to coactivation of cardiac vagal and sympathetic nerves.11 If the stimulus is threatening and more prolonged, then in both humans and animals, a more complex cardiovascular response is generated, characterized by increases in arterial pressure, cardiac output and heart rate, vasoconstriction in renal and vascular beds, and usually vasodilation in skeletal muscle beds12e15 (Fig. 28.1). These cardiovascular effects are accompanied by increased respiratory activity.7,16 The fact that both arterial pressure and sympathetic activity increase during emotional stress has led some investigators to conclude that the baroreceptor-sympathetic reflex is inhibited during such stress (e.g., the study by Hilton17). It is
FIGURE 28.1 Changes (means standard error) in mean arterial pressure (MAP), heart rate (HR), forearm vascular conductance (FVC), renal vascular conductance (RVC), and mesenteric vascular conductance (MVC), during a 5-min period of mental stress (mental arithmetic) in normal subjects lying supine compared with the baseline values measured before the onset of the mental stress period. Data are taken from Kuipers NT, Sauder CL, Carter JR, Ray CA. Neurovascular responses to mental stress in the supine and upright postures. J Appl Physiol. 2008;104:1129e1136.
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KEY BRAIN REGIONS ACTIVATED BY EMOTIONAL STRESS
now clear, however, that the baroreceptorsympathetic reflex is reset during such stress, such that the operating range of arterial pressure for the reflex is increased to higher levels, without any decrease in gain of the reflex.18 In fact, baroreflex resetting is a feature of cardiovascular changes associated with many different behavioral states in addition to defensive stressevoked behavior (e.g., exercise or sleep).19 Following the removal of the threatening stimulus, there is a recovery period, in which cardiovascular and respiratory variables gradually return to normal.20,21 As explained in more detail in the following, this is not merely because of a reduction in the specific autonomic response to the threat but also involves an additional mechanism associated with the recovery process.
KEY BRAIN REGIONS ACTIVATED BY EMOTIONAL STRESS In response to acute emotional stress in rodents, many neurons at all levels of the brain are activated (Fig. 28.2), as indicated by c-Fos expression.4,22e24 Many of these regions, such as the amygdaloid complex, hypothalamic paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH), perifornical area (PeF), midbrain periaqueductal gray (PAG), pontine parabrachial complex, nucleus tractus solitarius
(NTS), and ventrolateral medulla (VLM) also contain neurons that regulate cardiovascular and respiratory function. In addition, neurons within the prefrontal cortex are critical for the perception of stimuli that generate emotional responses. Of course, studies using only c-Fos or other markers of neuronal activation cannot distinguish between neurons that mediate cardiorespiratory responses to stress, as opposed to behavioral or neuroendocrine responses to stress. Furthermore, they cannot identify neurons that are inhibited by stress and which may evoke cardiorespiratory responses via disinhibition of other brain regions. Nevertheless, when the results of such studies are considered together with the findings of other studies using different experimental approaches, it is clear that there are two regions in particular (the amygdaloid complex and the DMH/PeF region) that are essential for the expression if cardiorespiratory responses to emotional stimuli. In addition, other brain regions (including the medial prefrontal cortex and the midbrain PAG) also have important roles in integrating inputs from different sources that contribute to the cardiorespiratory changes associated with emotional stress. There are complex interconnections between the DMH/PeF region, amygdaloid complex, medial prefrontal cortex, and midbrain PAG. In discussing the central pathways that subserve
mPFC PAG PVN KF/PB
NTS
Amyg DMH/PeF
RVLM
RPa
FIGURE 28.2 Sagittal section of the rat brain showing location of main brain regions that are activated during emotional stress. Amyg, amygdaloid complex; DMH, dorsomedial hypothalamus; KF, Ko¨llikereFuse nucleus; mPFC, medial prefrontal cortex; NTS, nucleus tractus solitarius; PAG, periaqueductal gray; PB, parabrachial nucleus; PeF, perifornical region; PVN, paraventricular nucleus; RPa, nucleus pallidus.
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cardiorespiratory responses to emotional stress, however, it is most logical to begin with the DMH/PeF region since as explained in the following the functional properties as well as anatomical connections of this region indicate that it is likely to be the major source of the stress-evoked drive to cardiovascular and respiratory nuclei in the lower brainstem and spinal cord.
DMH/PeF Region Since the work of Hess and Bru¨gger in the 1940s,25 it has been known that the hypothalamus contains neurons that can generate both behavioral and autonomic changes associated with emotion. Smith and coworkers26,27 were the first to show that electrolytic or chemical lesions of neurons within the DMH/PeF region and extending into the lateral hypothalamus reduced the cardiovascular response evoked by emotional stress. More recent studies have shown that microinjections of the neuronal inhibitory compound muscimol into the DMH/ PeF region greatly reduce the pressor response, tachycardia, and increase in respiratory activity evoked by emotional stressors5,28e30 (Fig. 28.3).
In contrast, inhibition of neurons in the PVN had no effect on the stress-evoked cardiovascular effects but did block the neuroendocrine component of the response.29 Furthermore, blockade of NMDA receptors in the DMH/PeF region reduces the increases in arterial pressure, heart rate, and respiratory rate evoked by lactate infusion in a rat model of panic disorder, which is considered to be an extreme case of emotional stress.31 Disinhibition of neurons in the DMH/PeF region evokes a pattern of cardiovascular and respiratory changes, including resetting of the baroreceptor reflex, that are similar to responses naturally evoked by emotional stress.32e36 In addition, as mentioned previously, emotional stress evokes a marked increase in c-Fos expression in the DMH/PeF region.23,28 Thus, all these observations support the view that the DMH/ PeF region contains neurons that are essential for the generation of cardiorespiratory responses to emotional stress. The output pathways from DMH/PeF region that mediate the cardiovascular and respiratory responses associated with emotional stress are not clearly defined, except in the case of the descending pathways mediating stress-evoked
FIGURE 28.3 Changes (means standard error) from baseline in heart rate and mean arterial pressure evoked by a period of air jet stress in conscious rats after injections of saline (control) or muscimol into the DMH (left panels). Sagittal section of the hypothalamus showing location of muscimol injection sites in the DMH (right panel). DMH, dorsomedial hypothalamus; PH, posterior hypothalamus; PVN, paraventricular nucleus; VMH, ventromedial hypothalamus. Modified from Stotz-Potter EH, Morin SM, DiMicco JA. Effect of microinjection of muscimol into the dorsomedial or paraventricular hypothalamic nucleus on air stress-induced neuroendocrine and cardiovascular changes in rats. Brain Res. 1996;742:219e224 with permission.
KEY BRAIN REGIONS ACTIVATED BY EMOTIONAL STRESS
increases in heart rate, cutaneous vasoconstriction, and increases in the activity of sympathetic nerves innervating brown adipose tissue (BAT). The premotor neurons regulating the sympathetic outflow to the heart, cutaneous blood vessels, and BAT are located in the nuclei in the midline medulla (mainly the raphe pallidus)37 and receive direct inputs from the DMH/PeF region38,39 (Fig. 28.4). Emotional stress has been shown to activate the descending pathways from the DMH/PeF region to the midline raphe nuclei that mediate increases in the activity of sympathetic nerves regulating heart rate, cutaneous vasoconstriction, and BAT activity in conscious rats or rabbits.37,39e41 Much more limited information is available in regard to the output pathways from the DMH/ PeF that mediate stress-evoked increases in the activity of sympathetic nerves innervating vascular beds in the kidney and other vascular beds. In anesthetized rats, inhibition of neurons in the rostral ventrolateral medulla (RVLM)
FIGURE 28.4
Schematic diagram showing the input and output connections of the DMH/PeF region that subserve the cardiovascular and respiratory responses to emotional stress. The unbroken lines indicate known connections (which may be monosynaptic or polysynaptic), whereas the dashed lines indicate postulated connections that have not yet been defined. There are also other interconnections between the medial PFC, amygdala, and dlPAG (not shown) that contribute to the cardiorespiratory response to emotional stress.
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results in a reduction in the increase in renal sympathetic nerve activity (RSNA) evoked by activation of the DMH/PeF region.32,33 This led to the suggestion that the RVLM, which is an essential component of the central pathways subserving baroreceptor and other cardiovascular reflexes,19,42 may also mediate increases in sympathetic vasomotor activity evoked by emotional stress.4,33 There is, however, little evidence for this from studies in conscious rats. Neither unconditioned nor conditioned emotional stressors result in significant c-Fos expression in neurons within the RVLM sympathetic premotor region.22,23,43 RVLM sympathetic neurons are tonically active and maintain sympathetic vasomotor tone via their direct connections to the spinal sympathetic outflow.19,42 The fact that increases in sympathetic vasomotor activity evoked by activation of the DMH/PeF region are reduced after inhibition of the RVLM suggests that increases in the activity of renal and other sympathetic nerves evoked by emotional stress are dependent upon the maintenance of a tonic input from the RVLM to spinal sympathetic vasomotor neurons. In fact, RVLM neurons must contribute to the overall stress-evoked increase in sympathetic vasomotor activity since they are an essential component of the baroreceptor-sympathetic reflex, which as pointed out previously is reset during emotional stress (Fig. 28.4). There are strong direct projections from the DMH/PeF region to the PVN.44 The PVN is another major source of sympathetic premotor neurons,45 but it is not essential for stressevoked increases in sympathetic vasomotor activity since stress-evoked cardiovascular responses are not affected after inhibition of the PVN.29,30 It therefore follows that the output pathways from the DMH/PeF region to the sympathetic vasomotor outflow are independent of the PVN. There is some evidence, however, that the DMH/PeF region regulates sympathetic vasomotor activity via direct projections to the spinal cord. Although there are no spinal projections from the DMH itself, there is from the PeF area.43 Furthermore, there is a direct projection
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from the DMH to the PeF,44 so the DMH may activate spinally projecting neurons via that route. Importantly, neurons in the PeF are the only spinally projecting neurons that are activated during conditioned fear, which is a form of emotional stress.43 It is therefore possible that the PeF-spinal pathway also mediates the increased activity of the sympathetic outflow to the kidney and other visceral organs in response to unconditioned emotional stressors, as shown in Fig. 28.4. Consistent with the latter possibility, PeF neurons are activated by air puff stress, as are DMH neurons.23 PeF neurons may also mediate other components of the cardiorespiratory response to emotional stress. There is a direct projection from the PeF to lower brainstem regions containing respiratory neurons such as the Ko¨llikere Fuse nucleus,46 and in anesthetized rats, disinhibition of the PeF increases respiratory activity.34,47 In addition, disinhibition of the PeF also causes resetting of the baroreceptorsympathetic reflex,35 which mimics the baroreflex resetting that occurs during emotional stress in conscious rats.18 Thus, in summary, the available evidence is consistent with the hypothesis that, in response to emotional stress, the DMH/ PeF region increases sympathetic activity to the heart and cutaneous vascular bed via the midline medullary raphe and evoked increases in sympathetic activity to other vascular beds (e.g., the renal and splanchnic beds), as well as increased respiratory activity and baroreflex resetting via the PeF and downstream nuclei in the lower brainstem and spinal cord (Fig. 28.4). Neurons containing the peptide orexin (also known as hypocretin) are located within the DMH/PeF region, but no other brain region.46,48 Orexin-containing neurons are believed to have a role in the regulation of many physiological functions, including the cardiorespiratory response to stress.48 In particular, in transgenic mice in which either the orexin peptide or else neurons containing orexin were ablated, increases in blood pressure, heart rate, and locomotor activity evoked by emotional stress were reduced compared with wild-type control mice.49,50 Orexin-containing neurons have widespread projections to many sites in the brain,
including the NTS, PAG, RVLM, spinal cord, and respiratory nuclei in the lower brainstem,46 and so it is possible that these neurons directly mediate cardiorespiratory responses to emotional stress. An alternate possibility, however, is that orexin-containing neurons act as a gain controller, such that they can amplify inputs to other neurons mediating cardiorespiratory responses to stress. The latter possibility seems more likely, as such facilitation of synaptic transmission by orexin has been demonstrated at the cellular level.51 Apart from the outputs from the DMH/PeF region, an important question is what are the sources of inputs to the DMH that drive these stress-evoked responses? The DMH/PeF region receives many inputs, many of which arise from other hypothalamic nuclei. In fact, as pointed out by Thompson and Swanson,52 the DMH, in particular, is quite unique in that it receives inputs from virtually every other hypothalamic nucleus. In addition, the DMH/PeF region receives major inputs from the medial, basolateral, and central nuclei of the amygdala, the bed nucleus of the stria terminalis (BNST) and the medial prefrontal cortex.52e54 The projections from the medial prefrontal cortex arise predominantly from the caudal parts of the prelimbic and infralimbic cortices.54 In addition, there are inputs arising from brainstem nuclei, including the dorsolateral PAG in the midbrain and parabrachial nucleus in the pons.52,54 The functional significance of these different inputs will be considered in the following sections.
Amygdaloid Complex The amygdaloid complex, consisting of the lateral nucleus, the medial nucleus, the basolateral complex, and central nucleus, is the only brain region apart from the DMH/PeF region that is essential for the expression of physiological responses to emotional stimuli. Blanchard and Blanchard55 first showed in the early 1970s that the amygdaloid complex mediates behavioral responses to emotional stimuli, while more recent studies in rats and rabbits have demonstrated that the amygdaloid complex is also essential for the expression of both
KEY BRAIN REGIONS ACTIVATED BY EMOTIONAL STRESS
cardiovascular and respiratory responses to both brief arousing stimuli and more prolonged threatening stimuli.7,8,56e58 Inputs to the amygdaloid complex conveying auditory, visual, olfactory, gustatory and somatosensory information arise from many sources, including the thalamus, sensory cortex, olfactory bulb, and brainstem.59 Many of the afferent inputs conveying this information terminate in the lateral nucleus, which then connects with other amygdaloid nuclei via intrinsic connections.59 In addition, there are inputs to the basolateral complex and central nucleus from the medial prefrontal cortex, and to the basolateral complex from the hippocampus.59,60 Thus the amygdaloid complex receives a vast array of information relating to actual as well as perceived threats. Several lines of evidence suggest that neurons in the medial and basolateral amygdala, in particular, may mediate the cardiorespiratory response to emotional stress. First, neurons in these nuclei, but not other amygdaloid nuclei are activated by emotional stress.22,23 Second, both of these nuclei project to the DMH/PeF region, which as discussed above is also essential for the expression of cardiorespiratory responses to emotional stress. The pathways from medial and basolateral amygdala to the DMH/PeF region are both direct and indirect, via the BNST.52,53 Third, activation of neurons in the basolateral amygdala increases arterial pressure and respiratory activity via activation of neurons within the DMH.61 In contrast to the medial and basolateral nuclei, neurons in the central nucleus of the amygdala (CeA) are not activated in response to emotional stress.22,23 It should be noted, however, that the neurons in the CeA that innervate the PAG, RVLM, and NTS are mainly GABAergic,62e64 and it is therefore possible that the CeA neurons that project to the DMH/ PeF region are also GABAergic. If that were the case, then it is possible that CeA neurons could activate cardiorespiratory neurons within the DMH/PeF region by disinhibition. Consistent with this possibility, there is abundant evidence that cardiorespiratory neurons within the DMH/PeF region receive tonic GABAergic
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inputs.34,35 In addition, it is also possible that CeA neurons projecting to the brainstem may contribute to stress-evoked sympathoexcitation via disinhibition of brainstem sympathoexcitatory neurons. There do not appear to have been any studies that have directly tested this possibility, although it has been shown that lesions of the CeA do not affect the sympathetically mediated tachycardia evoked by emotional stress in the rat.65 At the same time, lesions of the CeA may contribute to the vagally mediated bradycardia that is associated with passive behavior during poststress recovery.66
Midbrain PAG The midbrain PAG, which consists of four longitudinal columns (the dorsomedial [dmPAG], dorsolateral [dlPAG], lateral [lPAG], and ventrolateral [vlPAG] columns), has long been recognized as a critical region in generating defensive behavioral responses. These four columns differ greatly with respect to their anatomical connections and chemical properties, and there is a large body of evidence which indicates that they also differ greatly with respect to their specific functional roles. In particular, the lPAG and dlPAG generate active behavioral responses, while the vlPAG appears to have an important role in generating passive behavioral responses (for reviews see Refs.1,67e71). Although the lPAG and dlPAG both generate active behavioral responses, there are major differences with respect to the types of stimuli that activate these two regions. The lPAG (but not the dlPAG) receives afferent inputs arising from somatic receptors and generates behavioral and autonomic responses to physical stressors such as cutaneous pain, via descending inputs to relay nuclei in the medulla oblongata.1 In contrast, the dlPAG is the only PAG region that receives direct inputs from the primary auditory cortex and secondary visual cortex, as well as inputs from the superior colliculus that also relay visual and auditory signals.72e74 In addition, the dlPAG receives inputs signaling predator odor via the amygdala and ventromedial hypothalamic nucleus.70 Thus, the dlPAG receives various inputs that can signal the presence of a
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predator, which is a strong emotional stress (Fig. 28.4). Consistent with this, cat odor (olfactory input only) or exposure to a cat (visual, olfactory, and auditory inputs) results in increased c-Fos expression in the dlPAG, but not to a significant extent in the lPAG and vlPAG.75e77 In addition, an anatomical study in the rat revealed strong projections to the dlPAG (but not other PAG subregions) arising from the medial prefrontal cortex, particularly the caudal parts of the prelimbic and infralimbic cortices and dorsal anterior cingulate cortex.54 It is interesting to note that these same regions of the medial prefrontal cortex also project to the DMH/PeF region,54 as noted previously. The possible function of these inputs from the medial prefrontal cortex will be considered in the following. In anesthetized rats, stimulation of the dlPAG, but not adjacent PAG subregions, results in a large increase in RSNA and respiratory activity,47 similar to cardiorespiratory responses evoked by activation of the DMH/PeF region.34,35 Furthermore, in anesthetized rats, these PAG-evoked responses are blocked by inhibition of the DMH/ PeF region,78 indicating that there is a functional pathway mediating cardiorespiratory responses from the dlPAG to the DMH/PeF region. Consistent with this, as mentioned previously, there is a direct projection from the dlPAG to the DMH/ PeF region.52,54 In addition, there are major projections from the dlPAG to the cuneiform nucleus in the midbrain and superior lateral parabrachial nucleus in the pons,79,80 both of which project to hypothalamic nuclei including the DMH/PeF region.81e83 In conscious rats subjected to emotional stressors (e.g., cat odor or novelty stress), however, inhibition or lesions of the dlPAG block the behavioral response but only partly attenuate the stress-evoked cardiovascular and respiratory responses.6,84 Thus, in contrast to the DMH/PeF and the amygdaloid complex, the dlPAG is not essential for the expression of cardiorespiratory responses to emotional stress. During emotional stress, the vlPAG is also activated.23,69 Based on their observations of the effects of selective inhibition of the vlPAG
on the cardiovascular and behavioral responses to contextual fear and during poststress recovery, Walker and Carrive21 proposed that activation of neurons in the vlPAG causes immobility, as well as enhancing the recovery of arterial pressure and heart rate back to normal levels. Consistent with this interpretation, Tovote et al.64 have identified a direct descending pathway from the CeA to the vlPAG which, when activated, produces immobility. Furthermore, Furlong et al.23 found that vlPAG neurons projecting to the NTS are activated during emotional stress and could thus mediate the decrease in arterial pressure and heart rate, via resetting of the baroreceptor reflex.
Medial Prefrontal Cortex As described previously, there are major inputs to both the DMH/PeF region and dlPAG from neurons within the medial prefrontal cortex, particularly the caudal parts of the PL and IL cortices54 (Fig. 28.4). In addition, the prelimbic cortex projects to the basolateral nucleus of the amygdala.60 Thus, these anatomical connections allow the medial prefrontal cortex to initiate or modulate physiological responses to emotional stress. The role of the prelimbic and infralimbic cortices in regulating cardiorespiratory responses to emotional stress has been studied to only a limited extent. Bondarenko et al.85 found that inhibition of the prelimbic cortex inhibited the respiratory activation evoked by an emotional stressor but not that evoked by a brief arousing stimulus. In humans, Critchley et al.86 found that activity in the dorsal anterior cingulate cortex (homologous to the prelimbic cortex in rats) was correlated with increases in blood pressure during periods of psychological stress. In a further study, Critchley et al.87 found that in patients with cortical lesions that included the dorsal anterior cingulate cortex, cardiovascular responses to an emotional stressor were reduced compared with a control group, even though their cognitive abilities were not impaired. Thus, taking all these observations together, the available evidence suggests that the prelimbic cortex (or dorsal anterior cingulate
REFERENCES
cortex) does facilitate the cardiovascular and respiratory responses induced by emotional stress. The infralimbic cortex appears to have a different role, although again information is limited. A study in the rat showed that inhibition of the infralimbic cortex had no effect on the cardiovascular response to emotional stress, but activation of this region attenuated the response.88 Thus it appears that the infralimbic cortex contains neurons that can inhibit stress-evoked responses, although such neurons do not appear to be active under resting conditions.
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stimulus, whereas lesions of the PAG had the opposite effect. Emotional stress must involve the medial prefrontal cortex, and yet lesions of the medial prefrontal cortex do not appear to abolish cardiorespiratory responses to stimuli that have an emotional content. It this appears that such responses can be generated by subcortical pathways, as is the case for behavioral responses,59 while the function of inputs from the medial prefrontal cortex is to modify the responses to match the behavioral response, as a consequence of cognitive processing of all relevant information about the nature of the particular threat.
SUMMARY AND CONCLUSIONS The DMH/PeF region and amygdaloid complex are the only brain regions that are essential for the full expression of cardiovascular and respiratory responses to emotional stress. The DMH/PeF region, however, is downstream to the amygdaloid complex and is the major source of descending pathways to the brainstem and spinal cord that in turn generate increases in respiratory activity, heart rate, cutaneous and visceral vasoconstriction, increase in BAT activity, and baroreflex resetting. The pathways subserving these effects are illustrated in simplified form in Fig. 28.4. In addition, as described previously, there are also interconnections between the medial prefrontal cortex, amygdala, and PAG (not shown in Fig. 28.4) that also contribute to the generation of the cardiorespiratory responses. Although this review has focused on the stress-evoked cardiorespiratory responses, it should be emphasized that these responses essentially support the stress-evoked behavioral responses, together with neuroendocrine effects. A key question, therefore, is how all these components are integrated to produce an overall response that is appropriate for a particular threatening stimulus? It is clear that, at least at the level of the hypothalamus and midbrain, behavioral, and cardiorespiratory responses are generated by different groups of neurons. For example, LeDoux et al.89 found that lesions of the DMH/PeF region affected the cardiovascular but not behavioral response to an emotional
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25. Hess WR, Bru¨gger M. Das subkortikale Zentrum der affektiven Abwehrreaktion. Helv Physiol Pharmacol Acta. 1943;1:33e52. 26. Smith OA, Astley CA, DeVito JL, Stein JM, Walsh KE. Functional analysis of hypothalamic control of the cardiovascular responses accompanying emotional behavior. Fed Proc. 1980;39:2487e2494. 27. Smith OA, DeVito JL, Astley CA. Neurons controlling cardiovascular responses to emotion are located in lateral hypothalamus-perifornical region. Am J Physiol Regul Integr Comp Physiol. 1990;259:R943eR954. 28. McDougall SJ, Widdop RE, Lawrence AJ. Medial prefrontal cortical integration of psychological stress in rats. Eur J Neurosci. 2004;20:2430e2440. 29. Stotz-Potter EH, Morin SM, DiMicco JA. Effect of microinjection of muscimol into the dorsomedial or paraventricular hypothalamic nucleus on air stress-induced neuroendocrine and cardiovascular changes in rats. Brain Res. 1996;742:219e224. 30. Stotz-Potter EH, Willis LR, DiMicco JA. Muscimol acts in dorsomedial and not paraventricular hypothalamic nucleus to suppress cardiovascular effects of stress. J Neurosci. 1996;16:1173e1179. 31. Johnson PL, Shekhar A. Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors. J Neurosci. 2006;26:7093e7104. 32. Cao WH, Fan W, Morrison SF. Medullary pathways mediating specific sympathetic responses to activation of dorsomedial hypothalamus. Neuroscience. 2004;126: 229e240. 33. Fontes MAP, Tagawa T, Polson JW, Cavanagh SJ, Dampney RAL. Descending pathways mediating cardiovascular response from dorsomedial hypothalamic nucleus. Am J Physiol Heart Circ Physiol. 2001;280: H2891eH2901. 34. McDowall LM, Horiuchi J, Dampney RAL. Effects of disinhibition of neurons in the dorsomedial hypothalamus on central respiratory drive. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1728eR1735. 35. McDowall LM, Horiuchi J, Killinger S, Dampney RAL. Modulation of the baroreceptor reflex by the dorsomedial hypothalamic nucleus and perifornical area. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1020eR1026. 36. Tanaka M, McAllen RM. Functional topography of the dorsomedial hypothalamus. Am J Physiol Regul Integr Comp Physiol. 2008;294:R477eR486. 37. Morrison SF. Carl Ludwig distinguished lectureship of the APS neural control and autonomic regulation section: central neural pathways for thermoregulatory cold defense. J Appl Physiol. 2010;110:1137e1149. 38. Samuels BC, Zaretsky DV, DiMicco JA. Dorsomedial hypothalamic sites where disinhibition evokes tachycardia correlate with location of raphe-projecting neurons. Am J Physiol Regul Integr Comp Physiol. 2004;287(2):R472eR478. 39. Sarkar S, Zaretskaia MV, Zaretsky DV, Moreno M, DiMicco JA. Stress- and lipopolysaccharide-induced c-
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69. Carrive P. The periaqueductal gray and defensive behavior: functional representation and neuronal organization. Behav Brain Res. 1993;58:27e47. 70. Dampney RAL, Furlong T, Horiuchi J, Iigaya K. Role of dorsolateral periaqueductal grey in the coordinated regulation of cardiovascular and respiratory function. Auton Neurosci. 2013;175:17e25. 71. Vianna DM, Brandao ML. Anatomical connections of the periaqueductal gray: specific neural substrates for different kinds of fear. Braz J Med Biol Res. 2003;36:557e566. 72. Benzinger H, Massopust LC. Brain stem projections from cortical area 18 in the albino rat. Exp Brain Res. 1983;50:1e8. 73. Newman DB, Hileary SK, Ginsberg CY. Nuclear terminations of corticonuclear fiber systems in rats. Brain Behav Evol. 1989;34:223e264. 74. Rhoades RW, Mooney RD, Rohrer WH, Nikoletseas MM, Fish SE. Organization of the projection from the superficial to the deep layers of the hamster’s superior colliculus as demonstrated by the anterograde transport of Phaseolus vulgaris leucoagglutinin. J Comp Neurol. 1989;283: 54e70. 75. Canteras NS, Goto M. Fos-like immunoreactivity in the periaqueductal gray of rats exposed to a natural predator. Neuroreport. 1999;10:413e418. 76. Dielenberg RA, Hunt GE, McGregor IS. “When a rat smells a cat”: the distribution of Fos immunoreactivity in rat brain following exposure to a predatory odor. Neuroscience. 2001;104:1085e1097. 77. Motta SC, Goto M, Gouveia FV, Baldo MV, Canteras NS, Swanson LW. Dissecting the brain’s fear system reveals the hypothalamus is critical for responding in subordinate conspecific intruders. Proc Natl Acad Sci. 2009;106: 4870e4875. 78. Horiuchi J, McDowall LM, Dampney RAL. Vasomotor and respiratory responses evoked from the dorsolateral periaqueductal grey are mediated by the dorsomedial hypothalamus. J Physiol. 2009;587:5149e5162. 79. Krout KE, Jansen AS, Loewy AD. Periaqueductal gray matter projection to the parabrachial nucleus in rat. J Comp Neurol. 1998;401:437e454.
80. Redgrave P, Dean P, Mitchell IJ, Odekunle A, Clark A. The projection from superior colliculus to cuneiform area in the rat I. Anatomical studies. Exp Brain Res. 1988;72:611e625. 81. Bester H, Besson JM, Bernard JF. Organization of efferent projections from the parabrachial area to the hypothalamus: a Phaseolus vulgaris-leucoagglutinin study in the rat. J Comp Neurol. 1997;383:245e281. 82. Fulwiler CE, Saper CB. Subnuclear organization of the efferent connections of the parahrachial nucleus in the rat. Brain Res Rev. 1984;7:229e259. 83. Korte SM, Jaarsma D, Luiten PG, Bohus B. Mesencephalic cuneiform nucleus and its ascending and descending projections serve stress-related cardiovascular responses in the rat. J Auton Nerv Syst. 1992;41: 157e176. 84. Dielenberg RA, Leman S, Carrive P. Effect of dorsal periaqueductal gray lesions on cardiovascular and behavioral responses to car odor exposure in rats. Behav Brain Res. 2004;153:487e496. 85. Bondarenko E, Hodgson DM, Nalivaiko E. Prelimbic prefrontal cortex mediates respiratory responses to mild and potent prolonged, but not brief, stressors. Resp Physiol Neurobiol. 2014;204:21e27. 86. Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation. J Physiol. 2000;523:259e270. 87. Critchley HD, Josephs O, O’Doherty J, et al. Human cingulate cortex and autonomic cardiovascular control: converging neuroimaging and clinical evidence. Brain. 2003;216:2139e2156. 88. Mu¨ller-Ribeiro FC, Zaretsky DV, Zaretskaia MV, Santos RA, DiMicco JA, Fontes MA. Contribution of infralimbic cortex in the cardiovascular response to acute stress. Am J Physiol Regul Integr Comp Physiol. 2012;303(6):R639eR650. 89. LeDoux JE, Iwata J, Cicchetti P, Reis DJ. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J Neurosci. 1988;8(7):2517e2529.
28 Central Mechanisms Generating Cardiovascular and Respiratory Responses to Emotional Stress R.A.L. Dampney School of Medical Sciences (Physiology) and Bosch Institute, University of Sydney, Camperdown, NSW, Australia
O U T L I N E Introduction
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Summary and Conclusions
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Pattern of Cardiovascular and Respiratory Responses Associated With Emotional Stress 392 Key Brain Regions Activated by Emotional Stress DMH/PeF Region
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INTRODUCTION Animals, including humans, have evolved different types of stereotyped defensive behaviors that are triggered by real or perceived threatening stimuli in their external environments. These stimuli may be either unconditioned (i.e., stimuli that are innately threatening, such as the sight, sound, or odor of a predator) or conditioned (i.e., stimuli that are normally innocuous but which are perceived as threatening because of past experience). These stimuli can be referred to collectively as emotional stressors. In general,
Stress: Physiology, Biochemistry, and Pathology https://doi.org/10.1016/B978-0-12-813146-6.00028-X
the behavioral responses to emotional stressors can be classified as either active or passive. Active responses are usually evoked if the threat is escapable (e.g., presence of a predator or conspecific), while passive responses are usually evoked if the threat is inescapable (such as deep pain). Active responses are characterized by increased somatomotor activity, increased vigilance, and hyperreactivity, while passive responses are characterized by reduced somatomotor activity, decreased vigilance, and hyporeactivity.1 Each of these patterns of behavioral responses is accompanied by autonomic
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Copyright © 2019 Elsevier Inc. All rights reserved.
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and respiratory changes that support the particular behavior.
KEY POINTS • Emotional stress is triggered by real or perceived external threats. • This stress triggers defensive behavioral responses accompanied by appropriate neuroendocrine, autonomic, and respiratory responses. • Different pathways in the brain subserve different components of the response. • The amygdaloid complex and dorsomedial hypothalamus/perifornical region (DMH/PeF) are essential for the expression of the cardiorespiratory response to emotional stress. • Descending pathways from the DMH/PeF region to the brainstem and spinal cord subserve the cardiorespiratory response. • Other brain regions, including the medial prefrontal cortex and midbrain periaqueductal gray, also contribute to the cardiorespiratory response, via inputs to the amygdaloid complex and/or DMH/ PeF region. • Cognitive processing of the threatening stimulus occurs within the medial prefrontal cortex.
Many studies have focused on the brain mechanisms that mediate behavioral and neuroendocrine responses to emotional stress, as summarized in recent reviews.2e4 Less attention has been paid to the brain mechanisms subserving the autonomic and respiratory changes that accompany these behavioral and neuroendocrine responses. In this review I shall first describe the pattern of the evoked cardiovascular and respiratory responses that accompany active defensive behaviors. This will be followed by a description of the key brain regions that subserve these responses and the brain pathways and mechanisms that generate these responses.
PATTERN OF CARDIOVASCULAR AND RESPIRATORY RESPONSES ASSOCIATED WITH EMOTIONAL STRESS Brief alerting stimuli (e.g., a sudden noise) in animals evoke an immediate orienting response, typically characterized by cutaneous vasoconstriction and respiratory activation.5e8 Similarly, such stimuli in humans evoke an increase in cutaneous sympathetic and respiratory activity.9,10 There is usually little change in arterial pressure or blood flow to other vascular beds,8 but often biphasic changes in heart rate, due to coactivation of cardiac vagal and sympathetic nerves.11 If the stimulus is threatening and more prolonged, then in both humans and animals, a more complex cardiovascular response is generated, characterized by increases in arterial pressure, cardiac output and heart rate, vasoconstriction in renal and vascular beds, and usually vasodilation in skeletal muscle beds12e15 (Fig. 28.1). These cardiovascular effects are accompanied by increased respiratory activity.7,16 The fact that both arterial pressure and sympathetic activity increase during emotional stress has led some investigators to conclude that the baroreceptor-sympathetic reflex is inhibited during such stress (e.g., the study by Hilton17). It is
FIGURE 28.1 Changes (means standard error) in mean arterial pressure (MAP), heart rate (HR), forearm vascular conductance (FVC), renal vascular conductance (RVC), and mesenteric vascular conductance (MVC), during a 5-min period of mental stress (mental arithmetic) in normal subjects lying supine compared with the baseline values measured before the onset of the mental stress period. Data are taken from Kuipers NT, Sauder CL, Carter JR, Ray CA. Neurovascular responses to mental stress in the supine and upright postures. J Appl Physiol. 2008;104:1129e1136.
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KEY BRAIN REGIONS ACTIVATED BY EMOTIONAL STRESS
now clear, however, that the baroreceptorsympathetic reflex is reset during such stress, such that the operating range of arterial pressure for the reflex is increased to higher levels, without any decrease in gain of the reflex.18 In fact, baroreflex resetting is a feature of cardiovascular changes associated with many different behavioral states in addition to defensive stressevoked behavior (e.g., exercise or sleep).19 Following the removal of the threatening stimulus, there is a recovery period, in which cardiovascular and respiratory variables gradually return to normal.20,21 As explained in more detail in the following, this is not merely because of a reduction in the specific autonomic response to the threat but also involves an additional mechanism associated with the recovery process.
KEY BRAIN REGIONS ACTIVATED BY EMOTIONAL STRESS In response to acute emotional stress in rodents, many neurons at all levels of the brain are activated (Fig. 28.2), as indicated by c-Fos expression.4,22e24 Many of these regions, such as the amygdaloid complex, hypothalamic paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH), perifornical area (PeF), midbrain periaqueductal gray (PAG), pontine parabrachial complex, nucleus tractus solitarius
(NTS), and ventrolateral medulla (VLM) also contain neurons that regulate cardiovascular and respiratory function. In addition, neurons within the prefrontal cortex are critical for the perception of stimuli that generate emotional responses. Of course, studies using only c-Fos or other markers of neuronal activation cannot distinguish between neurons that mediate cardiorespiratory responses to stress, as opposed to behavioral or neuroendocrine responses to stress. Furthermore, they cannot identify neurons that are inhibited by stress and which may evoke cardiorespiratory responses via disinhibition of other brain regions. Nevertheless, when the results of such studies are considered together with the findings of other studies using different experimental approaches, it is clear that there are two regions in particular (the amygdaloid complex and the DMH/PeF region) that are essential for the expression if cardiorespiratory responses to emotional stimuli. In addition, other brain regions (including the medial prefrontal cortex and the midbrain PAG) also have important roles in integrating inputs from different sources that contribute to the cardiorespiratory changes associated with emotional stress. There are complex interconnections between the DMH/PeF region, amygdaloid complex, medial prefrontal cortex, and midbrain PAG. In discussing the central pathways that subserve
mPFC PAG PVN KF/PB
NTS
Amyg DMH/PeF
RVLM
RPa
FIGURE 28.2 Sagittal section of the rat brain showing location of main brain regions that are activated during emotional stress. Amyg, amygdaloid complex; DMH, dorsomedial hypothalamus; KF, Ko¨llikereFuse nucleus; mPFC, medial prefrontal cortex; NTS, nucleus tractus solitarius; PAG, periaqueductal gray; PB, parabrachial nucleus; PeF, perifornical region; PVN, paraventricular nucleus; RPa, nucleus pallidus.
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cardiorespiratory responses to emotional stress, however, it is most logical to begin with the DMH/PeF region since as explained in the following the functional properties as well as anatomical connections of this region indicate that it is likely to be the major source of the stress-evoked drive to cardiovascular and respiratory nuclei in the lower brainstem and spinal cord.
DMH/PeF Region Since the work of Hess and Bru¨gger in the 1940s,25 it has been known that the hypothalamus contains neurons that can generate both behavioral and autonomic changes associated with emotion. Smith and coworkers26,27 were the first to show that electrolytic or chemical lesions of neurons within the DMH/PeF region and extending into the lateral hypothalamus reduced the cardiovascular response evoked by emotional stress. More recent studies have shown that microinjections of the neuronal inhibitory compound muscimol into the DMH/ PeF region greatly reduce the pressor response, tachycardia, and increase in respiratory activity evoked by emotional stressors5,28e30 (Fig. 28.3).
In contrast, inhibition of neurons in the PVN had no effect on the stress-evoked cardiovascular effects but did block the neuroendocrine component of the response.29 Furthermore, blockade of NMDA receptors in the DMH/PeF region reduces the increases in arterial pressure, heart rate, and respiratory rate evoked by lactate infusion in a rat model of panic disorder, which is considered to be an extreme case of emotional stress.31 Disinhibition of neurons in the DMH/PeF region evokes a pattern of cardiovascular and respiratory changes, including resetting of the baroreceptor reflex, that are similar to responses naturally evoked by emotional stress.32e36 In addition, as mentioned previously, emotional stress evokes a marked increase in c-Fos expression in the DMH/PeF region.23,28 Thus, all these observations support the view that the DMH/ PeF region contains neurons that are essential for the generation of cardiorespiratory responses to emotional stress. The output pathways from DMH/PeF region that mediate the cardiovascular and respiratory responses associated with emotional stress are not clearly defined, except in the case of the descending pathways mediating stress-evoked
FIGURE 28.3 Changes (means standard error) from baseline in heart rate and mean arterial pressure evoked by a period of air jet stress in conscious rats after injections of saline (control) or muscimol into the DMH (left panels). Sagittal section of the hypothalamus showing location of muscimol injection sites in the DMH (right panel). DMH, dorsomedial hypothalamus; PH, posterior hypothalamus; PVN, paraventricular nucleus; VMH, ventromedial hypothalamus. Modified from Stotz-Potter EH, Morin SM, DiMicco JA. Effect of microinjection of muscimol into the dorsomedial or paraventricular hypothalamic nucleus on air stress-induced neuroendocrine and cardiovascular changes in rats. Brain Res. 1996;742:219e224 with permission.
KEY BRAIN REGIONS ACTIVATED BY EMOTIONAL STRESS
increases in heart rate, cutaneous vasoconstriction, and increases in the activity of sympathetic nerves innervating brown adipose tissue (BAT). The premotor neurons regulating the sympathetic outflow to the heart, cutaneous blood vessels, and BAT are located in the nuclei in the midline medulla (mainly the raphe pallidus)37 and receive direct inputs from the DMH/PeF region38,39 (Fig. 28.4). Emotional stress has been shown to activate the descending pathways from the DMH/PeF region to the midline raphe nuclei that mediate increases in the activity of sympathetic nerves regulating heart rate, cutaneous vasoconstriction, and BAT activity in conscious rats or rabbits.37,39e41 Much more limited information is available in regard to the output pathways from the DMH/ PeF that mediate stress-evoked increases in the activity of sympathetic nerves innervating vascular beds in the kidney and other vascular beds. In anesthetized rats, inhibition of neurons in the rostral ventrolateral medulla (RVLM)
FIGURE 28.4
Schematic diagram showing the input and output connections of the DMH/PeF region that subserve the cardiovascular and respiratory responses to emotional stress. The unbroken lines indicate known connections (which may be monosynaptic or polysynaptic), whereas the dashed lines indicate postulated connections that have not yet been defined. There are also other interconnections between the medial PFC, amygdala, and dlPAG (not shown) that contribute to the cardiorespiratory response to emotional stress.
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results in a reduction in the increase in renal sympathetic nerve activity (RSNA) evoked by activation of the DMH/PeF region.32,33 This led to the suggestion that the RVLM, which is an essential component of the central pathways subserving baroreceptor and other cardiovascular reflexes,19,42 may also mediate increases in sympathetic vasomotor activity evoked by emotional stress.4,33 There is, however, little evidence for this from studies in conscious rats. Neither unconditioned nor conditioned emotional stressors result in significant c-Fos expression in neurons within the RVLM sympathetic premotor region.22,23,43 RVLM sympathetic neurons are tonically active and maintain sympathetic vasomotor tone via their direct connections to the spinal sympathetic outflow.19,42 The fact that increases in sympathetic vasomotor activity evoked by activation of the DMH/PeF region are reduced after inhibition of the RVLM suggests that increases in the activity of renal and other sympathetic nerves evoked by emotional stress are dependent upon the maintenance of a tonic input from the RVLM to spinal sympathetic vasomotor neurons. In fact, RVLM neurons must contribute to the overall stress-evoked increase in sympathetic vasomotor activity since they are an essential component of the baroreceptor-sympathetic reflex, which as pointed out previously is reset during emotional stress (Fig. 28.4). There are strong direct projections from the DMH/PeF region to the PVN.44 The PVN is another major source of sympathetic premotor neurons,45 but it is not essential for stressevoked increases in sympathetic vasomotor activity since stress-evoked cardiovascular responses are not affected after inhibition of the PVN.29,30 It therefore follows that the output pathways from the DMH/PeF region to the sympathetic vasomotor outflow are independent of the PVN. There is some evidence, however, that the DMH/PeF region regulates sympathetic vasomotor activity via direct projections to the spinal cord. Although there are no spinal projections from the DMH itself, there is from the PeF area.43 Furthermore, there is a direct projection
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from the DMH to the PeF,44 so the DMH may activate spinally projecting neurons via that route. Importantly, neurons in the PeF are the only spinally projecting neurons that are activated during conditioned fear, which is a form of emotional stress.43 It is therefore possible that the PeF-spinal pathway also mediates the increased activity of the sympathetic outflow to the kidney and other visceral organs in response to unconditioned emotional stressors, as shown in Fig. 28.4. Consistent with the latter possibility, PeF neurons are activated by air puff stress, as are DMH neurons.23 PeF neurons may also mediate other components of the cardiorespiratory response to emotional stress. There is a direct projection from the PeF to lower brainstem regions containing respiratory neurons such as the Ko¨llikere Fuse nucleus,46 and in anesthetized rats, disinhibition of the PeF increases respiratory activity.34,47 In addition, disinhibition of the PeF also causes resetting of the baroreceptorsympathetic reflex,35 which mimics the baroreflex resetting that occurs during emotional stress in conscious rats.18 Thus, in summary, the available evidence is consistent with the hypothesis that, in response to emotional stress, the DMH/ PeF region increases sympathetic activity to the heart and cutaneous vascular bed via the midline medullary raphe and evoked increases in sympathetic activity to other vascular beds (e.g., the renal and splanchnic beds), as well as increased respiratory activity and baroreflex resetting via the PeF and downstream nuclei in the lower brainstem and spinal cord (Fig. 28.4). Neurons containing the peptide orexin (also known as hypocretin) are located within the DMH/PeF region, but no other brain region.46,48 Orexin-containing neurons are believed to have a role in the regulation of many physiological functions, including the cardiorespiratory response to stress.48 In particular, in transgenic mice in which either the orexin peptide or else neurons containing orexin were ablated, increases in blood pressure, heart rate, and locomotor activity evoked by emotional stress were reduced compared with wild-type control mice.49,50 Orexin-containing neurons have widespread projections to many sites in the brain,
including the NTS, PAG, RVLM, spinal cord, and respiratory nuclei in the lower brainstem,46 and so it is possible that these neurons directly mediate cardiorespiratory responses to emotional stress. An alternate possibility, however, is that orexin-containing neurons act as a gain controller, such that they can amplify inputs to other neurons mediating cardiorespiratory responses to stress. The latter possibility seems more likely, as such facilitation of synaptic transmission by orexin has been demonstrated at the cellular level.51 Apart from the outputs from the DMH/PeF region, an important question is what are the sources of inputs to the DMH that drive these stress-evoked responses? The DMH/PeF region receives many inputs, many of which arise from other hypothalamic nuclei. In fact, as pointed out by Thompson and Swanson,52 the DMH, in particular, is quite unique in that it receives inputs from virtually every other hypothalamic nucleus. In addition, the DMH/PeF region receives major inputs from the medial, basolateral, and central nuclei of the amygdala, the bed nucleus of the stria terminalis (BNST) and the medial prefrontal cortex.52e54 The projections from the medial prefrontal cortex arise predominantly from the caudal parts of the prelimbic and infralimbic cortices.54 In addition, there are inputs arising from brainstem nuclei, including the dorsolateral PAG in the midbrain and parabrachial nucleus in the pons.52,54 The functional significance of these different inputs will be considered in the following sections.
Amygdaloid Complex The amygdaloid complex, consisting of the lateral nucleus, the medial nucleus, the basolateral complex, and central nucleus, is the only brain region apart from the DMH/PeF region that is essential for the expression of physiological responses to emotional stimuli. Blanchard and Blanchard55 first showed in the early 1970s that the amygdaloid complex mediates behavioral responses to emotional stimuli, while more recent studies in rats and rabbits have demonstrated that the amygdaloid complex is also essential for the expression of both
KEY BRAIN REGIONS ACTIVATED BY EMOTIONAL STRESS
cardiovascular and respiratory responses to both brief arousing stimuli and more prolonged threatening stimuli.7,8,56e58 Inputs to the amygdaloid complex conveying auditory, visual, olfactory, gustatory and somatosensory information arise from many sources, including the thalamus, sensory cortex, olfactory bulb, and brainstem.59 Many of the afferent inputs conveying this information terminate in the lateral nucleus, which then connects with other amygdaloid nuclei via intrinsic connections.59 In addition, there are inputs to the basolateral complex and central nucleus from the medial prefrontal cortex, and to the basolateral complex from the hippocampus.59,60 Thus the amygdaloid complex receives a vast array of information relating to actual as well as perceived threats. Several lines of evidence suggest that neurons in the medial and basolateral amygdala, in particular, may mediate the cardiorespiratory response to emotional stress. First, neurons in these nuclei, but not other amygdaloid nuclei are activated by emotional stress.22,23 Second, both of these nuclei project to the DMH/PeF region, which as discussed above is also essential for the expression of cardiorespiratory responses to emotional stress. The pathways from medial and basolateral amygdala to the DMH/PeF region are both direct and indirect, via the BNST.52,53 Third, activation of neurons in the basolateral amygdala increases arterial pressure and respiratory activity via activation of neurons within the DMH.61 In contrast to the medial and basolateral nuclei, neurons in the central nucleus of the amygdala (CeA) are not activated in response to emotional stress.22,23 It should be noted, however, that the neurons in the CeA that innervate the PAG, RVLM, and NTS are mainly GABAergic,62e64 and it is therefore possible that the CeA neurons that project to the DMH/ PeF region are also GABAergic. If that were the case, then it is possible that CeA neurons could activate cardiorespiratory neurons within the DMH/PeF region by disinhibition. Consistent with this possibility, there is abundant evidence that cardiorespiratory neurons within the DMH/PeF region receive tonic GABAergic
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inputs.34,35 In addition, it is also possible that CeA neurons projecting to the brainstem may contribute to stress-evoked sympathoexcitation via disinhibition of brainstem sympathoexcitatory neurons. There do not appear to have been any studies that have directly tested this possibility, although it has been shown that lesions of the CeA do not affect the sympathetically mediated tachycardia evoked by emotional stress in the rat.65 At the same time, lesions of the CeA may contribute to the vagally mediated bradycardia that is associated with passive behavior during poststress recovery.66
Midbrain PAG The midbrain PAG, which consists of four longitudinal columns (the dorsomedial [dmPAG], dorsolateral [dlPAG], lateral [lPAG], and ventrolateral [vlPAG] columns), has long been recognized as a critical region in generating defensive behavioral responses. These four columns differ greatly with respect to their anatomical connections and chemical properties, and there is a large body of evidence which indicates that they also differ greatly with respect to their specific functional roles. In particular, the lPAG and dlPAG generate active behavioral responses, while the vlPAG appears to have an important role in generating passive behavioral responses (for reviews see Refs.1,67e71). Although the lPAG and dlPAG both generate active behavioral responses, there are major differences with respect to the types of stimuli that activate these two regions. The lPAG (but not the dlPAG) receives afferent inputs arising from somatic receptors and generates behavioral and autonomic responses to physical stressors such as cutaneous pain, via descending inputs to relay nuclei in the medulla oblongata.1 In contrast, the dlPAG is the only PAG region that receives direct inputs from the primary auditory cortex and secondary visual cortex, as well as inputs from the superior colliculus that also relay visual and auditory signals.72e74 In addition, the dlPAG receives inputs signaling predator odor via the amygdala and ventromedial hypothalamic nucleus.70 Thus, the dlPAG receives various inputs that can signal the presence of a
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28. CENTRAL MECHANISMS GENERATING CARDIOVASCULAR AND RESPIRATORY RESPONSES TO EMOTIONAL STRESS
predator, which is a strong emotional stress (Fig. 28.4). Consistent with this, cat odor (olfactory input only) or exposure to a cat (visual, olfactory, and auditory inputs) results in increased c-Fos expression in the dlPAG, but not to a significant extent in the lPAG and vlPAG.75e77 In addition, an anatomical study in the rat revealed strong projections to the dlPAG (but not other PAG subregions) arising from the medial prefrontal cortex, particularly the caudal parts of the prelimbic and infralimbic cortices and dorsal anterior cingulate cortex.54 It is interesting to note that these same regions of the medial prefrontal cortex also project to the DMH/PeF region,54 as noted previously. The possible function of these inputs from the medial prefrontal cortex will be considered in the following. In anesthetized rats, stimulation of the dlPAG, but not adjacent PAG subregions, results in a large increase in RSNA and respiratory activity,47 similar to cardiorespiratory responses evoked by activation of the DMH/PeF region.34,35 Furthermore, in anesthetized rats, these PAG-evoked responses are blocked by inhibition of the DMH/ PeF region,78 indicating that there is a functional pathway mediating cardiorespiratory responses from the dlPAG to the DMH/PeF region. Consistent with this, as mentioned previously, there is a direct projection from the dlPAG to the DMH/ PeF region.52,54 In addition, there are major projections from the dlPAG to the cuneiform nucleus in the midbrain and superior lateral parabrachial nucleus in the pons,79,80 both of which project to hypothalamic nuclei including the DMH/PeF region.81e83 In conscious rats subjected to emotional stressors (e.g., cat odor or novelty stress), however, inhibition or lesions of the dlPAG block the behavioral response but only partly attenuate the stress-evoked cardiovascular and respiratory responses.6,84 Thus, in contrast to the DMH/PeF and the amygdaloid complex, the dlPAG is not essential for the expression of cardiorespiratory responses to emotional stress. During emotional stress, the vlPAG is also activated.23,69 Based on their observations of the effects of selective inhibition of the vlPAG
on the cardiovascular and behavioral responses to contextual fear and during poststress recovery, Walker and Carrive21 proposed that activation of neurons in the vlPAG causes immobility, as well as enhancing the recovery of arterial pressure and heart rate back to normal levels. Consistent with this interpretation, Tovote et al.64 have identified a direct descending pathway from the CeA to the vlPAG which, when activated, produces immobility. Furthermore, Furlong et al.23 found that vlPAG neurons projecting to the NTS are activated during emotional stress and could thus mediate the decrease in arterial pressure and heart rate, via resetting of the baroreceptor reflex.
Medial Prefrontal Cortex As described previously, there are major inputs to both the DMH/PeF region and dlPAG from neurons within the medial prefrontal cortex, particularly the caudal parts of the PL and IL cortices54 (Fig. 28.4). In addition, the prelimbic cortex projects to the basolateral nucleus of the amygdala.60 Thus, these anatomical connections allow the medial prefrontal cortex to initiate or modulate physiological responses to emotional stress. The role of the prelimbic and infralimbic cortices in regulating cardiorespiratory responses to emotional stress has been studied to only a limited extent. Bondarenko et al.85 found that inhibition of the prelimbic cortex inhibited the respiratory activation evoked by an emotional stressor but not that evoked by a brief arousing stimulus. In humans, Critchley et al.86 found that activity in the dorsal anterior cingulate cortex (homologous to the prelimbic cortex in rats) was correlated with increases in blood pressure during periods of psychological stress. In a further study, Critchley et al.87 found that in patients with cortical lesions that included the dorsal anterior cingulate cortex, cardiovascular responses to an emotional stressor were reduced compared with a control group, even though their cognitive abilities were not impaired. Thus, taking all these observations together, the available evidence suggests that the prelimbic cortex (or dorsal anterior cingulate
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cortex) does facilitate the cardiovascular and respiratory responses induced by emotional stress. The infralimbic cortex appears to have a different role, although again information is limited. A study in the rat showed that inhibition of the infralimbic cortex had no effect on the cardiovascular response to emotional stress, but activation of this region attenuated the response.88 Thus it appears that the infralimbic cortex contains neurons that can inhibit stress-evoked responses, although such neurons do not appear to be active under resting conditions.
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stimulus, whereas lesions of the PAG had the opposite effect. Emotional stress must involve the medial prefrontal cortex, and yet lesions of the medial prefrontal cortex do not appear to abolish cardiorespiratory responses to stimuli that have an emotional content. It this appears that such responses can be generated by subcortical pathways, as is the case for behavioral responses,59 while the function of inputs from the medial prefrontal cortex is to modify the responses to match the behavioral response, as a consequence of cognitive processing of all relevant information about the nature of the particular threat.
SUMMARY AND CONCLUSIONS The DMH/PeF region and amygdaloid complex are the only brain regions that are essential for the full expression of cardiovascular and respiratory responses to emotional stress. The DMH/PeF region, however, is downstream to the amygdaloid complex and is the major source of descending pathways to the brainstem and spinal cord that in turn generate increases in respiratory activity, heart rate, cutaneous and visceral vasoconstriction, increase in BAT activity, and baroreflex resetting. The pathways subserving these effects are illustrated in simplified form in Fig. 28.4. In addition, as described previously, there are also interconnections between the medial prefrontal cortex, amygdala, and PAG (not shown in Fig. 28.4) that also contribute to the generation of the cardiorespiratory responses. Although this review has focused on the stress-evoked cardiorespiratory responses, it should be emphasized that these responses essentially support the stress-evoked behavioral responses, together with neuroendocrine effects. A key question, therefore, is how all these components are integrated to produce an overall response that is appropriate for a particular threatening stimulus? It is clear that, at least at the level of the hypothalamus and midbrain, behavioral, and cardiorespiratory responses are generated by different groups of neurons. For example, LeDoux et al.89 found that lesions of the DMH/PeF region affected the cardiovascular but not behavioral response to an emotional
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