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A5 and A6 Noradrenergic Cell Groups: Implications for Cardiorespiratory Control

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Manuel Víctor López-González, Marta González-García and Marc Stefan Dawid-Milner

Submitted: 25 May 2018 Reviewed: 08 June 2018 Published: 24 October 2018

DOI: 10.5772/intechopen.79389

From the Edited Volume

Autonomic Nervous System

Edited by Pavol Svorc

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Central pontine A5 and A6 noradrenergic cell groups are two of the main sources of noradrenaline release at the spinal cord, at the level of the superficial dorsal horn, the motoneuron pools of the ventral horn, lamina X and the thoracic and sacral intermediolateral cell columns. Noradrenergic ascending or descending pathways originating in the A5 or A6 noradrenergic cell groups are highly sensitive to stress and to other high-arousal states. These noradrenergic groups present extensive projections that play a key role in the modulation of all antinociceptive and autonomic responses elicited by painful or threatening situations. Depending on the locations of these projections, different possible roles for each noradrenergic cell groups are suggested. The A6 noradrenergic cell group might have the greatest effect on somatosensory transmission and the A5 group on sympathetic function. Consistent with this, stimulation of central noradrenergic pathways evokes an array of stresslike and antinociceptive effects, including changes in blood pressure, heart rate and respiratory rate. In addition, it also produces an increase in excitability, which leads to a high degree of arousal and a potentiation of cortical and subcortical mechanism generating the necessary cognitive, behavioral and autonomic responses to confront these physical or psychological situations.


  • pontine noradrenergic cell groups
  • A5 region
  • locus coeruleus
  • cardiovascular control
  • analgesia

1. Introduction

Noradrenergic (NA) central pathways located at the level of the brainstem were initially described by Dahlström and Fuxe in 1964 and contain several clusters or groups of neurons classified from A1 to A7. These clusters extend rostrocaudally from the lateral pons to the caudal ventrolateral medulla. Afferent and efferent connections are sent and come from very different locations along the central nervous system (CNS) and are implicated in physiological and behavioral functions associated with a wide cascade of processes, such as homeostasis, arousal, memory, learning, autonomic and behavioral responses to stress and pain, among others [1, 2].

NA neurons are characterized by the presence, within the synaptic terminal, of the cytoplasmatic enzymatic machinery, which is necessary to biosynthesize noradrenaline from the amino acid tyrosine through a precise and sequential enzymatic reaction. Tyrosine hydroxylase (TH) is the limiting enzyme. It transforms tyrosine into dihydroxyphenylalanine (L-DOPA), which is converted into dopamine by L-DOPA decarboxylase. Finally, dopamine is used as a substrate by dopamine-β-hydroxylase (DBH), which transforms dopamine into noradrenaline [3]. DBH immunodetection is specific for NA neurons and NA central demand [4]. Although once the noradrenaline is a precursor to adrenaline synthesis, the immunodetection of DBH is not restricted to noradrenergic neurons except in the cases where the referred group is isolated from adrenergic neurons (as A6 and A5). After its release into the synaptic cleft, noradrenaline can bind to the pre- or post-synaptic adrenergic receptors and activates intracellular signaling cascades depending on the specific function of the subtype of the adrenergic receptor activated (facilitatory or inhibitory receptors).

Briefly, in terms of the precise location of the different NA cell groups: the A1 NA cell group is found in the ventrolateral medulla; the A2, located close to the dorsal vagal complex, has an intimate relationship (as part of) with caudal NTS complex, starting in very caudal level of medulla until the open of fourth ventricle; A3 neurons are included within the medullary reticular formation, and neurons of the A4 cell group are situated in the surroundings of the fourth ventricle. The precise location of the most studied NA cell groups, the A5, A6 and A7, is the following: the A5 NA cell group is located in the ventrolateral pons; A6, which represents the locus coeruleus, is located in the lateral floor of the fourth ventricle and, finally, A7 is found in the lateral part of the pons. These last three groups of NA neurons represent the most important NA clusters with projections to the spinal cord [5, 6].

Early studies using retrograde transport of horseradish peroxidase combined with immunostaining for DBH or retrograde transport of anti-DBH antibodies demonstrated that the NA endings of the spinal cord arise from the A5, A6 and A7 cell groups in the pons [7]. The projections from the neurons located in the A5, A6 and A7 cell groups are found throughout the spinal cord, but the highest density of synaptic contacts is established at the level of the superficial dorsal horn, the motoneuron pools of the ventral horn, lamina X and the thoracic and sacral intermediolateral cell columns (IML) [5].

In this chapter, the main focus is centered on the main pontine NA cell groups, which project to the spinal cord (A5 and A6), and their implications for cardiorespiratory control.


2. Spinal projections

The A5 and A6 pontine NA clusters of neurons project widely across the spinal cord [5]. These projections reach the dorsal and ventral horns (laminae I-VII) and the IML of the spinal cord at thoracic levels. These descending projections of the NA cell groups are crucial in explaining their functional implications in central cardiorespiratory control and in other important autonomic functions involved in behavioral responses to stress or pain.

2.1. Spinal projections from the A6 (locus coeruleus)

The projections from A6 cells use two main pathways: through the spinal cord in the ventral funiculi and through the dorsal surface of the dorsal horn. The A6 NA cell group supplies the highest concentration of synaptic endings at all levels. It includes all regions of the spinal gray matter, but it is especially dense at the level of the dorsal horn, although it has a small number of axons to the ventral horn and IML [5]. Extensive literature for this exists, not only at an anatomical level [6, 7, 8, 9, 10, 11, 12] but also with electrophysiological evidence [13, 14]. Intra and extracellular neuronal recording studies provide the assignment to caudal A6 NA neurons with a role in regulating the excitability of the cell bodies of somatic alpha motoneurons located within the ventral horn of the spinal cord.

2.2. Spinal projections from the A5

It is well established that the spinally projecting axons of the A5 NA group mainly travel through the spinal cord within the lateral funiculi to end at the level of the IML cell column of the thoracic spinal cord segments [5, 15, 16, 17]. There are also projections to the dorsal horn of the spinal cord (laminae IV–VII) [5, 16], where a high density of nociceptive neurons can be observed [18]. The A5 NA cell group contributes only with sparse projections to the dorsal and ventral horns at cervical and lumbosacral levels, but it supplies the thoracic IML with the densest projections, particularly to sympathetic preganglionic neurons [5].

In summary, the projections of A5 and A6 NA cell groups to the spinal cord are distributed in a complementary and topographic way. This suggests a different possible role for each of these cell groups, which depend on the precise location of their projections. Therefore, the A6 NA cell group might have its main effect on somatosensory transmission, and the A5 group on sympathetic autonomic function (Figure 1).

Figure 1.

Schematic diagram of a sagittal section of human brain in which the main pontine noradrenergic nuclei (A5 and A6) and their main efferent connections are positioned. (A5) A5 noradrenergic cell group. (A6) A6 noradrenergic cell group, Locus Coeruleus. (Amyg) Amygdala. (CVL) Caudal ventrolateral medulla. (DMH-PeF) Dorsomedial Hypothalamic nucleus and perifornical area. (Hyppoc) Hyppocampus. (IML) Intermedio lateral cell collum of the spinal cord. (KF) Kölliker-Fuse nucleus. (LH) Lateral Hypothalamus. (NTS) Nucleus Tractus Solitarii. (PAG) Periaqueductal gray. (PBc) Parabrachial complex. (PVN) Paraventricular nucleus. (RVL) Rostral ventrolateral medulla.


3. Functional pathways related to central and spinal projections

Although the previously described spinal projections are enough to explain the roles of each NA cell group, the efferent connections that these nuclei send to other areas of the CNS involved in autonomic control are what reinforce their role in autonomic control and homeostasis.

3.1. A6

The pontine A6 NA cell group, also called “locus coeruleus,” is the most exhaustively studied NA nucleus in the brain. This NA region, which projects mainly to the dorsal horn of the spinal cord, has been linked with antinociception or modulation of pain together with the A7 NA cell group in Harlan Sprague-Dawley and Wistar rats [2, 19, 20, 21, 22, 23].

Neurons of the A6 region, as other catecholaminergic nuclei, are known to be immunoreactive for TH and DBH, the two enzymes critically involved in noradrenaline biosynthesis. A6 NA neurons also express a wide selection of neuropeptides including neuropeptide Y, somatostatin and cholecystokinin [24]. Most of the A6 NA neurons have different neurochemical characteristics and morphologies, presenting predominantly a medium size with fusiform and polar morphology, and three or four long thin dendrites [25].

A6 NA neurons send axons with extensive bifurcations, which travel long distances and establish connections even with cortical domains [26]. In addition, neurons located in the rostral part of the A6 NA region have widely branched axons that innervate forebrain areas, providing the main source of noradrenalin to the neocortex, hippocampus, amygdala, thalamus and cerebellum [27, 28]. Specifically, at the level of the hypothalamus, the A6 region makes contact with the paraventricular and supraoptic nuclei [29]. Other projections from the A6 NA neurons target the superior colliculus [30]. An activation of all these superior structures enhances arousal, vigilance and attention to sensory stimuli [31]. It has been reported that electrical stimulation of the A6 region also elicits a pressor response [32]. Furthermore, pharmacological inhibitions or activations of the activity of the A6 NA neurons also evoke changes in blood pressure [33].

With regard to these multiple ascending pathways, it is known that the A6 NA region has a critical role in stress responses, autonomic function, emotional memory, attention and the control modulation of motor and sensory functions. Furthermore, it has been shown that noradrenalin exerts potent neuromodulatory actions, reducing neuronal baseline activity and increasing the responsiveness of target cells to novel synaptic stimuli. Within the neocortex, hippocampus, amygdala and cerebellum, noradrenaline also facilitates synaptic plasticity, including long-term potentiation [34, 35, 36].

Tracing and immunocytochemical studies clearly describe all the descending projections from the A6 NA neurons to the brainstem and spinal cord [37]. These studies show the differences between the projections that originate from the subcoeruleus and coeruleus regions. However, the A6 NA neurons primarily project to the parasympathetic neurons of the dorsal motor nucleus of the vagus, nucleus ambiguus and sacral spinal cord, and subcoeruleus neurons send their projections to sympathetic preganglionic neurons and somatic cranial nerve nuclei. Both pathways have widespread projections to the brainstem reticular formation and dorsal horn of the spinal cord [38], and to the region surrounding the central canal and the ventral horn [37, 38].

Finally, A6 NA neurons also play a major role in behavioral and autonomic responses to stress [39]. A6 NA cells orexin 1 receptors are activated by stress-related orexin axons projecting from neuronal cell bodies located in the perifornical hypothalamus [40]. Furthermore, A6 noradrenergic neurons also modulate the interaction between the amygdala and hippocampus, thus promoting emotional memory [41], which involves an activation of β receptors within the basolateral amygdala [39]. In a recent report [42], it has been shown that A6 noradrenergic neurons participate in the tachycardia evoked during autonomic responses to stress and also are recognized as central chemoreceptors [43, 44].

3.2. A5

Multiple reports demonstrate that A5 neurons provide the major component of NA input to sympathetic preganglionic neurons of the IML of the spinal cord. Once there, they branch and establish buttons along the cell bodies and proximal dendrites of cholinergic preganglionic neurons, thus sustaining the earlier anatomical [5, 17] and physiological studies [45, 46, 47, 48, 49, 50], which indicate a role for the A5 region in regulating sympathetic function.

The A5 region contains NA and non-NA neurons. The non-NA cells are mainly located at the level of the most caudal part of the A5 region [51]. These neurons seem to have similar properties to respiratory chemoreceptors cells previously identified in the rostral medulla oblongata [52]. By employing immunocytochemical and in situ hybridization techniques, neurons of the A5 region are shown to express ionotropic and metabotropic glutamate receptors. Ionotropic NMDA receptors show NR1-NR2D subunits [53], while the non-NMDA types are both AMPA and kainate [54]. The A5 metabotropic receptors observed within the A5 region are mGluR I, II and III [55].

Focusing on the descending connections from the A5 region, there is a dense connectivity with several medullary nuclei. These include the nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM), rostral ventrolateral medulla (RVLM), the caudal pressor area and the retrotrapezoid nucleus. There is also significant ascending connectivity, showing reciprocal projections with the Kölliker-Fuse, medial and lateral parabrachial nuclei in the pons, the perifornical area and the paraventricular nucleus in the hypothalamus and with the amygdala [15, 56, 57, 58, 59, 60]. The location and connectivity of A5 region cells, the so-called ventrolateral pons, with an entire network of ascending and descending connections with other regions of the CNS involved in cardiorespiratory regulation, supports the idea that these neurons are the perfect candidates to drive and modulate the control of both sympathetic activity and cardiorespiratory function (Figure 1) [15, 45, 56, 58, 59, 61, 62, 63].

We have studied the functional relations between this sympathetic NA region and other hypothalamic, pontine and medullary regions involved in cardiorespiratory control. We first demonstrated that the stimulation of A5 NA cell bodies with glutamate mainly produces an increase in both blood pressure and heart rate [47] (Figure 2). It is known that the simultaneous increase of sympathetic vasomotor activity, arterial blood pressure and heart rate implies a reset of the baroreceptor reflex but without attenuation in the sensitivity of the reflex [64]. Furthermore, A5 neurons are activated during baroreceptor unloading [45] and carotid chemoreceptors stimulation [65]. Thus, it has been proposed that A5 neurons may play an important role in the carotid sympathetic chemoreflex triggered by hypoxia [66, 67, 68].

Figure 2.

(A), (B), (C). Cardiorespiratory responses to A5 region stimulation in spontaneously breathing animals. Blood pressure (upper traces), heart rate (middle traces) and integrated phrenic activity (lower traces) during (A) electrical stimulation (10 μA, 0.4 ms, 50 Hz for 5 s) and (B) glutamate injection (1.5 nmol, 15 nl, over 5 s) in the same animal showing a decrease in respiratory rate with an increase in blood pressure and heart rate. (C) The response of another animal to glutamate injection (2.5 nmol, 25 nl, over 5 s), in which the respiratory response is similar to (B), but the cardiovascular response is bi-phasic and the increase in heart rate smaller.

However, not only do A5 NA neurons have a cardiovascular role, but they also play an important role in respiratory control, modulating the activity of respiratory neurons [69]. A5 neurons are also synaptically connected to phrenic motoneurons [70] and contribute to the respiratory responses evoked by hypoxia and hypercapnia [66, 68, 71]. We have also demonstrated that the A5 region and medial Parabrachial and Kölliker Fuse nuclei have a role in modifying the activity of laryngeal motoneurons localized in the nucleus ambiguus, producing laryngeal constriction and increasing subglottic pressure (Figure 3) [50]. Finally, A5 NA neurons also participate in the cardiorespiratory response elicited by the activation of the parabrachial complex (Figure 4) [46], which is a critical component of the brainstem respiratory network required for eupnoea [72].

Figure 3.

Laryngeal and respiratory responses to glutamate microinjection in the A5 region. Respiratory airflow, pleural pressure, subglottic pressure, phrenic nerve discharge and integrated phrenic nerve discharge, showing a expiratory facilitatory response with increase of subglottic pressure during a glutamate injection (10 nl over 5 s) in the A5 region. The arrows shows the onset of injection.

Figure 4.

Extracellular recordings of three cells (superimposed sweeps) from the A5 region showing electrophysiological relations between the Parabrachial complex and the A5 region.

Similarly to A6 NA neurons, the A5 region is also involved in the control of stress-related responses. The terms “defense region” or “defense response” have been classically used in the literature to describe the areas of the CNS from which we can evoke a pattern of autonomic and behavioral changes that are typically observed when an animal is confronted with threatening stimuli from different types of stressors [73, 74, 75]. The complexity of defensive behavior requests different interconnected regions, which plays specific roles according to the origin of the stressor agent or source of fear. It has been reported that there are two important regions from which this “defense response” can be elicited: the dorsomedial hypothalamic and perifornical area (DMH-PeF) in the hypothalamus, and the dorsolateral periaqueductal gray (dlPAG) in the midbrain [76]. The DMH-PeF and the dlPAG are part of an extensive network that coordinates defensive behavior.

The defense response is characterized by hypertension, tachycardia and tachypnea. As previously described, the simultaneous increase of arterial blood pressure, heart rate and sympathetic vasomotor activity implies that the baroreceptor reflex is reset to higher levels of arterial pressure, but without attenuation in the sensitivity of the reflex. A potentiation of the chemoreceptor reflex is known to be involved in this effect [77], as well as an activation of GABAergic mechanisms at the level of the NTS [78, 79].

With electrophysiological and neuropharmacological techniques, we have demonstrated the functional and anatomical interrelations between the Parabrachial complex and the A5 NA region in modulating the cardiorespiratory response evoked from DMH-PeF [80, 81] (Figures 5 and 6) and that glutamate is a possible neurotransmitter candidate involved in these interactions [81, 82]. In unpublished observations, we have obtained similar results with the interactions between the dlPAG and the A5 region [83].

Figure 5.

Instantaneous respiratory rate (upper trace), respiratory flow, pleural pressure, instantaneous heart rate and blood pressure in a spontaneously breathing rat, showing the cardiorespiratory response evoked on DMH-PeF stimulation before (A) and after the microinjection of muscimol (50 nl over 5 s) in the A5 region (B) The segment shows the duration (5 s) of the DMH-PeF electrical stimulation.

Figure 6.

Extracellular recordings (superimposed sweeps) from the A5 region showing electrophysiological relations between the DMH-PeF and the A5 region: (a) Silent axon (upper trace) with constant-latency responses to DMH-PeF stimulation (lower trace). (b) Spontaneously active A5 cell (upper trace) inhibited by DMH-PeF stimulation (lower trace). (c) Spontaneously active A5 cell (upper trace) excited with double short- and long-latency responses to DMH-PeF stimulation (lower trace). (d) Inset shows recording of respiratory flow, pleural pressure, neuronal activity of a putative respiratory-modulated A5 cell and blood pressure. Main graph shows respiratory flow (inspiration downwards), and neuronal activity, while lower trace shows DMH-PeF-triggered histograms. This recordings show the complexity of the neuronal interactions between A5 and DMH-Pef.

We have also shown that the tachycardia evoked from these defense regions is decreased when the A5 region is pharmacologically blocked with the GABA agonist muscimol. For this reason, we propose the existence of two different pathways that subserve the tachycardia and the pressor response elicited from the stimulation of these defense regions [81, 84]. The tachycardia and the hypertension evoked during defense stimulation involve a direct activation of the neurons of the RVLM. These neurons send direct projections to preganglionic neurons of the IML that are ultimately responsible for the abrupt increase in blood pressure [85]. In addition, a direct activation of the adrenal medulla contributes to a secondary increase in blood pressure due to the liberation of adrenaline. Furthermore, in a parallel pathway to the activation of the RVLM and the preganglionic neurons in the IML, the stimulation of defense regions increases the intensity of the chemoreceptor reflex by means of an excitation or facilitation of chemoreceptor neurons in the NTS [77]. In a parallel circuit, an inhibition of the response to baroreceptor inputs is produced by disfacilitation or inhibition of baroreceptor neurons at the level of the NTS [78, 86]. This inhibition seems to be mediated by GABAergic interneurons in the NTS [78].

Other groups have also suggested the existence of these separates pathways [76]. It has been hypothesized that cardiorespiratory sympathoexcitatory changes evoked during defense stimulation are produced via indirect polysynaptic projections from the dlPAG to the medulla through connections with the DMH-PeF, Parabrachial complex and cuneiform nucleus. Our results suggest that the A5 region is one of the best candidates to mediate in these cardiorespiratory descending pathways because of its excitatory direct connections with the IML and the inhibitory direct projections with the CVLM, which are a source of inhibition to the RVLM [59]. Therefore, the stimulation of both defense regions, DMH-PeF and dlPAG, results in an activation of the A5 region. Thus, this activation will reinforce the pressor response, supporting the hypothesis that neurons within the A5 region are involved in the decrease of the sensitivity of the baroreceptor reflex at the level of the NTS, after the activation of the so-called defense regions, DMH-PeF and dlPAG.


4. Clinical implications

The A5 region is also involved in the impairment of sympathetic cardiovascular and respiratory control observed in multiple system atrophy (MSA) [87] and in syndromes such as Sudden Infant Death Syndrome, Rett syndrome, Ondine’s syndrome and other genetic failures related to Phox2a, Ret, Mecp2, BDNF and Phox2b mutations [88].

Growing evidence supports the presence of earlier noradrenaline deficiency in neurodegenerative disorders including Parkinson disease (PD). PD dysautonomic symptoms are common, especially in cardiovascular, gastrointestinal and genitourinary systems. Most patients with PD have imaging evidence of cardiac sympathetic denervation. Selective degeneration of the noradrenergic neurons of the A6 NA cell group precedes that of dopaminergic neurons of the substantia nigra pars compacta and has been increasingly recognized as a potential major contributor to cognitive manifestations in early PD, particularly impaired attention. This makes the A6 NA system a major contributor to the pathophysiology and potential target for therapy of PD [19, 89, 90].


5. Summary and perspectives

This chapter focuses on the different spinal projections and main modulatory actions of the two main NA pontine cell groups derived from this connectivity. Among these NA modulatory actions, a high variety of physiological and behavioral processes can be found that involve multiple cortical and subcortical structures. The diversity of anatomical, morphological, pharmacological and electrophysiological studies carried out in these NA cell groups has demonstrated that A5 and A6 NA pontine cell groups seem to be the best neuronal substrate to articulate the necessary responses to a wide range of psychological and physical stressors. A6 NA neurons present the necessary projections to modulate analgesic responses, while the A5 NA region seems to modulate all of the necessary autonomic responses needed to confront threatening stimuli or situations.

Regarding pain, bidirectional NA modulatory actions of spinal nociceptive processing depends on the type of pain. Moreover, this modulation is not only referred to by the type of nociceptive stimulus but, in addition, is affected by other CNS structures that are involved in emotional, motivational or attentional states. As has been previously explained, A6 and A5 NA cell groups may be the key centers for all modulatory actions exerted from superior structures within the CNS, which inhibit nociceptive transmission at the level of the spinal dorsal horn acting via presynaptic alpha2 receptors.

This chapter has laid the groundwork for further investigations on the topic and numerous unanswered questions remain. For example, how do these noradrenergic nuclei respond when functional or structural diseases caused by genetic or epigenetic factors appear? Are all these centers and their connections equally affected under these different pathological states? Are NA cells of these nuclei affected in the same manner by different external stressors or do they have different functional responses depending on their location within each nucleus or their projections? Does the selective degeneration that occurs in A5 and A6 neurons in diseases, such as MSA and PD, have a relationship with the evolution of the dysautonomia or the cognitive alterations observed in these patients?

Further basic and clinical studies are needed to assess the role of the NA pontine cell groups on physiology and pathophysiology based on these questions.



The study was supported by a program grant Junta de Andalucía, Group n° CTS-156, Spain.


  1. 1. Dahlström A, Fuxe K. Localization of monoamines in the lower brain stem. Experientia. 1964;20:398-399. DOI: 10.1007/BF02147990
  2. 2. Pertovaara A. Noradrenergic pain modulation. Progress in Neurobiology. 2006;80:53-83. DOI: 10.1016/j.pneurobio.2006.08.001
  3. 3. Armstrong DM, Ross CA, Pickel VM, et al. Distribution of dopamine; noradrenaline and adrenaline-containing cell bodies in the rat medulla oblongata: Demonstrated by the immunocytochemical localization of catecholamine biosynthetic enzymes. The Journal of Comparative Neurology. 1982;212:173-187. DOI: 10.1002/cne.902120207
  4. 4. Bacopoulos NG, Bhatnagar RK. Correlation between tyrosine hydroxylase activity and catecholamine concentration or turnover in brain regions. Journal of Neurochemistry. 1977;29:639-643. DOI: 10.1111/j.1471-4159.1977.tb07780.x
  5. 5. Bruinstroop E, Cano G, Vanderhorst VGJM, et al. Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats. The Journal of Comparative Neurology. 2012;520:1985-2001. DOI: 10.1002/cne.23024
  6. 6. Proudfit HK, Clark FM. The projections of locus coeruleus neurons to the spinal cord. Progress in Brain Research. 1991;88:123-141
  7. 7. Westlund KN, Bowker RM, Ziegler MG, Coulter JD. Noradrenergic projections to the spinal cord of the rat. Brain Research. 1983;263:15-31. DOI: 10.1016/0006-8993(83)91196-4
  8. 8. Clark FM, Yeomans DC, Proudfit HK. The noradrenergic innervation of the spinal cord: Differences between two substrains of Sprague-Dawley rats determined using retrograde tracers combined with immunocytochemistry. Neuroscience Letters. 1991;125:155-158. DOI: 10.1016/0304-3940(91)90015-L
  9. 9. Clark FM, Proudfit HK. The projection of locus coeruleus neurons to the spinal cord in the rat determined by anterograde tracing combined with immunocytochemistry. Brain Research. 1991;538:231-245. DOI: 10.1016/0006-8993(91)90435-X
  10. 10. Clark FM, Proudfit HK. The projection of noradrenergic neurons in the A7 catecholamine cell group to the spinal cord in the rat demonstrated by anterograde tracing combined with immunocytochemistry. Brain Research. 1991;547:279-288. DOI: 10.1016/0006-8993(91)90972-X
  11. 11. Clark FM, Proudfit HK. Anatomical evidence for genetic differences in the innervation of the rat spinal cord by noradrenergic locus coeruleus neurons. Brain Research. 1992;591:44-53
  12. 12. Proudfit HK. The behavioral pharmacology of the noradrenergic descending system. In: JMR B, Guilbaud, editors. Towards the Use of Noradrenergic Agonists. Amsterdam: Elsevier; 1992
  13. 13. Chan JYH, Fung SJ, Chan SHH, Barnes CD. Facilitation of lumbar monosynaptic reflexes by locus coeruleus in the rat. Brain Research. 1986;369:103-109. DOI: 10.1016/0006-8993(86)90517-2
  14. 14. Fung SJ, Manzoni D, Chan JY, et al. Locus coeruleus control of spinal motor output. Progress in Brain Research. 1991;88:395-409
  15. 15. Byrum CE, Guyenet PG. Afferent and efferent connections of the A5 noradrenergic cell group in the rat. The Journal of Comparative Neurology. 1987;261:529-542. DOI: 10.1002/cne.902610406
  16. 16. Clark FM, Proudfit HK. The projections of noradrenergic neurons in the A5 catecholamine cell group to the spinal cord in the rat: Anatomical evidence that A5 neurons modulate nociception. Brain Research. 1993;616:200-210
  17. 17. Loewy AD, McKellar S, Saper CB. Direct projections from the A5 catecholamine cell group to the intermediolateral cell column. Brain Research. 1979;174:309-314
  18. 18. Light A. The initial processing of pain and its descending control: Spinal and trigeminal systems. In: Pain and Headache. Switzerland: Karger; 1992
  19. 19. Benarroch EE. Locus coeruleus. Cell and Tissue Research. 2017;373(1):221-232. DOI: 10.1007/s00441-017-2649-1
  20. 20. Holden JE, Schwartz EJ, Proudfit HK. Microinjection of morphine in the A7 catecholamine cell group produces opposing effects on nociception that are mediated by alpha1- and alpha2-adrenoceptors. Neuroscience. 1999;91:979-990
  21. 21. Holden JE, Van Poppel AY, Thomas S. Antinociception from lateral hypothalamic stimulation may be mediated by NK(1) receptors in the A7 catecholamine cell group in rat. Brain Research. 2002;953:195-204
  22. 22. Iwamoto ET, Marion L. Adrenergic, serotonergic and cholinergic components of nicotinic antinociception in rats. The Journal of Pharmacology and Experimental Therapeutics. 1993;265:777-789
  23. 23. Nuseir K, Proudfit HK. Bidirectional modulation of nociception by GABA neurons in the dorsolateral pontine tegmentum that tonically inhibit spinally projecting noradrenergic A7 neurons. Neuroscience. 2000;96:773-783
  24. 24. Miller MA, Kolb PE, Leverenz JB, et al. Preservation of noradrenergic neurons in the locus ceruleus that coexpress galanin mRNA in Alzheimer’s disease. Journal of Neurochemistry. 1999;73:2028-2036
  25. 25. Chan-Palay V, Asan E. Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression. The Journal of Comparative Neurology. 1989;287:357-372. DOI: 10.1002/cne.902870307
  26. 26. Foote SL, Morrison JH. Extrathalamic modulation of cortical function. Annual Review of Neuroscience. 1987;10:67-95. DOI: 10.1146/
  27. 27. Levitt P, Moore RY. Origin and organization of brainstem catecholamine innervation in the rat. The Journal of Comparative Neurology. 1979;186:505-528. DOI: 10.1002/cne.901860402
  28. 28. Mason ST, Fibiger HC. Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase. The Journal of Comparative Neurology. 1979;187:703-724. DOI: 10.1002/cne.901870405
  29. 29. Ginsberg SD, Hof PR, Young WG, Morrison JH. Noradrenergic innervation of the hypothalamus of rhesus monkeys: Distribution of dopamine-beta-hydroxylase immunoreactive fibers and quantitative analysis of varicosities in the paraventricular nucleus. The Journal of Comparative Neurology. 1993;327:597-611. DOI: 10.1002/cne.903270410
  30. 30. Morrison JH, Foote SL. Noradrenergic and serotoninergic innervation of cortical, thalamic, and tectal visual structures in old and new world monkeys. The Journal of Comparative Neurology. 1986;243:117-138. DOI: 10.1002/cne.902430110
  31. 31. Aston-Jones G, Shipley MT, Chouvet G, et al. Afferent regulation of locus coeruleus neurons: Anatomy, physiology and pharmacology. Progress in Brain Research. 1991;88:47-75
  32. 32. Gurtu S, Pant KK, Sinha JN, Bhargava KP. An investigation into the mechanism of cardiovascular responses elicited by electrical stimulation of locus coeruleus and subcoeruleus in the cat. Brain Research. 1984;301:59-64
  33. 33. Valentino RJ, Martin DL, Suzuki M. Dissociation of locus coeruleus activity and blood pressure. Effects of clonidine and corticotropin-releasing factor. Neuropharmacology. 1986;25:603-610
  34. 34. Hagena H, Hansen N, Manahan-Vaughan D. β-Adrenergic control of hippocampal function: Subserving the choreography of synaptic information storage and memory. Cerebral Cortex. 2016;26:1349-1364. DOI: 10.1093/cercor/bhv330
  35. 35. Lim EP, Tan CH, Jay TM, Dawe GS. Locus coeruleus stimulation and noradrenergic modulation of hippocampo-prefrontal cortex long-term potentiation. The International Journal of Neuropsychopharmacology. 2010;13:1219-1231. DOI: 10.1017/S1461145709991131
  36. 36. Lippiello P, Hoxha E, Volpicelli F, et al. Noradrenergic modulation of the parallel fiber-Purkinje cell synapse in mouse cerebellum. Neuropharmacology. 2015;89:33-42. DOI: 10.1016/j.neuropharm.2014.08.016
  37. 37. Westlund KN, Craig AD. Association of spinal lamina I projections with brainstem catecholamine neurons in the monkey. Experimental Brain Research. 1996;110:151-162
  38. 38. Westlund KN, Coulter JD. Descending projections of the locus coeruleus and subcoeruleus/medial parabrachial nuclei in monkey: Axonal transport studies and dopamine-beta-hydroxylase immunocytochemistry. Brain Research. 1980;2:235-264
  39. 39. Roozendaal B, McGaugh JL. Memory modulation. Behavioral Neuroscience. 2011;125:797-824. DOI: 10.1037/a0026187
  40. 40. Johnson PL, Federici LM, Fitz SD, et al. Orexin 1 and 2 receptor involvement in CO2-induced panic-associated behavior and autonomic responses. Depression and Anxiety. 2015;32:671-683. DOI: 10.1002/da.22403
  41. 41. Strange BA, Dolan RJ. Adrenergic modulation of emotional memory-evoked human amygdala and hippocampal responses. Proceedings of the National Academy of Sciences. 2004;101:11454-11458. DOI: 10.1073/pnas.0404282101
  42. 42. Wang X, Pinol RA, Byrne P, Mendelowitz D. Optogenetic stimulation of locus ceruleus neurons augments inhibitory transmission to parasympathetic cardiac vagal neurons via activation of brainstem 1 and 1 receptors. The Journal of Neuroscience. 2014;34:6182-6189. DOI: 10.1523/JNEUROSCI.5093-13.2014
  43. 43. de Carvalho D, Patrone LGA, Marques DA, Vicente MC, Szawka RE, Anselmo-Franci JA, Bícego KC, Gargaglioni LH. Participation of locus coeruleus in breathing control in female rats. Respiratory Physiology & Neurobiology. 2017 Nov;245:29-36. DOI: 10.1016/j.resp.2017.06.008
  44. 44. Patrone LGA, Biancardi V, Marques DA, Bícego KC, Gargaglioni LH. Brainstem catecholaminergic neurones and breathing control during postnatal development in male and female rats. The Journal of Physiology. 2018. [Epub ahead of print]. DOI: 10.1113/JP275731
  45. 45. Dampney RAL, Polson JW, Potts PD, et al. Functional organization of brain pathways subserving the baroreceptor reflex: Studies in conscious animals using immediate early gene expression. Cellular and Molecular Neurobiology. 2003;23:597-616
  46. 46. Dawid-Milner MS, Lara JP, López de Miguel MP, et al. A5 region modulation of the cardiorespiratory responses evoked from parabrachial cell bodies in the anaesthetised rat. Brain Research. 2003;982:108-118
  47. 47. Dawid-Milner MS, Lara JP, Gonzaléz-Barón S, Spyer KM. Respiratory effects of stimulation of cell bodies of the A5 region in the anaesthetised rat. Pflügers Archiv. 2001;441:434-443
  48. 48. Guyenet PG. The sympathetic control of blood pressure. Nature Reviews. Neuroscience. 2006;7:335-346. DOI: 10.1038/nrn1902
  49. 49. Huangfu DH, Koshiya N, Guyenet PG. A5 noradrenergic unit activity and sympathetic nerve discharge in rats. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 1991;261:R393-R402. DOI: 10.1152/ajpregu.1991.261.2.R393
  50. 50. Lara JP, Dawid-Milner MS, López MV, et al. Laryngeal effects of stimulation of rostral and ventral pons in the anaesthetized rat. Brain Research. 2002;934:97-106
  51. 51. Goodchild AK, Phillips JK, Lipski J, Pilowsky PM. Differential expression of catecholamine synthetic enzymes in the caudal ventral pons. The Journal of Comparative Neurology. 2001;438:457-467
  52. 52. Mulkey DK, Stornetta RL, Weston MC, et al. Respiratory control by ventral surface chemoreceptor neurons in rats. Nature Neuroscience. 2004;7:1360-1369. DOI: 10.1038/nn1357
  53. 53. Guthmann A, Herbert H. Expression of N-methyl-D-aspartate receptor subunits in the rat parabrachial and Kölliker-Fuse nuclei and in selected pontomedullary brainstem nuclei. The Journal of Comparative Neurology. 1999;415:501-517
  54. 54. Wisden W, Seeburg PH, Monyer H. AMPA, kainate and NMDA ionotropic glutamate receptor expression — an in situ hybridization atlas. In: Ottersen OP, Storm-Mathisen J (eds). Elsevier, Amsterdam: Handbook of Chemical Neuroanatomy: Glutamate; 2000. pp. 99-143
  55. 55. Shigemoto R, Mizuno N. Metabotropic glutamate receptors - immunocytochemical and in situ hybridization analysis. In: Ottersen OP, Storm-Mathisen J (eds) Handbook of Chemical Neuroanatomy: metabotropic glutamate receptors: immunocytochemical and in situ hybridization analyses. Elsevier, London. 2000. pp. 63-98
  56. 56. Abbott SB, Kanbar R, Bochorishvili G, et al. C1 neurons excite locus coeruleus and A5 noradrenergic neurons along with sympathetic outflow in rats. The Journal of Physiology. 2012;590:2897-2915. DOI: 10.1113/jphysiol.2012.232157
  57. 57. Madden CJ, Ito S, Rinaman L, et al. Lesions of the C1 catecholaminergic neurons of the ventrolateral medulla in rats using anti-DbetaH-saporin. The American Journal of Physiology. 1999;277:R1063-R1075
  58. 58. Rosin DL, Chang DA, Guyenet PG. Afferent and efferent connections of the rat retrotrapezoid nucleus. The Journal of Comparative Neurology. 2006;499:64-89. DOI: 10.1002/cne.21105
  59. 59. Tavares I, Lima D, Coimbra A. The pontine A5 noradrenergic cells which project to the spinal cord dorsal horn are reciprocally connected with the caudal ventrolateral medulla in the rat. The European Journal of Neuroscience. 1997;9:2452-2461
  60. 60. Usunoff KG, Itzev DE, Rolfs A, et al. Brain stem afferent connections of the amygdala in the rat with special references to a projection from the parabigeminal nucleus: A fluorescent retrograde tracing study. Anatomy and Embryology (Berlin). 2006;211:475-496. DOI: 10.1007/s00429-006-0099-8
  61. 61. Spyer KM. Annual review prize lecture. Central nervous mechanisms contributing to cardiovascular control. The Journal of Physiology. 1994;474:1-19
  62. 62. Taxini CL, Moreira TS, Takakura AC, et al. Role of A5 noradrenergic neurons in the chemoreflex control of respiratory and sympathetic activities in unanesthetized conditions. Neuroscience. 2017;354:146-157. DOI: 10.1016/j.neuroscience.2017.04.033
  63. 63. Taxini CL, Takakura AC, Gargaglioni LH, Moreira TS. Control of the central chemoreflex by A5 noradrenergic neurons in rats. Neuroscience. 2011;199:177-186. DOI: 10.1016/j.neuroscience.2011.09.068
  64. 64. McDowall LM, Horiuchi J, Killinger S, Dampney RAL. Modulation of the baroreceptor reflex by the dorsomedial hypothalamic nucleus and perifornical area. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2006;290:R1020-R1026. DOI: 10.1152/ajpregu.00541.2005
  65. 65. Guyenet PG, Koshiya N, Huangfu D, et al. Central respiratory control of A5 and A6 pontine noradrenergic neurons. The American Journal of Physiology. 1993;264:R1035-R1044. DOI: 10.1152/ajpregu.1993.264.6.R1035
  66. 66. Kanbar R, Depuy SD, West GH, et al. Regulation of visceral sympathetic tone by A5 noradrenergic neurons in rodents. The Journal of Physiology. 2011;589:903-917. DOI: 10.1113/jphysiol.2010.198374
  67. 67. Koshiya N, Guyenet PG. A5 noradrenergic neurons and the carotid sympathetic chemoreflex. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 1994;267:R519-R526. DOI: 10.1152/ajpregu.1994.267.2.R519
  68. 68. Song G, Xu H, Wang H, et al. Hypoxia-excited neurons in NTS send axonal projections to Kölliker-Fuse/parabrachial complex in dorsolateral pons. Neuroscience. 2011;175:145-153. DOI: 10.1016/j.neuroscience.2010.11.065
  69. 69. Hilaire G, Viemari J-C, Coulon P, et al. Modulation of the respiratory rhythm generator by the pontine noradrenergic A5 and A6 groups in rodents. Respiratory Physiology & Neurobiology. 2004;143:187-197. DOI: 10.1016/j.resp.2004.04.016
  70. 70. Dobbins EG, Feldman JL. Brainstem network controlling descending drive to phrenic motoneurons in rat. The Journal of Comparative Neurology. 1994;347:64-86. DOI: 10.1002/cne.903470106
  71. 71. Schlenker EH, Prestbo A. Elimination of the post-hypoxic frequency decline in conscious rats lesioned in pontine A5 region. Respiratory Physiology & Neurobiology. 2003;138:179-191
  72. 72. WM S-J, Paton JFR. Role of pontile mechanisms in the neurogenesis of eupnea. Respiratory Physiology & Neurobiology. 2004;143:321-332. DOI: 10.1016/j.resp.2004.05.010
  73. 73. Carrive P. The periaqueductal gray and defensive behavior: Functional representation and neuronal organization. Behavioural Brain Research. 1993;58:27-47
  74. 74. DiMicco JA, Samuels BC, Zaretskaia MV, Zaretsky DV. The dorsomedial hypothalamus and the response to stress: Part renaissance, part revolution. Pharmacology Biochemistry and Behavior. 2002;71:469-480
  75. 75. Keay KA, Bandler R. Parallel circuits mediating distinct emotional coping reactions to different types of stress. Neuroscience and Biobehavioral Reviews. 2001;25:669-678
  76. 76. Dampney RAL. Central mechanisms regulating coordinated cardiovascular and respiratory function during stress and arousal. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2015;309:R429-R443. DOI: 10.1152/ajpregu.00051.2015
  77. 77. Silva-Carvalho L, Dawid-Milner MS, Goldsmith GE, Spyer KM. Hypothalamic modulation of the arterial chemoreceptor reflex in the anaesthetized cat: Role of the nucleus tractus solitarii. The Journal of Physiology. 1995;487(Pt 3):751-760
  78. 78. Jordan D, Mifflin SW, Spyer KM. Hypothalamic inhibition of neurones in the nucleus tractus solitarius of the cat is GABA mediated. The Journal of Physiology. 1988;399:389-404
  79. 79. Silva-Carvalho L, Dawid-Milner MS, Spyer KM. The pattern of excitatory inputs to the nucleus tractus solitarii evoked on stimulation in the hypothalamic defence area in the cat. The Journal of Physiology. 1995;487(Pt 3):727-737
  80. 80. Díaz-Casares A, López-González MV, Peinado-Aragonés CA, et al. Role of the parabrachial complex in the cardiorespiratory response evoked from hypothalamic defense area stimulation in the anesthetized rat. Brain Research. 2009;1279:58-70. DOI: 10.1016/j.brainres.2009.02.085
  81. 81. López-González MV, Díaz-Casares A, González-García M, et al. Glutamate receptors of the A5 region modulate cardiovascular responses evoked from the dorsomedial hypothalamic nucleus and perifornical area. Journal of Physiology and Biochemistry. 2018;74(2):325-334. DOI: 10.1007/s13105-018-0612-6
  82. 82. Díaz-Casares A, López-González MV, Peinado-Aragonés CA, et al. Parabrachial complex glutamate receptors modulate the cardiorespiratory response evoked from hypothalamic defense area. Autonomic Neuroscience. 2012;169:124-134. DOI: 10.1016/j.autneu.2012.06.001
  83. 83. Peinado-Aragonés CA. Interrelaciones de la sustancia gris periacueductal dorsolateral y la región protuberancial A5 en el control central cardiorrespiratorio. [thesis]. Universidad de Málaga, España; 2016. URI:
  84. 84. López-González MV, Díaz-Casares A, Peinado-Aragonés CA, et al. Neurons of the A5 region are required for the tachycardia evoked by electrical stimulation of the hypothalamic defence area in anaesthetized rats. Experimental Physiology. 2013;98:1279-1294. DOI: 10.1113/expphysiol.2013.072538
  85. 85. Loewy AD. Forebrain nuclei involved in autonomic control. Progress in Brain Research. 1991;87:253-268
  86. 86. Mifflin SW, Spyer KM, Withington-Wray DJ. Baroreceptor inputs to the nucleus tractus solitarius in the cat: Modulation by the hypothalamus. The Journal of Physiology. 1988;399:369-387
  87. 87. Benarroch EE, Schmeichel AM, Low PA, et al. Loss of A5 noradrenergic neurons in multiple system atrophy. Acta Neuropathologica. 2008;115:629-634. DOI: 10.1007/s00401-008-0351-9
  88. 88. Hilaire G. Endogenous noradrenaline affects the maturation and function of the respiratory network: Possible implication for SIDS. Autonomic Neuroscience. 2006;126-127:320-331. DOI: 10.1016/j.autneu.2006.01.021
  89. 89. Espay AJ, LeWitt PA, Kaufmann H. Norepinephrine deficiency in Parkinson’s disease: The case for noradrenergic enhancement. Movement Disorders. 2014;29:1710-1719. DOI: 10.1002/mds.26048
  90. 90. Kaufmann H, Goldstein DS. Autonomic dysfunction in Parkinson disease. Handbook of Clinical Neurology. 2013;117:259-278. DOI: 10.1016/B978-0-444-53491-0.00021-3

Written By

Manuel Víctor López-González, Marta González-García and Marc Stefan Dawid-Milner

Submitted: 25 May 2018 Reviewed: 08 June 2018 Published: 24 October 2018