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 DOI: 10.1177/0269881113490326 2013 27: 659 originally published online 12 June 2013J Psychopharmacol

Elemer SzabadiFunctional neuroanatomy of the central noradrenergic system

  

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Journal of Psychopharmacology27(8) 659 –693

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Contents1. Introduction2. Noradrenergic nuclei3. The noradrenergic neurone4. Efferents of the locus coeruleus4.1 Telencephalon4.1.1 Neocortex4.1.2 Basal forebrain4.2 Limbic system4.2.1 Amygdala4.2.2 Hippocampus4.3 Diencephalon4.3.1 Thalamus4.3.2 Hypothalamus4.3.2.1 Ventrolateral preoptic area4.3.2.2 Lateral hypothalamic/perifornical area

4.3.2.3 Paraventricular nucleus4.3.2.4 Arcuate nucleus/tuberinfundibular area4.4 Brainstem4.4.1 Sympathetic premotor nuclei4.4.1.1 Rostroventrolateral medulla4.4.1.2 Caudal raphe nuclei

Functional neuroanatomy of the central noradrenergic system

Elemer Szabadi

AbstractThe central noradrenergic neurone, like the peripheral sympathetic neurone, is characterized by a diffusely arborizing terminal axonal network. The central neurones aggregate in distinct brainstem nuclei, of which the locus coeruleus (LC) is the most prominent. LC neurones project widely to most areas of the neuraxis, where they mediate dual effects: neuronal excitation by α1-adrenoceptors and inhibition by α2-adrenoceptors. The LC plays an important role in physiological regulatory networks. In the sleep/arousal network the LC promotes wakefulness, via excitatory projections to the cerebral cortex and other wakefulness-promoting nuclei, and inhibitory projections to sleep-promoting nuclei. The LC, together with other pontine noradrenergic nuclei, modulates autonomic functions by excitatory projections to preganglionic sympathetic, and inhibitory projections to preganglionic parasympathetic neurones. The LC also modulates the acute effects of light on physiological functions (‘photomodulation‘): stimulation of arousal and sympathetic activity by light via the LC opposes the inhibitory effects of light mediated by the ventrolateral preoptic nucleus on arousal and by the paraventricular nucleus on sympathetic activity. Photostimulation of arousal by light via the LC may enable diurnal animals to function during daytime. LC neurones degenerate early and progressively in Parkinson‘s disease and Alzheimer‘s disease, leading to cognitive impairment, depression and sleep disturbance.

KeywordsLocus coeruleus, noradrenaline, neuroanatomy, forebrain, telencephalon, diencephalon, brainstem, spinal cord, arousal, autonomic functions, photomodulation

AbbreviationsAD: Alzheimer‘s disease; BF: basal forebrain, CNS: central nervous system; CR: caudal raphe; CRF: corticotrophin releasing factor; DMH: dorsomedial hypothalamus; DMV: dorsal motor nucleus of the vagus; DR: dorsal raphe nucleus; EEG: electroencephalogram; EMG: electromyogram; EWN: Edinger-Westphal nucleus; GABA: γ-aminobutyric acid; GH: growth hormone; GHRH: growth hormone releasing hormone; 5HT: 5hydroxytryptamine; IML: intermediolateral cell column (of the spinal cord); ipRGC: intrinsically photosensitive retinal ganglion cell; LC: locus coeruleus; LDT: laterodorsal tegmental nucleus; LH/PF: lateral hypothalamic/perifornical area; NIF: non-image forming; NMDA: N-methyl D-aspartate; OPN: olivary pretectal nucleus; PAG: periaqueductal grey matter; PD: Parkinson‘s disease; PGi: nucleus paragigantocellularis lateralis; PPT: pedunculopontine tegmental nucleus; PrH: nucleus prepositus hypoglossi; PVN: paraventricular nucleus; REM: rapid eye movement; RVLM: rostroventrolateral medulla; SCN: suprahiasmatic nucleus; SWS: slow wave sleep; TMN: tuberomamillary nucleus; VLPO: ventrolateral preoptic area; VTA: ventral tegmental area.

Division of Psychiatry, University of Nottingham, Nottingham, UK

Corresponding author:Elemer Szabadi, Division of Psychiatry, School of Community Health Sciences, University of Nottingham, Room B109, Medical School, Queen‘s Medical Centre, Nottingham NG7 2UH, UK. Email: elemer.szabadi@nottingham.ac.uk

490326 JOP27810.1177/0269881113490326Journal of Psychopharmacology Szabadi2013

Review

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4.4.2 Parasympathetic preganglionic nuclei4.4.2.1 Edinger-Westphal nucleus4.4.2.2 Salivatory nuclei4.4.2.3 Vagal nuclei4.4.3 Motor nuclei4.4.3.1 Oculomotor nucleus4.4.3.2 Trigeminal motor nucleus4.4.3.3 Facial nucleus4.4.3.4 Hypoglossal nucleus4.4.4 Sensory nuclei4.4.4.1 Sensory trigeminal nuclei4.4.4.2 Cochlear nuclei4.4.5 Sleep/arousal regulating nuclei4.4.5.1 Dorsal raphe nucleus4.4.5.2 Pedunculopontine tegmental and laterodorsal tegmental

nuclei4.5 Cerebellum4.6 Spinal cord4.6.1 Dorsal horn4.6.2 Ventral horn4.6.3. Intermediolateral cell column5. Afferents of the locus coeruleus5.1 Neocortex5.2 Amygdala5.3 Hypothalamus5.3.1 Ventrolateral preoptic area5.3.2 Lateral hypothalamic/perifornical area5.3.3 Tuberomammillary nucleus5.3.4 Paraventricular nucleus5.4 Brainstem5.4.1 Midbrain and pons5.4.1.1 Ventral tegmental area5.4.1.2 Periaqueductal grey matter5.4.1.3 Dorsal raphe nucleus5.4.1.4 Pedunculopontine and laterodorsal tegmental nuclei5.4.2 Medulla oblongata5.4.2.1 Rostral ventrolateral medulla5.4.2.2 Dorsomedial rostral medulla5.4.3 Sensory trigeminal nuclei5.5 Spinal cord6 The locus coeruleus in regulatory networks6.1 Sleep/arousal network6.2 Autonomic network6.3 Photomodulation network7 Neuropathology of the locus coeruleus8 Pathophysiology of the locus coeruleus9 Conclusions

1. IntroductionInterest in the noradrenergic system goes back to the discovery by Otto Loewi (1921) that a chemical substance released by sympa-thetic nerve endings transmits the effect of sympathetic stimula-tion to the heart. Although it was established relatively early that this substance was a catecholamine, probably adrenaline, it took another 30 years to accumulate a convincing body of evidence to show that it was noradrenaline (Von Euler, 1951). Soon after this, noradrenaline was found in the brain (Vogt, 1954), and later local-ized in distinct sets of neurones (Dahsltröm and Fuxe, 1964). For

a historical review of noradrenergic neurotransmission, the reader is referred to Iversen (1967) and Livett (1973).

The topic of this review is the functional neuroanatomy of the central noradrenergic system. After a brief description of the noradrenergic neurone, the efferent and afferent connections of the locus coeruleus (LC), the major noradrenergic nucleus, will be discussed. In this section, the Jacksonian concept of the hier-archical organization of the brain (Greenblatt, 1999) will be fol-lowed, starting at the cerebral cortex and finishing with the spinal cord (for examples, see Szabadi (1993)). Finally, the func-tional importance of these connections will be illustrated by con-sidering the role of the LC in a number of regulatory networks of the brain.

Due to limitations of space, this review is not aimed at com-prehensive coverage, but rather attempts to illustrate the func-tional importance of the anatomical hardware. A number of excellent reviews of the anatomy of the central noradrenergic system have been published over the years, covering different aspects of the topic at variable degrees of details (e.g. Amaral and Sinnamon, 1977; Aston-Jones et al., 1991b; Byrum and Guyenet, 1987; Cederbaum and Aghajnaian, 1978; Foote et al., 1983; Guyenet, 1991; Loughlin et al., 1986a, 1986b; Luppi et al., 1995; Moore and Bloom, 1979; Nieuwenhuys, 1985; Van Dongen, 1981). The present paper relies, in parts, on a recent review with a focus on the role of the LC in the regulation of arousal and autonomic functions (Samuels and Szabadi, 2008a, 2008b).

2. The noradrenergic neuroneThe nerve terminals of the peripheral noradrenergic sympathetic neurone arborize profusely to create a dense meshwork (‘sympa-thetic ground plexus‘). The terminal fibers contain enlargements (‘varicosities‘) which give a string-of-beads-like appearance to the fibers. The varicosities have the structure and function of pre-synaptic terminals or ‘boutons‘, and have been identified as sites of release (Geffen and Livett, 1971; Livett, 1973). Interestingly, an analogous situation has been described in several structures of the central nervous system (CNS), such as the cerebral cortex (Beaudet and Descarries, 1978; Descarries et al., 1977), amygdala (Farb et al., 2010) and hypothalamus (Marrotte and Raisman, 1974). In fact, the release of noradrenaline from axonal varicosi-ties is now regarded as a general feature of central noradrenergic neurones (Chiti and Teschemacher, 2007; Kasparov and Teschemacher, 2008). Although some of the noradrenergic bou-tons form one-to-one contacts with adjoining neurones, many of them are located in interstitial spaces without any identifiable syn-aptic contacts. The existence of non-synaptic boutons suggests that noradrenaline, apart from acting as synaptic transmitter, may also have a more diffuse hormone-like action in the brain (Beaudet and Descarries, 1978; Descarries and Mechawar, 2000). Interestingly, such a dual synaptic and non-synaptic action has also been demonstrated for the other monoamine neurotransmit-ters, dopamine and 5-hydroxytryptamine (serotonin) (Descarries and Mechawar, 2000) and for neuropeptide transmitters (Del Cid-Pellitero and GarzÓn, 2011). The terms ‘wiring transmission‘ and ‘volume transmission‘ have been used to refer to the two kinds of neurotransmission (Fuxe et al., 2010). A different terminology has been suggested by Nieuwenhuys (1985), referring to the synaptic

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release of the neurotransmitter as ‘neurocrine secretion‘ and the non-synaptic release as ‘paracrine secretion‘.

Noradrenergic neurones may contain and release neurotrans-mitters other than noradrenaline (‘cotransmission‘: Burnstock, 2004; Campbell, 1987; Kupfermann, 1991). Cotransmitters in peripheral (sympathetic) noradrenergic neurones include adeno-sine triphosphate (ATP) and neuropetide Y (NPY) (Burnstock, 2004, 2009; Wier et al., 2009), and in central noradrenergic neu-rones ATP (Burnstock, 2004, 2009), NPY (Xu et al., 1998), gluta-mate (Fung et al., 1994a, 1994b), enkephalin (Fung et al., 1994a, 1994b) and the neuropeptide galanin (Le Maître et al., 2013; Xu et al., 1998). The cotransmitter may modulate the action of noradrenaline both at pre-synaptic sites (release) and post-synap-tic sites (neurotransmission) (Burnstock 2004, 2009; Herring and Paterson, 2009).

Central noradrenergic neurones make contacts not only with neurones but also with non-neuronal elements of the CNS, such as glia cells and blood vessels. Both types of macroglial cells (astro-cytes and oligodendrocytes) have been shown to possess intimate contacts with noradrenergic nerve fibers (Paspalas and Papadopoulos, 1996). Both α- and β-adrenoceptors have been identified on glia cells. The α-adrenoceptors belong mainly to the α1 subclass, whereas both β1 and β2 adrenoceptors are present in large densities on astrocytes (Hertz et al., 2004; Stone and Ariano, 1989). Recently β3-adrenoceptors have also been identified on astrocytes (Catus et al., 2011). The noradrenergic innervation of astrocytes has been implicated in the generalized metabolic response of the brain to stress via the activation of glycogenolysis, production of neurotrophic substances (e.g. nerve growth factor), mediation of glial-neuronal signaling (Farb et al., 2010; Stone and Ariano, 1989), and consolidation of memory (Hertz et al., 2004). Less information is available about the functional relevance of the noradrenergic innervation of oligodendrocytes. The major func-tion of oligodendroglia is the production of myelin: the myelin sheath of axons allows for the fast transmission of signals via ‘sal-tatory conduction‘ (Baumann and Pham-Dinh, 2001). While cen-tral noradrenergic axons, like the axons of peripheral sympathetic neurones, are unmyelinated (Kasparov and Teschemacher, 2008; Kiernan, 2005), the noradrenergic innervation of oligodendro-cytes may play an important role in the myelination of other path-ways (Davis et al., 2012).

Small blood vessels also receive an innervation from central noradrenergic neurones (Hartman et al., 1972; Paspalas and Papadopoulos, 1996; Raichle et al., 1975). This innervation has been implicated in the control of cerebral microcirculation: while the large extraparenchymal intracranial blood vessels receive their sympathetic noradrenergic innervation from the superior cervical ganglion, the small intraprenchymal vessels are under direct cen-tral noradrenergic control (Raichle et al., 1975). Both α- and β-adrenoceptors have been detected in cerebral microvessels (Kobayashi et al., 1982; Yokoo et al., 2000), and the α-adrenoceptors have been further characterized as belonging mainly to the α1A subtype (Yokoo et al., 2000). Although there are direct contacts between noradrenergic nerve terminals and cere-bral microvessels, in a number of instances the noradrenergic influence on the blood vessel seems to be mediated by glia cells, as indicated by the interposition of an astrocytic foot between the noradrenergic terminal and the vessel (Cohen et al., 1997; Paspalas and Papadopoulos, 1996).

As the peripheral and central neurones have common ori-gins, they share their genetic make-up and biochemical,

physiological and pharmacological properties. Figure 1 shows the pharmacologically sensitive sites of the noradrenergic neurone. In both peripheral and central noradrenergic neu-rones, noradrenaline is synthesized from the amino acid tyros-ine via the steps tyrosine → dopa → dopamine → noradrenaline, and stored in synaptic vesicles in the nerve terminal. The oper-ation of distinct transporter proteins in the vesicular and cel-lular membranes provides the mechanism for the accumulation and conservation of the transmitter within the synaptic vesi-cles and nerve terminals. Adrenoceptors stimulated by the released noradrenaline occur both post-synaptically and on the noradrenergic neurone itself (‘autoreceptors‘). Postsynaptic adrenoceptors in the periphery are located on smooth muscle or gland cells, and in the CNS on follower neurones and glia cells, and belong to any sub-class (α1, α2 or β) of adrenoceptor (Szabadi and Bradshaw, 1991; Szabadi et al., 1985). The auto-receptors are of the α2 sub-class and inhibitory in action: in a somato-dendritic location they inhibit neuronal firing (Huang et al., 2012), while located on the nerve terminal membrane (‘presynaptic receptors‘) they inhibit noradrenaline release (Starke, 2001). Noradrenergic neuronal activity is auto-regu-lated by the reuptake and re-storage of the released transmit-ter, and inhibition of noradrenaline release and cellular firing via the activation of inhibitory autoreceptors.

Interestingly, presynaptic release-modulating adrenoceptors occur not only on the axon terminals of noradrenergic neurones (autoreceptors), but also on the nerve terminals of other neurones (heteroreceptors) (Gilsbach and Hein, 2012; Starke, 2001). The presynaptic heteroreceptors, like the autoreceptors, belong to the α2 subclass and are inhibitory in nature. In the CNS, presynaptic heteroreceptors have been identified on the terminals of seroton-ergic (Millan et al., 2000; Scheibner et al., 2001), dopaminergic (Millan et al., 2000) and glutamatergic (Jiménez-Rivera et al., 2012; Shields et al., 2009) neurones. Furthermore, release-inhibit-ing adrenoceptors have been described on the nerve terminals of cholinergic neurones in the myenteric plexus (‘enteric nervous system‘) (LePard et al., 2004; Scheibner et al., 2002).

The three major sub-classes of adrenoceptor comprise a num-ber of subtypes that have been characterized pharmacologically on the basis of their affinities for selective ligands. Most of the receptor subtypes have been genetically defined and cloned. The α1-adrenoceptor sub-class comprises the subtypes α1A, α1B and α1D, and the α2-adrenoceptor sub-class consists of the subtypes α2A/D, α2B and α2C (Civantos Calzada and Aleixandre de Artiñano, 2001). The β-adrenoceptor sub-class comprises three subtypes: β1, β2 and β3 (Hieble and Ruffolo, 1995). All adrenoceptor subtypes have been identified in the CNS: α1-adrenoceptor subtypes (Day et al., 1997; Domyancic and Morilak, 1997; Shen et al., 2000; Szot et al., 2005; Williams and Morilak, 1997), α2-adrenoceptor subtypes (Flügge et al., 2003; Guyenet et al., 1994; Owesson et al., 2003; Scheinin et al., 1994; Tavares et al., 1996), and β-adrenoceptor subtypes (Hillman et al., 2005; Joyce et al., 1992; Paschalis et al., 2009; Summers et al., 1995; Ursino et al., 2009). Presynaptic adrenoceptors, both autoreceptors and heterorecep-tors, belong to the α2A/D subtype (Gilsbach and Hein, 2012; Starke, 2001).

3. Noradrenergic nucleiNoradrenergic neurones occur in clusters both in the periphery (sympathetic ganglia) and in the CNS (noradrenergic nuclei). A

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general feature of the central noradrenergic system is that the cell bodies are located in a relatively small number of distinct nuclei in the lower brainstem (pons and medulla oblongata), and the axons project to most parts of the brain and the spinal cord. There is a diffuse projection from the brainstem nuclei: many axon collater-als may arise from one neurone which may reach several remote areas of the CNS (e.g. cerebral cortex, limbic areas, hypothala-mus, cerebellum, spinal cord). However, in parallel with the dif-fuse noradrenergic projection, more targeted outputs to distinct destinations have also been identified (Nieuwenhuys, 1985; Papadopoulos and Parnavelas, 1991).

Seven noradrenergic nuclei can be distinguished, and they are labeled A1–A7 (Dahlström and Fuxe, 1964). Although these nuclei have originally been described in rats, most of them have also been identified in primates (Felten and Sladek, 1983; Jacobowitz and MacLean, 1978), including man (Bogerts, 1981). This suggests that the central noradrenergic system is a develop-mentally ancient system of the brain.

The noradrenergic nuclei can be divided into three groups: caudal (or medullary) group, central (or medullo-pontine) group, and rostral (or pontine) group. The rostral group is the most important in man: it consists of only one nucleus, area A6 (LC). The LC is the largest noradrenergic nucleus: it contains almost 50% of all the noradrenergic neurones. The LC is located in the dorsal tegmentum of the rostral area of the pons: it appears as a

bluish-grey (‘coeruleus‘) patch on the floor of the fourth cere-bral ventricle (Figure 2). The color of the LC is due to the pres-ence of the pigment neuromelanin in LC neurones. The presence of neuromelanin has led to the development of the technique of neuromelanin magnetic resonance imaging which has enabled the visualization of the LC in the human brain in vivo (Shibata et al., 2006) (Figure 2).

The fiber projections arising from the noradrenergic nuclei can be divided into two major groups: fibers arising from the caudal and central nuclear groups (A1, A2, A5 and A7) and fibers originating from the LC (A6). Fibres originating from areas A1, A2, A5 and A7 give rise to both ascending and descending fiber systems. The ascending fiber system forms the ventral noradrenergic bundle which innervates the mid-brain reticular formation, the entire hypothalamus and parts of the limbic cortex. The descending fibers form two bulbos-pinal bundles which terminate in the ventral and the interme-diate nuclear columns of the spinal cord. It should be noted that many of the targets of the ventral noradrenergic pathway also receive inputs from the LC. Thus, for example, while a major noradrenergic input to the hypothalamus derives from the A1, A2, A5 and A7 nuclei (ventral noradrenergic bundle), the LC also contributes to the noradrenergic innervation of the hypothalamus via the dorsal noradrenergic bundle (Nieuwenhuys, 1985).

Figure 1. Pharmacologically sensitive sites of the noradrenergic neurone. (Left) Adrenoceptors. Noradrenaline released from the axon terminals of the neurone can activate postsynaptic adrenoceptors on the target cells. Adrenoceptors are of three classes: α1 (excitatory); α2 (inhibitory); β (excitatory or inhibitory). There are also adrenoceptors on the noradrenergic neurone itself (autoreceptors): these are of the α2 subtype, and mediate inhibition. The autoreceptors are stimulated by noradrenaline released from the noradrenergic neurone. Terminal autoreceptors are located on the nerve terminals (‘presynaptic receptors‘) and inhibit the release of noradrenaline (‘release-modulating receptors’): somatodendritic autoreceptors are located on the cell body or the dendrites, and inhibit neuronal firing. Somatodendritic autoreceptors are stimulated by noradrenaline released either from the dendrites (‘dendritic release‘) or from recurrent nerve terminals. The stimulation of autoreceptors dampens the activity of the neurone (‘autoregulation‘). (Right) Noradrenergic synapse. Noradrenaline released from the nerve terminal stimulates postsynaptic receptors (1); it is eliminated from the synaptic gap by reuptake into the nerve terminal (2), and then can be taken up into the synaptic vesicle via vesicular uptake and re-stored in the vesicle (3).

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The fiber projections from the LC give rise to three path-ways: the ascending pathway (dorsal noradrenergic bundle), the cerebellar pathway and the descending pathway. The ascending pathway innervates structures in the midbrain (periaqueductal grey substance, nucleus raphe dorsalis, colliculi), thalamus, lim-bic system (amygdala, hippocampus, cingulate and parahip-pocampal gyri), and all areas of neocortex. The cerebellar pathway projects to the cerebellar nuclei and cerebellar cortex via the superior cerebellar peduncle. The descending pathway sends collaterals to motor nuclei in the lower brainstem (dorsal nucleus of the vagus, inferior olivary complex), and then descends to the spinal cord (coeruleo-spinal pathway), innervat-ing spinal neurones in all three nuclear columns. The functions of the noradrenergic pathways are discussed in detail with their targets in Section 4.

Although the organization of the noradrenergic nuclei and their fiber projections show great similarity between different mammalian species, there are also some differences. In pri-mates, nucleus A3 is absent (Nieuwenhuys, 1985) and while the medullary tegmental nuclei (A1 and A2) are very similar to those in rodents, the pontine nuclei (A4, A5, A6, A7) con-tain a much larger number of noradrenergic neurones than in

rodents (Schofield and Everitt, 1981). In carnivores (e.g. cat: Poitras and Parent, 1978; dog: Ishikawa et al., 1975), the pon-tine nuclei have large noradrenergic cell numbers like those in primates, however, the neurones are less aggregated into distinct nuclei and have a more diffusely distributed localiza-tion. In ungulates (e.g. sheep: Tillet and Thibault, 1989), the noradrenergic neurones are more loosely clustered than in rodents and primates, and the number of neurones is lower in the medullary noradrenergic nuclei (Tillet and Kitahama, 1998). For a detailed discussion of the species differences in the organization of central noradrenergic nuclei and the dis-tribution of their fiber projections, see Schofield and Everitt (1981). Although the anatomical differences between species are significant, they are relatively minor compared to differ-ences between the functional markers of central noradrener-gic activity. Thus major species differences in the distributions of both α- and β-adrenoceptors (Booze et al., 1989; Palacios et al., 1987) and the localization of the peptide co-transmitter galanin (Le Maître et al., 2013) have been reported. These observations indicate that caution is required when results obtained in rodents are extrapolated to other species, includ-ing man.

Figure 2. Location of the locus coeruleus (LC) in the brainstem. (Top left) Sagittal section through the brainstem showing the level of the cross-section displayed on the right. (Top right) Horizontal section through the upper pons showing the fourth cerebral ventricle. The loci coerulei are located in the lateral corners of the ventricle (shown in red). Reproduced, with permission, from Warner (2001) (copyright: Elsevier).(Bottom) Nuclear magnetic resonance image showing a cross-section of the upper pons displaying the loci coerulei. The picture was taken in a healthy human subject, with the modification of the method of Sasaki et al. (2006), on a 3-tesla scanner to obtain a neuromelanin signal to identify the loci coerulei. The loci coerulei are shown by the small white areas in the bottom corners of the fourth cerebral ventricle, indicated by yellow arrows. By courtesy of D Auer, Queen‘s Medical Centre, Nottingham. Reproduced from Samuels ER and Szabadi E (2008b) Functional neuroanatomy of the norad-renergic locus coeruleus: Its roles in the regulation of arousal and autonomic function. Part II: Physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans. Curr Neuropharmacol 6: 254–285 with permission from Bentham Science Publishers.

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4. Efferents of the LCFigure 3 shows a schematic overview of LC efferents.

4.1 Telencephalon

The telencephalon is the most anterior part of the forebrain, com-prising the cerebral cortex and the basal ganglia. Other parts of the forebrain include the limbic system and the diencephalon.

4.1.1 Neocortex. The neocortex receives a rich noradrenergic innervation which derives entirely from the LC. Indeed, there is a close correlation between LC activity and noradrenaline release in the neocortex (Berridge and Abercrombie, 1999).

The LC projects (coeruleo-cortical pathway), via the dorsal noradrenergic bundle, to all areas of the neocortex (Gatter and Powell, 1977; Jones and Yang, 1985; Séguéla et al., 1990). The extensive nature of the noradrenergic innervation of the neocortex suggests that the projection from the LC exerts a diffuse influence on this structure (Nieuwenhuys, 1985). Although there is anatomi-cal evidence consistent with a diffuse pattern of noradrenergic innervation (Loughlin et al., 1982; Nagai et al., 1981), a large degree of topographic specificity has also been found (Foote et al., 1983; Levitt et al., 1984; Morrison et al., 1979, 1982; Papadopoulos and Parnavelas, 1991). This topographic specificity is illustrated by the recent observation that LC neurones that receive afferents from the orexinergic neurones of the lateral hypothalamic area project to the medial prefrontal cortex (Del Cid-Pellitero and Garzόn, 2011).

Figure 3. Efferents of the locus coeruleus (LC). Arrows indicate projections. Red arrowhead: excitatory; blue arrowhead: inhibitory. Coloring of target area indicates function (for code see figure).A: amygdala; BF: basal forebrain; Cllm: cerebellum; CR: caudal raphe; DR: dorsal raphe; Hc: hippocampus; Ht: hypothalamus; IL: intralaminar nuclei; LH: lateral hypo-thalamic area; PPT/LDT; pedunculopontine/laterodorsal tegmental nuclei; PVN: paraventricular nucleus; RVLM: rostroventrolateral medulla; SS: somatosensory thalamus; symp: sympathetic preganglionic neurones; Tinf: tuberoinfundibular area; Th thalamus; VLPO: ventrolateral preoptic area.In the brainstem, encircled Arabic numbers indicate functional nuclear groups: (1), motor; (2), sensory; (3), premotor sympathetic; (4), preganglionic parasympathetic; (5), sleep/wakefulness-modulating. Roman numbers correspond to cranial nerves: III: oculomotor; V: trigeminal; VII: facial; VIII: auditory; IX: glossopharyngeal; X: vagus. The LC exerts an excitatory influence on the neocortex, hippocampus, amygdala and cerebellum, on wakefulness-promoting neurones in the BF, thalamus (IL) and brainstem (DR, PPT/LDT), on motor neurones in the brainstem and spinal cord, on sensory neurones in the thalamus (SS) and brainstem, on premotor sympathetic neu-rones in the hypothalamus (PVN) and brainstem (CR) and on neuroendocrine neurones in the hypothalamus (PVN and Tinf), and on preganglionic sympathetic neurones in the spinal cord. It should be noted, however, that the noradrenergic innervation of the preganglionic sympathetic neurones derives mainly from the A5/A7 pontine nuclei. On the other hand, the LC inhibits sleep-promoting neurones in the BF, hypothalamus (VLPO) and brainstem (PPT/LDT), some wakefulness-promoting neurones in the hypothalamus (LH), some premotor sympathetic neurones in the brainstem (RVLM), preganglionic parasympathetic neurones in the brainstem, some trigeminal (not shown, see Section 5.4.3) and spinal sensory neurones.

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The LC exerts an excitatory influence on the cerebral cortex. This is largely due to the stimulation of excitatory α1-adrenoceptors that are expressed in high concentrations through-out the cortex (Domyancic and Morilak, 1997; Jones et al., 1985; Papay et al., 2006; Pieribone et al., 1994). All three subtypes of α1-adrenoceptor have been identified in the neocortex: α1A (Day et al., 1997; Domyancic and Morilak, 1997; Pieribone et al., 1994), α1B (Acosta-Martinez et al., 1999; Day et al., 1997; Pieribone et al., 1994) and α1D (Day et al., 1997; Pieribone et al., 1994). Inhibitory α2-adrenoceptors have also been identified, however, in smaller numbers than the α1-adrenoceptors and in a more selective distribution (Pascual et al., 1992; Talley at al., 1996). The cortical α2-adrenoceptors belong mainly to the α2A subtype (Blake et al., 1998; Scheinin et al., 1994). It has been proposed that these receptors may be located on inhibitory interneurones where their stimulation would disinhibit cortical neurones leading to cortical excitation (Andrews and Lavin, 2006). β-Adrenoceptors are also detectable in the neocortex (Wanaka et al., 1989): all three subtypes have been identified (Chen et al., 2012; Joyce et al., 1992; Paschalis et al., 2009; Rodriguez et al., 1995; Van Warde et al., 1997).

There is a close relationship between LC activity and overall cortical activity as shown by the electroencephalogram (EEG): activation of the LC leads to the activation of the cerebral cortex (Berridge and Foote, 1991), whereas inactivation of the LC results in a reduction in cortical EEG activity (Berridge et al., 1993; Danysz et al., 1989). Cortical activation by the LC under-lies the role of the LC as a major wakefulness-promoting nucleus (see Section 6.1). Indeed, there is a close parallelism between LC activity and the level of arousal (Aston-Jones and Bloom, 1981; Aston-Jones et al., 1991a; Foote et al., 1991; Rajkowski et al., 1994).

4.1.2 Basal forebrain. The BF comprises the medial septal area, medial preoptic area and substantia innominata. All three areas receive a noradrenergic innervation from the LC (España and Berridge, 2006). The BF contains both cholinergic excitatory and γ-aminobutyric acid (GABA)ergic inhibitory neurones (Gritti et al., 1993). Both types of neurone project to the neocortex and play a role in the modulation of arousal (Jones, 2004; Modirrousta et al., 2004): the cholinergic neurones are active during wakeful-ness and quiescent during sleep (Manns et al., 2000a) whereas the reverse pattern of activity applies to the GABAergic neurones (Manns et al., 2000b). The noradrenergic projection from the LC modulates the activity of both types of neurone (Figure 4). Nor-adrenaline released from the noradrenergic terminals activates the wakefulness-promoting cholinergic neurones (Fort et al., 1995; Jones, 2004), via the stimulation of excitatory α1- and β1-adrenoceptors (Berridge et al., 2003) whereas it suppresses the activity of sleep-promoting GABAergic neurones, via the stimula-tion of inhibitory α2-adrenoceptors (Manns et al., 2003). Overall, the LC exerts a wakefulness-promoting effect via the BF. Thus, the indirect activation of the neocortex via the BF enhances the wakefulness-promoting effect of the LC resulting from cortical activation by the coeruleo-cortical pathway (see above).

4.2 Limbic system

4.2.1 Amygdala. The LC sends a dense noradrenergic projec-tion to the amygdala, mainly to the central and basal nuclei (Fal-lon et al., 1978; Jones and Moore, 1977). The adrenoceptors expressed in the amygdala are mainly of the α1 sub-class (Jones et al., 1985; Papay et al., 2006; Pieribone et al., 1994), although a smaller population of α2-adrenoceptors has also been identified (Glass et al., 2002; Pascual et al., 1992). The α1- adrenoceptors

Figure 4. Dual influence of the basal forebrain (BF) on cortical arousal. Circles represent neurones and arrows represent connections (red, excitatory; blue, inhibitory). Neurotransmitters: ACh: acetylcholine; GABA: γ-aminobutyric acid; NA: noradrenaline. Cholinergic neurones of the BF stimulate, and GABAergic neurones inhibit, cortical activity. The locus coeruleus (LC) modulates BF activity by a dual action: it stimulates the excitatory cholinergic neurones via α1-adrenoceptors, and inhibits the inhibitory GABAergic neurones via α2-adrenoceptors. Overall, the LC exerts a powerful wakefulness-promoting influence via the BF (see Section 4.1.2 for details).

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belong mainly to the α1A subtype (Day et al., 1997), and the α2- adrenoceptors to the α2A subtype (Glass et al., 2002; Scheinin et al., 1994). β-Adrenoceptors are also present in the amygdala, both in the central and basolateral nuclei (Wanaka et al., 1989): they have been identified as belonging to the β1 (Ghiasvand et al., 2011; Paschalis et al., 2009; Qu et al., 2008; Silberman et al., 2012) and the β2 (Qu et al., 2008) subtypes. Specific functions have been attributed to β-adrenoceptors in different amygdaloid nuclei: β-adrenoceptors in the lateral nucleus have been impli-cated in fear-conditioning (Farb et al., 2010), in the basolateral nucleus in anxiety (Silberman et al., 2012), in consolidation of fear memory (Qu et al., 2008) and in the central nucleus in state-dependent memory (Ghiasvand et al., 2011). Both excitatory and inhibitory neuronal responses to locally applied noradrenaline and to LC stimulation have been observed in the basolateral nucleus, the excitatory responses being mediated via β-adrenoceptors and the inhibitory responses via α2-adrenoceptors (Buffalari and Grace, 2007).

The amygdala plays a key role in mediating fear and anxiety responses to threatening environmental stimuli (Damasio, 1998; LeDoux, 1998). The stimulation of the LC, electrically or by the administration of an α2-adrenoceptor antagonist (e.g. yohimbine), leads to an increase in anxiety (McDougle et al., 1995; Redmond and Huang, 1979), consistent with the activation of the amygdala which suggests that the overall noradrenergic influence on the amygdala is likely to be excitatory. The noradrenergic projection to the amygdala has also been implicated in the formation and retrieval of emotional memories (Chen and Sara, 2007; Sterpenich et al., 2006).

4.2.2 Hippocampus. The LC also sends a projection to the hip-pocampus: in fact, the LC is the sole source of noradrenaline in this structure (Fu et al., 1999; Loughlin et al., 1986b). Both α1- (Jones et al., 1985; Pieribone et al., 1994) and α2-adrenoceptors (Pascual et al., 1992; Scheinin et al., 1994) have been identified in the hippocampus. There is a species difference in the densities of hippocampal α1-adrenoceptors between primates and rodents: these receptors are much more numerous in primates than in rodents (Palacios et al., 1987). The α1-adrenoceptors belong mainly to the α1A subtype (Day et al., 1997; O‘Malley et al., 1998; Pieribone et al., 1994; Szot et al., 2005), although α1D adrenocep-tors are also present (Williams et al., 1997). The α2-adrenoceptors belong mainly to the α2A subtype (Scheinin et al., 1994). β-Adrenoceptors are also present in the hippocampus (Wanaka et al., 1989): both β1 and β2 subtypes have been identified (Guo and Li, 2007; Hillman et al., 2005; Joyce et al., 1992; Paschalis et al., 2009).There is also evidence of the presence of β3 adreno-ceptors in the hippocampus (Summers et al., 1995). The LC pro-jection to the hippocampus has been implicated both in the formation (Sullivan et al., 1994) and retrieval (Sara and Devauges, 1988) of memories.

4.3 Diencephalon

The diencephalon consists of the thalamus and hypothalamus.

4.3.1 Thalamus. The thalamus receives a profuse noradrener-gic projection from the LC (Ishikawa and Tanaka, 1977; Jones and Yang, 1985). Excitatory α1-adrenoceptors are abundant in

the thalamus (Jones et al., 1985): they belong to the α1B subtype (Day et al., 1997; Pieribone et al., 1994). A smaller population of α2-adrenoceptors is also present in the thalamus: these belong to the α2B subtype (Scheinin et al., 1994). β1-Adrenoceptors have been identified in the medial habenular nucleus of the thalamus, but most other areas of the thalamus are devoid of this adreno-ceptor sub-class (Paschalis et al., 2009). The noradrenergic pro-jection to the thalamus has been implicated in the promotion of wakefulness (McBride and Sutin, 1976; McCormick et al., 1991) and the modulation of pain (Westlund et al., 1991; Zhang et al., 1998a).

4.3.2 Hypothalamus. Although the noradrenergic innervation of the hypothalamus derives largely from the A1/A5 nuclei via the ventral noradrenergic bundle, the LC also contributes to it (Cun-ningham and Sawchenko, 1988; Niewenhuys, 1985).

Two arousal-modulating hypothalamic nuclei, the ventrolat-eral preoptic area (VLPO) and the lateral hypothalamic/periforni-cal area (LH/PF) are under noradrenergic influence.

4.3.2.1 VLPO. The VLPO, the major sleep-promoting nucleus, receives a noradrenergic input from the LC (Chou et al., 2002; Osaka and Matsumura, 1994). Noradrenaline, released from LC nerve terminals during wakefulness, inhibits GABAergic VLPO neurones via the stimulation of α2-adrenoceptors (Gallo-pin et al., 2000; Modirrousta et al., 2004; Osaka and Matsumura, 1994), and thereby promotes wakefulness (Nelson et al., 2002). The α2-adrenoceptors in this nucleus belong to the α2A subtype (Scheinin et al., 1994).

4.3.2.2 LH/PF. The LC also projects to the wakefulness-promoting orexinergic neurones in the LH/PF (Baldo et al., 2003; Yamanaka et al., 2003). There is only a sparse presence of α1-adrenoceptors in the lateral hypothalamus, mainly in the form of α1B-adrenoceptors (Day et al., 1997). On the other hand, α2-adrenoceptors are more abundant (α2A subtype: Scheinin et al., 1994). The noradrenergic projection to this area exerts an inhibitory influence on the orexinergic neurones (Li and van den Pol, 2005; Yamanaka et al., 2003), probably via the stimulation of inhibitory α2A-adrenoceptors. Interestingly, these α2-adrenoceptors seem to be subject to regulation by sleep-depriva-tion: it has been reported that the α2-adrenoceptor agonist clonidine inhibits orexinergic neurones only in sleep-deprived animals, whereas it is ineffective in non-sleep deprived controls (Uschakov et al., 2011). As the orexinergic neurones send a powerful excitatory projection to the LC (see Section 5.3.2), the inhibitory output from the LC to the LH/PF constitutes a nega-tive feedback loop which may serve to protect the LC from over-excitation during arousal (Samuels and Szabadi, 2008a). For details of the role of the LC in the regulation of sleep and arousal, see Section 6.1.

4.3.2.3 Paraventricular nucleus. The LC sends a projec-tion to the paraventricular nucleus (PVN) of the hypothalamus (Jones and Moore, 1977; Jones and Yang, 1985). The PVN is a major premotor autonomic nucleus that modulates the activity of both sympathetic and parasympathetic preganglionic neurones (i.e. ‘vegetative motor neurones‘) (Buijs et al., 2003; Swanson and Sawchenko, 1980, 1983). The sympathetic preganglionic neurones are located in the intermedio-lateral nuclear column (IML) of the spinal cord, whereas the parasympathetic pregangli-onic neurones are situated in the medulla oblongata. The PVN projects to both these sites (Holstege, 1987; Hosoya et al., 1991;

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Papay et al., 2006; Pyner, 2009; Ranson et al., 1998; Saper et al., 1976; Sawchenko and Swanson, 1982). Both α1- (Chong et al., 2004; Day et al., 1997) and α2-adrenoceptors (Chong et al., 2004; Li et al., 2005) are expressed in the PVN. The α1-adrenoceptors belong to the α1A (Chong et al., 2004; Day et al., 1997) and the α1B subtypes (Williams and Morilak, 1997) and the α2-adrenoceptors to the α2A subtype (Chong et al., 2004; Scheinin et al., 1994). β-Adrenoceptors are also present in this nucleus (Boundy and Cincotta, 2000; Takano et al., 1989; Wanaka et al., 1989), mainly in the form of β1-adrenoceptors (Paschalis et al., 2009). The acti-vation of both α-adrenoceptor subtypes leads to excitation of PVN neurones: α1-adrenoceptor activation directly, and α2-adrenoceptor activation indirectly, by switching off the activity of GABAergic inhibitory interneurones on which these receptors are located (Li et al., 2005). Apart from the premotor autonomic neu-rones, there is also a population of smaller (‘parvocellular‘) neu-rones in the PVN which have neurosecretory (neuroendocrine) functions (Cunningham and Sawchenko, 1988; Daftary et al., 2000; Swanson and Sawchenko, 1980). These neurones, that secrete trope hormones regulating pituitary activity, are also under noradrenergic influence (Sands and Morilak, 1999). Noradrena-line excites the majority of parvocellular neurones via α1-adrenoceptors, but inhibits a subpopulation via β-adrenoceptors (Daftary et al., 2000). The noradrenergic projection to the PVN has been implicated in mediating autonomic and endocrine responses to stress (Bienkowski and Rinaman, 2008; Herman et al., 2003; Li et al., 1996).

4.3.2.4 Arcuate nucleus/tuberinfundibular area. The arcuate nucleus of the tuberinfundibular area of the hypothala-mus also receives a noradrenergic input both from the LC (Jones and Moore, 1977; Pickel et al., 1974), and the A1 noradrener-gic nucleus in the medulla (Palkovits et al., 1980). The arcuate nucleus, like the PVN, is a major neuroendocrine nucleus which, through its manifold connections, is involved in the integration of endocrine, emotional, sensory, vegetative homeostatic and autonomic functions (Chronwall, 1985). Both excitatory α1- and β-adrenoceptors (Acosta-Martinez et al., 1999; Kang et al., 2000) and inhibitory α2-adrenoceptors (Young and Kuhar, 1980) have been identified in the arcuate nucleus. The α1-adrenoceptors belong mainly to the α1A subtype (Day et al., 1997), the α2-adrenoceptors to the α2A subtype (Scheinin et al., 1994) and the β-adrenoceptors to the β1 subtype (Paschalis et al., 2009). The secretion of growth hormone (GH) by the pituitary is under con-trol by growth-hormone-releasing hormone (GHRH) that stim-ulates GH secretion and somatostatin that inhibits it (Guistina and Veldhuis, 1998). GHRH and somatostatin are secreted by neurosecretory peptidergic arcuate neurones into the portal cir-culation. The secretion of GH is modulated by the noradrenergic system via α2-adrenoceptors. Although it is well documented that the stimulation of central α2-adrenoceptors (e.g. by the admin-istration of the α2-adrenoceptor agonist clonidine) leads to an increase in GH secretion, the location of these receptors remains controversial, both GHRH- and somatostatin-secreting arcuate neurones having been implicated (Giustina and Veldhuis, 1998). Dopaminergic neurones in the arcuate nucleus (‘tuberoinfundib-ular dopamine (TIDA) neurones‘) are responsible for the tonic inhibition of the release of prolactin by the pituitary (Ben-Jon-athan and Hnasko, 2001; Lyons et al., 2012). The noradrenergic system is likely to be involved in the regulation of the activity of TIDA neurones, since it has been shown that these neurones

receive a noradrenergic input (Hrabovsky and Liposits, 1994). Furthermore, it has been reported that the wakefulness-promot-ing drug modafinil, believed to enhance noradrenergic LC activ-ity (Hou et al., 2005), reduces prolactin secretion (Samuels et al., 2006) which is consistent with the stimulation of TIDA neurones via α1-adrenoceptors (Kang et al., 2000).

4.4 Brainstem

The LC projects, together with other noradrenergic nuclei, to a large number of neuronal groups in the brainstem. These include autonomic (sympathetic premotor and parasympathetic pregan-glionic) nuclei, somatic (motor and sensory) nuclei, and also nuclei involved in the regulation of sleep and arousal. The para-sympathetic preganglionic nuclei, together with the somatic motor and sensory nuclei, are usually described under the head-ing ‘cranial nerves‘.

4.4.1. Sympathetic premotor nuclei. Two important neuronal groups in the medulla have higher order (i.e. premotor) sympa-thetic functions: the rostroventrolateral medulla (RVLM) and the caudal raphe (CR) nuclei.

4.4.1.1 RVLM. Glutamatergic neurones of the RVLM pro-ject to preganglionic sympathetic neurones in the IML of the spi-nal cord (Barman and Gebber, 1985; Zagon and Smith, 1993). RVLM neurones possess an intrinsic pacemaker activity, and play a role in the maintenance of blood pressure and heart rate (Damp-ney, 1994; Sun, 1995). In general, the RVLM has a stimulatory effect on blood pressure (Kapoor et al., 1992) and also contributes to the efferent branch of the baroreflex (Dampney, 1994). The LC projects to the RVLM (Van Bockstaele et al., 1989) (‘coeruleo-vasomotor pathway‘), where noradrenaline exerts an inhibitory effect via the stimulation of α2–adrenoceptors (Head et al., 1998; Tavares at al., 1996). However, the stimulation of the LC is asso-ciated with moderate increases in heart rate and blood pressure (Drolet and Gauthier, 1985; Gurtu et al., 1984), suggesting that the vasodepressor effect of the LC, arising from the inhibition of the RVLM, may be superseded by a vasopressor effect. The likely substrate for this vasopressor effect is the stimulation of excita-tory α1-adrenoceptors on preganglionic sympathetic neurones via a direct output from the LC to the spinal cord (‘coeruleo-spinal pathway‘, see below). For a detailed description of the role of the LC in cardiovascular regulation, see Section 6.2.

4.4.1.2 CR nuclei. The nuclei (raphe magnus, obscurus and pallidus) of the CR are involved in modulating sympathetic functions via serotonergic outputs to the IML of the spinal cord (Allen and Cechetto, 1994; Loewy, 1981). The LC projects to the CR (Hermann et al., 1997). The adrenoceptors identified in the CR are mainly of the α1 subtype (Domyancic and Morilak, 1997), although α2-adrenoceptors have also been detected (Guy-enet et al., 1994). The CR has been implicated in mediating thermoregulatory functions (Nakamura et al., 2004, 2005): cold exposure excites CR neurones (Rathner et al., 2001). The noradr-energic stimulation of CR neurones by the LC would be expected to lead to sympathetic excitation resulting in an increase in body temperature. A subgroup of CR neurones projects to the dorsal column of the spinal cord (Kwiat and Basbaum, 1992; Rivot et al., 1982), and is involved in the suppression of nociception (Furst, 1999; Millan, 2002). The noradrenergic projection to the

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antinociceptive CR neurones has been shown to modulate sero-tonergic antinociception (Bie et al., 2003).

4.4.2 Parasympathetic preganglionic nuclei. These nuclei include the Edinger-Westphal nucleus (EWN) (cranial nerve III), the salivatory nuclei (cranial nerves VII and IX), and the vagal nuclei (cranial nerve X). The preganglionic neurones are choliner-gic, and project to the cholinergic neurones of the parasympa-thetic ganglia. They receive a noradrenergic input from the LC which exerts an inhibitory action on them via the stimulation of α2-adrenoceptors.

4.4.2.1 EWN. This nucleus is part of the oculomotor nuclear complex of the midbrain, situated in the ventral periaqueductal grey on the dorsal tip of the somatomotor nucleus of the third cra-nial nerve. EWN neurones project to postganglionic neurones in the ciliary ganglion (CG), which in turn innervate smooth muscle fibers in the sphincter pupillae muscle of the iris and the ciliary body. EWN neurones are light-sensitive: light stimulates mel-anopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), which project to the EWN via the olivary pretec-tal nucleus (OPN) (Gooley et al., 2003; Kawasaki and Kardon, 2007). Light evokes pupil constriction via the ‘retina → OPN → EWN → CG → sphincter pupillae muscle‘ pathway (‘pupillary light reflex‘) (Thompson, 1996). The EWN receives a noradren-ergic input that may originate from both both the A5/A7 nuclei (Levitt and Moore, 1979) and the LC (Breen et al., 1983). The noradrenergic innervation inhibits the activity of the EWN neu-rones via the stimulation of α2-adrenoceptors (Koss, 1986, Koss et al., 1984). Indeed, there is evidence that LC activation (e.g. by anxiety) leads to the inhibition of the pupillary light reflex (Samu-els and Szabadi, 2008b).

4.4.2.2 Salivatory nuclei. The two salivatory nuclei are located in the medulla: the superior salivatory nucleus in a dor-solateral, and the inferior salivatory nucleus in a ventrolateral position (Nicholson and Severin, 1981). The superior salivatory nucleus projects, through the facial nerve (cranial nerve VII), to two parasympathetic ganglia: the submandibular ganglion which innervates the submandibular and sublingual salivary glands (Chibuzo and Cummings, 1980); and the pterygopalatine gan-glion which innervates the lacrimal gland (Tóth et al., 1999). The inferior salivatory nucleus projects, through the glossopharyngeal nerve (cranial nerve IX), to the otic ganglion, from which post-ganglionic fibers innervate the parotid gland and the lingual (von Ebner) salivary glands (Fukami and Bradley, 2005; Kim et al., 2004a). Noradrenergic nerve terminals have been detected in the salivatory nuclei (Nemoto et al., 1995). The noradrenergic inner-vation of the preganglionic salivatory neurones has been traced back to the A5 pontine noradrenergic nucleus (Spencer et al., 1990) and the LC (Jansen et al., 1992). Inhibitory α2-adrenoceptors have been identified on salivatory neurones (Lung, 1994). It has been suggested that salivation is under tonic inhibitory noradrenergic control (Takakura et al., 2003).

4.4.2.3 Vagal nuclei. There are two vagal nuclei that con-tain preganglionic parasympathetic neurones: the dorsal motor nucleus of the vagus (DMV) and the nucleus ambiguous (Loewy and Spyer, 1990; Nosaka et al., 1982). These vagal nuclei are responsible for the parasympathetic nerve supply of the heart, respiratory tracts and lungs, nasopharynx, esophagus, gastroin-testinal tract, liver and pancreas. The parasympathetic ganglia to which the vagal nuclei project are located on the surface of the

organs supplied or embedded in their tissue. Both nuclei play an important role in cardiovascular regulation, however, the nucleus ambiguous plays the major role (Dampney, 1994). The integrity of the nucleus ambiguous is critical for the heart rate response to baroreceptor stimulation (Cheng et al., 2004). Injection of glutamate into the DMV (Chen and Chai, 2002) or the nucleus ambiguous (Machado and Brody, 1990) has been reported to induce bradycardia, consistent with a cardioinhibitory effect. The direct cardioinhibitory effect of the nucleus ambiguous via the vagus nerve is likely to be augmented be an inhibitory projection from the nucleus to the RVLM (McKitrick and Calaresu, 1996), a major sympathetic premotor nucleus involved in cardiovascular regulation (see above). The A5 noradrenergic nucleus projects to the DMV (Loewy et al., 1979), and the LC, via the coeruleo-vagal pathway, projects to both the DMV (Ter Horst et al., 1991; Westlund and Coulter, 1980) and the nucleus ambiguous (Jones and Yang, 1985; Westlund and Coulter, 1980). The central noradrenergic system exerts an inhibitory influence on the activ-ity of vagal parasympathetic preganglionic neurones: inhibitory α2-adrenoceptors have been identified in the DMV (Robertson and Leslie, 1985). The α2-adrenoceptors belong to the α2A sub-type (Flügge et al., 2003; Scheinin et al., 1994). Noradrenaline inhibits DMV neurones by stimulating these receptors (Fukuda et al., 1987; Martinez-Peña y Valenzuela et al., 2004). Apart from α2-adrenoceptors on DMV neurones, both α1A-adrenoceptors (Day et al., 1997) and β1-adrenoceptors (Bateman et al., 2012; Paschalis et al., 2009) have been detected in the nucleus ambigu-ous. For details of the role of the interplay between the LC and the vagal nuclei in cardiac control, see Section 6.2.

4.4.3 Motor nuclei. The LC projects to motoneurones both in the brainstem and spinal cord, exerting a facilitatory effect on these neurones via the activation of α1-adrenoceptors.

4.4.3.1 Oculomotor nucleus. This nucleus, belonging to the system of cranial nerve III, is responsible for the innervation of the majority of the external muscles of the eye, together with the levator palpebrae muscle. The nucleus has been shown to be supplied by noradrenergic fibers (Carpenter et al., 1992). α1-Adrenoceptors have been identified in the nucleus, with α1A being the dominant subtype (Day et al., 1997; Domyanic and Morilak, 1997; Pieribone et al., 1994).

4.4.3.2 Trigeminal motor nucleus. The trigeminal motor nucleus, belonging to the system of cranial nerve V, is responsi-ble for innervating the muscles involved in chewing. This nucleus receives its noradrenergic innervation mainly form the A1/A7 noradrenergic nuclei, with only a sparse contribution from the LC (Lyons and Grzanna, 1988). α1-Adrenoceptors are present in high density in this nucleus, with α1A being the most prevalent subtype (Day et al., 1997; Pieribone et al., 1994). Noradrenaline exerts a facilitatory influence on the activity of trigeminal motoneurones (Shao and Sutin, 1991).

4.4.3.3 Facial nucleus. The facial nucleus, belong-ing to the system of cranial nerve VII, is responsible for inner-vating the muscles of the face. It receives a rich noradrenergic input from the LC (Jones and Yang, 1985; McBride and Sutin, 1976). α1-Adrenoceptors are present in the facial nucleus, with α1A-adrenoceptors being the dominant subtype (Day et al., 1997; Domyanic and Morilak, 1997; Pieribone et al., 1994). Noradren-aline applied to facial motoneurones increases their activity (Larkman and Kelly, 1992; Rasmussen and Aghajanian, 1990;

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VanderMaelen and Aghajanian, 1980). The excitatory projection from the LC to the facial motoneurones is instrumental in main-taining the tone of facial muscles.

4.4.3.4 Hypoglossal nucleus. This nucleus, belonging to the system of cranial nerve XII, is responsible for innervating the muscles of the tongue. There is only limited information on afferents to the hypoglossal nucleus. A projection has been described from the subcoeruleus nucleus to the hypoglossal nucleus, and this projection may contain some noradrenergic fibers (Aldes, 1990). Indeed, catecholaminergic nerve termi-nals have been shown to synapse with hypoglossal motoneu-rones (Aldes et al., 1990). All three sub-classes of adrenoceptor have been detected in the hypoglossus nucleus: the α1- adreno-ceptors are mainly of the α1A subtype (Day et al., 1997; Pieri-obone et al., 1994), although α1B- and α1D-adrenoceptors are also present (Day et al., 1997), the α2-adrenoceptors are of the α2A subtype (Scheinin et al., 1994), and the β-adrenoceptors are of the β1 subtype (Paschalis et al., 2009). The α1- and β-adrenoceptors are present in high densities, whereas there is only a sparse presence of α2-adrenoceptors. Noradrenaline has been shown to excite hypoglossal neurones via the stimulation of α1-adrenoceptors (Parkis et al., 1995).

4.4.4 Sensory nuclei

4.4.4.1 Sensory trigeminal nuclei. These nuclei, belong-ing to the system of cranial nerve V, receive a rich noradrener-gic input from the LC (Levitt and Moore, 1979; Senba et al., 1981): this pathway has been implicated in antinociception (Cahusac et al., 1995; Couto et al., 2006; Tsuruoka et al., 2003). α1-Adrenoceptors are present in the sensory trigeminal nuclei: they belong to the α1A subtype (Day et al., 1997; Pieribone et al., 1994). α2-Adrenoceptors have been identified in both the mes-encephalic (Scheinin et al., 1994) and spinal (Scheinin et al., 1994; Zhang et al., 1998b) sensory trigeminal nuclei: these α2-adrenoceptors belong to the α2A subtype (Scheinin et al., 1994). The α2-adrenoceptors mediate the inhibitory effect of noradrena-line on spinal trigeminal neurones (Zhang et al., 1998b). Electrical stimulation of the LC has been shown to inhibit pain-sensitive trigeminal neurones (Matsutani et al., 2000; Sasa et al., 1974; Tsu-ruoka et al., 2003).

4.4.4.2 Cochlear nuclei. The cochlear nuclei, together with the vestibular nuclei, belong to the system of cranial nerve VIII. The LC projects to the cochlear nuclei (Klepper and Her-bert, 1991; Kromer and Moore, 1980; Schuerger and Balaban, 1993). α1D-Adrenoceptors have been identified in the cochlear nuclei (Day et al., 1997) and it has been shown that noradrenaline excites cochlear neurones (Ebert, 1996), probably by interacting with these receptors. The noradrenergic projection to the cochlear nuclei suggests that the LC may modulate auditory processing.

4.4.5 Sleep/arousal regulating nuclei. Apart from the LC itself, there are two other major sleep/arousal regulating nuclear complexes in the brainstem: the dorsal raphe (DR) nucleus and the pedunculopontine tegmental (PPT) nucleus/ laterodorsal tegmen-tal (LDT) nucleus. Both these nuclear complexes are under norad-renergic control from the LC (for details, see Section 6.1).

4.4.5.1 DR. The serotonergic neurones of the DR have a wakefulness-promoting function (McGinty and Harper, 1976;

Monti, 2011; Trulson and Jacobs, 1979). The LC sends a noradr-energic projection to the DR (Kim et al., 2004b; Levitt and Moore, 1979; Sakai et al., 1977). All subtypes of α1-adrenoceptor (α1A, α1B and α1D) are present on DR neurones (Day et al., 1997). The LC projection exerts an excitatory influence on DR neurones (Brown et al., 2002), and it has been shown that noradrenaline excites DR neurones via an action at α1-adrenoceptors (Pan et al., 1994; Pudovkina et al., 2003; Yoshimura et al., 1985).

4.4.5.2 PPT and LDT. These nuclei contain cholinergic neurones that are involved both in the promotion of wakefulness and initiation of rapid eye movement (REM) sleep (El Mansaari et al., 1989; Jones, 2005; Kayama et al., 1992; Sakai, 1988). It is likely that there are separate wakefulness-promoting and REM-promoting neurones in the PPT/LDT, the wakefulness-promoting neurones being active during wakefulness and quiescent during REM sleep, and the REM-promoting neurones being quiescent during wakefulness and active during REM sleep (Pal and Mal-lick, 2007). There is a noradrenergic projection from the LC to the pontine nuclei (Nieuwenhuys, 1985) that may exert differential effects on the two populations of cholinergic neurones: the wake-fulness-promoting neurones are excited via the stimulation of α1-adrenoceptors, while the REM-promoting neurones are inhibited via the stimulation of α2-adrenoceptors (Bay et al., 2006; Hou et al., 2002) (for details, see Section 6.1)

4.5 Cerebellum

The cerebellum is responsible for motor coordination that involves the timing, force and extent of muscle contractions (Kiernan, 2005). The LC projects profusely to wide areas of the cerebellum, and in particular to the cerebellar cortex (coeruleo-cerebellar pathway: Olson and Fuxe, 1971; Saigal et al., 1980). All sub-classes of adrenoceptor have been detected in the cerebellar cor-tex. The cerebellar α1-adrenoceptors (Schambra et al., 2005; Stone et al., 2006) belong mainly to the α1A subtype (Day et al., 1997), the α2-adrenoceptors to the α2A subtype (Scheinin et al., 1994), and the β-adrenoceptors to the β1 subtype (Paschalis et al., 2009). The importance of the noradrenergic input for cerebellar function is highlighted by the observation that depletion of the cerebellum of noradrenaline leads to motor impairment (Watson and McElligott, 1984).

4.6 Spinal cord

The LC sends a descending projection (coeruleo-spinal pathway) to all three neuronal pools of the spinal cord: to sensory neurones in the dorsal horn; motoneurones in the ventral horn; and pregan-glionic sympathetic neurones in the IML (Hancock and Fougerousse, 1976; Leong et al., 1984; Proudfit and Clark, 1991; Sluka and Westlund, 1992).

4.6.1 Dorsal horn. The sensory neurones of the dorsal horn are involved in the detection of pain, temperature, touch, and posi-tion/movement (proprioception) (Kiernan, 2005). The LC sends a profuse projection to this compartment of the spinal cord (Frit-schy and Grzanna, 1990; Proudfit and Clark, 1991; Westlund and Coulter, 1980), indicating that the LC can modulate the process-ing of sensory information. The predominant adrenoceptor in this

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region is of the α2 subtype (Shi et al., 1999; Smith et al., 1995). Presynaptic inhibitory α2-adrenoceptors have been identified on excitatory peptidergic interneurones in the dorsal horn, and have been implicated in the inhibition of spinal sensory processing by the LC (Olave and Maxwell, 2002). The modulation of pain sen-sation (nociception) by the LC is well documented (for reviews, see Ossipov et al., 2010; Pertovaara and Almeida, 2006; Willis and Westlund, 1997). It has been shown that electrical stimulation of the LC leads to the inhibition of nociception (Margalit and Segal, 1979; West et al., 1993). Furthermore, α2-adrenoceptor agonists (e.g. clonidine) produce analgesia (Eisenach et al., 1996; Sawynok and Reid, 1986), whereas α2-adrenoceptor antagonists cause hyperalgesia (Green et al., 1998).

4.6.2 Ventral horn. Apart from motoneurones in the brain-stem (see Section 4.4.3), innervating the muscles of the face and head, the LC also projects to motoneurones in the ventral horn of the spinal cord (Jones and Yang, 1985; Nygren and Olson, 1977; Westlund et al., 1983), innervating the skeletal muscula-ture. Excitatory α1-adrenoceptors are present on spinal moto-neurones (Day et al., 1997; Pieribone et al., 1994; Smith et al., 1999) and, via the stimulation of these receptors, the LC exerts a facilitatory action on motoneurone activity (White et al., 1991). In fact, LC activity seems to be essential for the mainte-nance of muscle tone: the suspension of LC activity which occurs during REM sleep (Gottesmann, 2011), and attacks of cataplexy (Wu et al., 1999), leads to total atonia (Peever, 2011).

4.6.3 Intermediolateral cell column. Sympathetic pregangli-onic (cholinergic) neurones are located in the intermediolateral cell column (IML) of the thoracolumbar segments (T1–L2) of the spinal cord, and project to sympathetic ganglia innervating spe-cific target organs (Hamill, 1996). These neurones form distinct clusters (nuclei): this organization enables the selective activa-tion of distinct areas of the sympathetic nervous system, as opposed to generalized sympathetic activation (Appel and Elde, 1988). Although the LC projects to the sympathetic pregangli-onic neurones (Pacák and Palkovits, 2001), the main innervation of these neurones derives from the A5/A7 pontine noradrenergic nuclei (Jones and Yang, 1985; Loewy et al., 1979; Westlund et al., 1983, 1984). Noradrenaline exerts mainly an excitatory effect on these neurones (Lewis and Coote, 1990; Yoshimura et al., 1987), via the activation of α1-adrenoceptors (Day et al., 1997; Pieribone at al., 1994).

Parasympathetic preganglionic (cholinergic) neurones are located in the IML of the sacral segments (S2–S4) of the spinal cord, and project to parasympathetic ganglia embedded in the walls of pelvic target organs or located in their proximity (Hamill, 1996). There is a dense noradrenergic projection from the LC to the sacral IML (Jones and Yang, 1985; Sasa and Yoshimura, 1994; Westlund and Coulter, 1980; Westlund et al., 1984; Yoshimura et al., 1990a, 1990b). Both α1-adrenoceptors (Yoshimura et al., 1990a) and α2-adrenoceptors (Smith et al., 1995; Unnerstall et al., 1984; Yaïci et al., 2002) have been described in the IML of the sacral spinal cord. As there is an intricate intrinsic neuronal net-work in this area, involving both excitatory and inhibitory interneurones (Ranson et al., 2006; Shefchyk, 2001), the cellular localization of the adrenoceptors is likely to be complex. Thus parasympathetic inhibition could result from the direct stimula-tion of inhibitory α2-adrenoceptors on the preganglionic neurones themselves, or may arise indirectly via the stimulation of excitatory

α1-adrenoceptors on inhibitory GABAergic interneurones that synapse with the preganglionic neurones. Alternatively, the stimu-lation of α1-adrenoceptors on excitatory interneurones synapsing with the preganglionic neurones would lead to the excitation of the preganglionic neurones themselves (Yoshimura et al., 1990a). The noradrenergic output from the LC to the IML of the sacral spinal cord has been implicated in the control of pelvic reflexes, such as micturition (Sasa and Yoshimura, 1994; Yoshimura et al., 1990b) and penile erection (Giuliano and Rampin, 2000; Yaïci et al; 2002).

5. Afferents of the LCFigure 5 shows a schematic overview of LC afferents.

The general pattern of inputs to the LC is that of reciprocal innervation: most structures to which the LC projects also send outputs to the LC (for comprehensive reviews of afferents of the LC, see Aston-Jones et al., 1991b; Cederbaum and Aghajnaian, 1978; Luppi et al., 1995: for a review of the neurochemistry of LC afferents, see Singewald and Philippu, 1998).

5.1 Neocortex

Although most areas of the neocortex project to the LC (Cederbaum and Aghajanian, 1978; Luppi et al., 1995), the pre-frontal cortex provides the strongest reciprocal link with it (Arnsten and Goldman-Rakic, 1984; Sesack et al., 1989). There is a powerful excitatory connection from the prefrontal cortex to the LC mediated by excitatory amino acids (Jodo and Aston-Jones, 1997). It has been proposed that this excitatory input may provide tonic activation of the LC (Jodo et al., 1998).

5.2 Amygdala

There is a strong reciprocal connection between the LC and the amygdala: the LC sends a dense projection to the central and basal nuclei of the amygdala (see Section 4.2.1), and receives an input from the central nucleus of the amygdala (Cederbaum and Aghajanian, 1978; Charney et al., 1998; Wallace et al. 1989). Corticotrophin-releasing factor (CRF) has been impli-cated as the neurotransmitter in the pathway from the amyg-dala to the LC (Van Bockstaele et al., 1998b). As the amygdala is the key structure in processing fear and anxiety (Canteras et al., 2010; Charney et al., 1998; Pare and Duvarci, 2012), the two-way connection between the LC and the amygdala under-lies the involvement of the LC in fear and anxiety. On the one hand, the activation of the LC, via the stimulation of the amyg-dala, leads to anxiety (McDougle et al., 1995; Redmond and Huang, 1979). On the other hand, stressful and fear-inducing stimuli (including conditioned fear) via the activation of the amygdala, lead to increased LC activity (Charney and Redmond, 1983; Cullinan et al., 1995; Rasmussen and Jacobs, 1986; Redmond and Huang, 1979).

5.3 Hypothalamus

All three arousal-modulating nuclei of the hypothalamus (VLPO, LH/PF, tuberomammillary nucleus (TMN)) project to the LC, consistent with the central role of the LC in the sleep-arousal net-work (see Section 6.1).

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5.3.1 VLPO. The VLPO is a major sleep-promoting nucleus, containing GABAergic inhibitory neurones (Szymusiak and McGinty, 2008). The VLPO sends an inhibitory projection to the LC (Cederbaum and Aghajanian, 1978; Lee et al., 2005a; Peyron et al., 1995; Steininger et al., 2001). This projection forms one limb of a reciprocal inhibitory connection between the VLPO and the LC: the LC inhibits the VLPO via an inhibitory norad-renergic output involving the stimulation of α2-adrenoceptors on VLPO neurones (see Section 4.3.2.1). During slow wave sleep, the GABAergic VLPO neurones are active (Szymusiak and McGinty, 2008), and inhibit the activity of noradrenergic

neurones in the LC (Gervasoni et al., 1998; Nitz and Siegel, 1997). On the other hand, during wakefulness, the LC neurones are active, and inhibit the sleep-promoting neurones of the VLPO (for details, see Section 6.1).

5.3.2 LH/PF. The LH/PF is a major wakefulness-promoting nucleus, containing orexinergic (hypocretinergic) excitatory neu-rones (De Lecea et al., 1998; Szymusiak and McGinty, 2008). The LH/PF densely innervates the neurones of the LC (Date et al., 1999; España et al., 2005; Horvath et al., 1999; Lee et al., 2005a). This pathway has been shown to activate the LC, leading to an

Figure 5. Afferents of the locus coeruleus (LC). Arrows indicate projections. Red arrow: excitatory; blue arrow: inhibitory. Lettering next to arrow indicates neurotransmitter involved: Coloring of source area indicates function (for code see figure). 5-HT: 5-hydroxytryptamine (serotonin); A: adrenaline; A (in circle): amygdala; ACh: acetylcholine; CRF: corticotrophin releasing factor; DA: dopamine; DR: dorsal raphe; Enc: encephalin; GABA: γ-aminobutyric acid; Glu: glutamate; H: histamine; LH: lateral hypothalamic area; Ox: orexin; PAG: periaqueductal grey; PPT/LDT: pedunculopontine tegmental/laterodorsal tegmental nuclei; PrH: nucleus prepositus hypoglossi (dorsomedial rostral medulla); PVN: paraventricular nucleus; RVLM: rostroventrolateral medulla; TMN: tuberomammillary nucleus; V: sensory trigeminal nuclei; VLPO: ventrolateral preoptic area; VP: vasopressin; VTA: ventral tegmental area. Sleep-promoting neurones in the hypothalamus promote slow wave sleep (SWS), and in the brainstem rapid eye movement (REM) sleep. The four nuclear groups in the RVLM are REM-sleep-promoting GABAergic neurones; premotor sympathetic/wakefulness-promoting glutamatergic neurones, premotor sympathetic adrenergic neurones, and pain-modulating encephalinergic sensory relay neurones. The amygdala sends an excitatory projection to the LC. Projections of the wakefulness-promoting neurones in the hypothalamus (LH, TMN) and the brainstem (VTA, PAG, PT/LDT, DR) have excitatory effects, whereas projections of sleep promoting neurones in the hypothalamus (VLPO) and REM-sleep-active neurones in the brainstem (PrH and GABArgic neurones of RVLM) have inhibitory effects on the LC. Premotor sympathetic neurones in the hypothalamus (PVN) and the brainstem (glutamatergic neurones in the RVLM) stimulate the LC, whereas adrenergic premotor sympathetic neurones in the RVLM inhibit the LC. The glutamatergic projection from the RVLM to the LC, by activating the LC, also has a wakefulness promoting function (see Section 5.4.2.1). Trigeminal and spinal sensory neurones evoke excitatory effects, whereas encephalinergic sensory relay neurones in the RVLM have inhibitory effects on the LC.

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increase in arousal and suppression of REM sleep (Bourgin et al., 2000; Hagan et al., 1999). It has been shown recently that the orexinergic input from the LH/PF activates a subgroup of LC neu-rones that project to the medial prefrontal cortex, and it has been suggested that this pathway may malfunction in narcolepsy, lead-ing to excessive daytime sleepiness (Del Cid-Pellitero and Garzn, 2011).

5.3.3 TMN. The TMN is a wakefulness-promoting nucleus, containing histaminergic neurones (Szymusiak and McGinty, 2008). An excitatory projection from the TMN to the cerebral cor-tex, involving the stimulation of H1 histamine receptors, has been implicated in the wakefulness-promoting function of this nucleus (Haas and Panula, 2003). There is a projection from the TMN to the LC (Iwase et al., 1993; Lee et al., 2005b), which exerts an excitatory effect via the activation of H1 histamine receptors (Korotkova et al., 2005). In this way, the direct wakefulness-pro-moting effect of the TMN via its cortical projection is likely to be augmented indirectly via the activation of the LC. There is no strong direct reciprocal connection between the TMN and the LC, since the noradrenergic innervation of the TMN derives mainly from nuclei A1/A2, and the projection from the LC to this nucleus is rather weak (Ericson et al., 1989). However, the LC exerts a powerful indirect influence on TMN activity via inhibition of the VLPO (see Section 6.1).

5.3.4 PVN. The PVN is an important premotor sympathetic nucleus which projects directly to preganglionic sympathetic neu-rones in the spinal cord (Hosoya et al., 1991; Ranson et al., 1998) via vasopressinergic fibers (Pyner, 2009). The PVN also projects indirectly to spinal preganglionic sympathetic neurones via the LC. The LC receives a dense projection from the PVN (Luiten et al., 1985; Luppi et al., 1995; Reyes et al., 2005). This projection consists of CRF-containing nerve fibers, which exert an excitatory influence on noradrenergic neurones in the LC (Reyes et al., 2005). Thus the PVN potentiates the sympathoexcitatory effect of the LC. On the other hand, the LC facilitates PVN activity via a reciprocal excitatory projection to this nucleus (see Section 4.3.2.3).

5.4 Brainstem

5.4.1 Midbrain and pons. Apart from the LC itself, there are four nuclear groups in the upper brainstem that are intimately linked to sleep/arousal mechanisms. All these four nuclear groups project to the LC.

5.4.1.1 Ventral tegmental area. Apart from their well-established roles in reward, motivation and drug addiction (Nicola et al., 2005; Wise, 2004), the dopaminergic neurones of the ven-tral tegmental area (VTA) are also associated with a wakefulness-promoting function (Monti and Jantos, 2008; Monti and Monti, 2007; Niepel et al., 2013). The VTA projects to the LC (‘meso-coerulear pathway‘) (Beckstead et al., 1979; Ornstein et al., 1987; Simon et al., 1979a, 1979b), and there is evidence that this path-way exerts an excitatory influence on LC neurones (Deutch et al., 1986). Thus, the wakefulness-promoting function of the VTA may be mediated, at least partly, by the LC. Indeed, it has been shown that dopamine applied to the LC inhibits sleep (Crochet and Sakai, 2003).

5.4.1.2 Periaqueductal grey matter. The periaqueductal grey matter (PAG) consists of a heterogeneous group of neurones surrounding the cerebral aqueduct in the midbrain. The PAG has been implicated in a number of diverse functions, such as pain control (Heinricher et al., 2009), fear and anxiety (Canteras et al., 2010), arousal (Monti and Jantos, 2008), REM sleep (Luppi et al., 2012) and cardiovascular control (Dampney et al., 2013). Inter-estingly, the central noradrenergic system is also involved in the regulation of these same functions (see Sections 4.1.1, 4.6.1 and 6.1). The ventrolateral PAG receives a noradrenergic input from the A1 and A2 groups of neurones (Herbert and Saper, 1992), and in turn projects to the A5 (Bajic et al., 2012) and A7 (Bajic et al., 2001) noradrenergic nuclei. There is evidence that the LC (A6 group of noradrenergic neurones) also receives an input from neurones in the PAG (Bajic and Proudfit, 1999; Cameron et al., 1995; Ennis et al., 1991; Lee et al., 2005a; Luppi et al., 1995; Van Bockstaele et al., 2001). Neurones in the ventrolateral PAG project to the ventromedial aspect of the peri-LC (Van Bockstaele et al., 2001) where they synapse with the dendrites of LC neurones (Bajic et al., 2000). The projection from the ventrolateral PAG to spinally projecting noradrenergic neurones is involved in pain modulation: stimulation of neurones in the PAG produces antin-ociception (Bajic and Proudfit, 1999). A degree of topographic functional specifity of the projections from the PAG to noradren-ergic nuclei has been suggested: the projection to the A7 nucleus may play a role mainly in analgesia (Bajic and Proudfit, 1999; Bajic et al., 2001) whereas the projection to the A5 nucleus and the LC has been implicated in cardiovascular regulation (Bajic and Proudfit, 1999; Bajic et al., 2012). A group of wakefulness-active dopaminergic neurones have been identified in the ventro-lateral PAG (Lu et al., 2006): these neurones may contribute to the activation of the LC during wakefulness which, in turn, could lead to the augmentation of dopaminergic arousal (Niepel et al., 2013).

5.4.1.3 DR. The DR is a wakefulness-promoting nucleus, and the serotonergic neurones of the DR are active during wake-fulness (Monti, 2011; Monti and Jantos, 2008). DR neurones pro-ject to the LC (Kim et al., 2004b; Luppi et al., 1995; Pasquier et al., 1977; Vertes and Kocsis, 1994), forming one limb of the reciprocal connection between the two nuclei.

5.4.1.4 PPT/LDT. The cholinergic neurones of the PPT/LDT perform a dual role in the sleep/arousal network: some of these neurones are wakefulness promoting (Datta et al., 2011), whereas others are involved in the initiation/mediation of REM sleep (Jones, 1991; Xi et al., 2012). The PPT/LDT neurones project to the LC (Jones and Yang, 1985). Cholinergic nerve terminals are detectable in the LC (Jones, 1990), and acetylcho-line has an excitatory effect on noradrenergic neurones in the LC (Egan and North, 1985; Engberg and Svenson, 1980). The cholinergic output from the PPT/LDT also seems to facilitate noradrenergic neurotransmission in target areas, such as the VLPO (Saint-Mleux et al., 2004) and the DR (Li et al., 1998), by stimulating release-modulating nicotinic receptors on noradr-energic nerve terminals.

5.4.2 Medulla oblongata. The medulla contains a large num-ber of varied neuronal groups involved in the regulation of a num-ber of physiological functions, such as autonomic activity, cardiovascular regulation, respiration, thermoregulation and pain processing (Goodchild and Moon, 2009; Heinricher et al., 2009; Kumagai et al., 2012; Morrison and Nakamura, 2011; Van

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Bockstaele and Aston-Jones, 1995), and many of these neuronal groups project to the LC. It is beyond the scope of this review to cover all these connections in detail, however, some of the most important ones are described below.

5.4.2.1 RVLM. The RVLM, an important premotor sympa-thetic area (see Sections 4.4.1.1 and 6.2), contains a number of distinct subnuclei with distinct neurochemical identities and pro-jection patterns. One group of neurones is identified as the nucleus paragigantocellularis (PGi), another one as the C1 nucleus of adr-energic neurones (Astier et al., 1990). Neurones in the RVLM project to the LC (Astier et al., 1990; Aston-Jones et al., 1986; Guyenet and Young, 1987; Van Bockstaele and Aston-Jones, 1992; Van Bockstaele et al., 1998a). Interestingly, some neurones in the RVLM send collaterals both to the LC and spinal pregan-glionic sympathetic neurones (Van Bockstaele and Aston-Jones, 1995).

There is a major glutamatergic output from the RVLM to the LC which exerts an excitatory influence on LC neurones (Ennis and Aston-Jones, 1986, 1988; Van Bockstaele and Aston-Jones, 1995). This projection activates the LC, and the glutamatergic neurones have the function of premotor sympathetic neurones. It has been suggested that the activation of the LC by the RVLM may contribute to the wakefulness-promoting function of the LC (Van Bockstaele and Aston-Jones, 1995). Indeed, it has been reported that stimulation of inhibitory α2-adrenoceptors in the RVLM, evoked by the local injection of clonidine, leads to seda-tion (Yamazato et al., 2001).

Adrenergic neurones in the C1 nucleus within the RVLM pro-ject to the LC, and exert an inhibitory effect on LC neurones via the stimulation of α2-adrenoceptors (Aston-Jones et al., 1992; Van Bockstaele and Aston-Jones, 1995).

Inhibitory GABAergic neurones in the RVLM send efferent fibers to the LC: some of these neurones are active during REM sleep, and may play a role in switching off the LC during REM sleep (Sirieix, 2012).

The RVLM also contains enkephalinergic neurones (Johnson et al., 2002) which project to the LC (Drolet et al., 1992). This projection activates opiate receptors on LC neurones (Van Bockstaele, 1998) which leads to the inhibition of neuronal firing (Illes and Norenberg, 1990; Pepper and Henderson, 1980). The LC has been implicated in opiate-induced analgesia (Drolet et al., 1992) and opiate withdrawal (Johnson et al., 2002).

5.4.2.2 Dorsomedial rostral medulla. In this area of the medulla the nucleus prepositus hypoglossi (PrH) has been identi-fied as a distinct group of neurones projecting to the LC (Aston-Jones et al., 1986). The PrH neurones are GABAergic, and exert an inhibitory action on the LC (Ennis and Aston-Jones, 1989a, 1989b). The GABAergic neurones in the PrH have been impli-cated in the regulation of REM sleep: the inhibitory output to the wakefulness-promoting LC neurones may be responsible for the silencing of these neurones during REM sleep (Kaur et al., 2001). The involvement of the PrH in REM sleep is supported by its reciprocal connection to the PPT (Higo et al., 1990) which has a role in the generation of REM sleep that is well established (see Sections 4.4.5.2 and 5.4.1.4). It should be noted, however, that other GABAergic medullary nuclei, sending projections to the LC, such as the dorsal paragigantocellular reticular nucleus (Goutagny et al., 2008) and the lateral paragigantocellular nucleus (see Sec-tion 5.4.2.1), have also been implicated in the neuronal network responsible for the generation and regulation of REM sleep.

5.4.3. Sensory trigeminal nuclei. The three sensory trigemi-nal nuclei stretch through the whole length of the brainstem: the principal sensory nucleus is located in the pons, the mesence-phalic nucleus occupies the midbrain, and the spinal nucleus extends through the whole length of the medulla as far as the dor-sal column of the spinal cord (Kiernan, 2005). The sensory tri-geminal nuclei project to the LC (Couto et al., 2006; Craig, 1992), providing the anatomical basis for the processing and modulation of pain signals from the face and head. It has been shown that noxious stimulation of the trigeminal sensory area (e.g. electrical tooth pulp stimulation or noxious air puff to the face) activates the LC (Kimura and Nakamura, 1985; Singewald et al., 1999; Voisin et al., 2005). Furthermore, the noxious stimulation-evoked LC activation leads to concomitant neuronal activation in the somato-sensory thalamus, consistent with the processing of pain signals via the LC (Voisin et al., 2005).

5.5 Spinal cord

Sensory neurones in the dorsal horn of the spinal cord send an ascending projection to the LC (Cederbaum and Aghajanian, 1978; Craig, 1992). This pathway has been implicated in the detection and processing of thermal and nociceptive stimuli. There is extensive experimental evidence showing that noxious and/or thermal stimulation leads to the activation of the LC (Elam et al., 1986; Hirata and Aston-Jones, 1994; Kimura and Nakamura, 1985; Palkovits et al., 1995; Rasmussen et al., 1986; Sugiyama et al., 2012).

6. The LC in regulatory networksThe full functional significance of the connections of the central noradrenergic neurones, and in particular of the LC, becomes apparent when the integrated neuroanatomy of physiological reg-ulatory neural networks is considered. Such networks include the sleep/arousal network, the autonomic network and the network related to the modulation of physiological functions by light (‘photomodulation‘). The LC also plays a role in some other important networks, such as the fear/anxiety and the pain modula-tion networks (see Section 8; Samuels and Szabadi, 2008b; Szabadi, 2012).

6.1 Sleep/arousal network

This neural network is responsible for the regulation of arousal. Three states of arousal (also referred to as vigilance states, e.g. Fort et al., 2009) can be distinguished: wakefulness, characterized by fast, small-amplitude, desynchronized EEG, active muscle tone and conscious awareness; slow wave sleep (non-REM sleep), characterized by syn-chronized, slow, large-amplitude EEG, reduced muscle tone, lack of conscious awareness; REM sleep (paradoxical or active sleep), charac-terized by fast, desynchronized EEG, loss of muscle tone, and variable levels of conscious awareness (Jones, 2005; Lin et al., 2011). The sleep/arousal network consists of distinct wakefulness-promoting and sleep-promoting nuclei, and their connections, located in the diencephalon (thalamus and hypothalamus) and the brainstem: the wakefulness-pro-moting nuclei are active during wakefulness and quiescent during sleep, whereas the sleep-promoting nuclei are active during sleep and quiescent during wakefulness (Aston-Jones, 2005; De Andrés et al.,

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2011; Fuller et al., 2006; Haas and Lin, 2012; Jones, 2005; Lin et al., 2011; Schwartz and Roth, 2008; Szabadi, 2006; Szymusiak and McGinty, 2008). The three vigilance states, and the transitions between them, are regulated by the subcortical sleep/arousal network. During slow wave sleep the cerebral cortex displays its synchronized intrinsic activity: wakefulness and/or REM sleep ensue when this ‘cortical solil-oquy‘ is disrupted by afferent inputs from subcortical areas, such as the diencephalon and the brainstem (Lin et al., 2011). The main role of the GABAergic sleep-promoting neurones is to switch off the wakeful-ness-promoting neuronal groups and allow sleep to develop (Lin et al., 2011) although the GABAergic sleep-promoting neurones of the BF exert a direct inhibitory influence on cortical excitability (see Section 4.1.2). A separate network has been implicated in the regulation of REM sleep, involving complex interactions between GABAergic, glu-tamatergic and cholinergic neurones in the brainstem (Fort et al., 2009; Fuller et al., 2007; Vetrivelan et al., 2011): however, a detailed discus-sion of this network is beyond the scope of this review.

A schematic diagram of the sleep/arousal network is shown in Figure 6. All the wakefulness-promoting nuclei project directly to the cerebral cortex. These include, in the diencephalon, the glutamatergic neurones of the medial and intralaminar nuclei of the thalamus (Jones, 2005; Lin et al., 2011), and, in the hypothalamus, the histaminergic

neurones of the TMN and the orexinergic neurones of the LH/PF (Haas and Lin, 2012). The wakefulness-promoting nuclei in the brain-stem are the serotonergic DR (Monti, 2011), the dopaminergic neu-rones of the periaqueductal grey and the VTA (Monti and Jantos, 2008; Niepel et al., 2012), and some of the cholinergic neurones of the pedunculopontine/laterodorsal nuclei (Jones, 2005). The LC is a major wakefulness-promoting nucleus in the brainstem, sending a powerful excitatory projection to the cerebral cortex (see Section 4.1.1). The major sleep-promoting nucleus is the VLPO of the hypothalamus: GABAergic neurones in this nucleus exert a powerful inhibitory influ-ence on the TMN and the LC, and thus promote sleep.

The LC occupies a central position in the hub of the sleep/arousal network, where it fulfils four wakefulness-promoting functions. Firstly, it evokes a direct alerting effect via its cortical projection. Secondly, it augments the alerting influence of other wakefulness-promoting nuclei by sending excitatory projections to them (see Sections 4.1.2, 4.3.1, 4.4.5.1, 4.4.5.2) (connections to BF and DR are not shown in Figure 6). Thirdly, it receives inputs from other wakefulness-promoting nuclei (see Sections 5.3.2, 5.3.3, 5.4.1.1, 5.4.1.2, 5.4.1.3, 5.4.1.4), which potentiate the alert-ing effect of the LC. Fourthly, by inhibitory projections it switches off the activities of sleep-promoting neurones in the BF (see

Figure 6. Schematic diagram of the connections within the arousal-controlling neuronal network. γ-Aminobutyric acid (GABA)ergic interneurones, in (white). LC: locus coeruleus; LH/PF: lateral hypothalamic/perifornical area; PPT: pedunculopontine tegmental nucleus; R: raphe nuclei; Th: thalamus; TMN: tuberomammillary nucleus; VLPO: ventrolateral preoptic nucleus; VTA: ventral tegmental area. Neuronal outputs: excitatory (red arrows); inhibitory (blue arrows). Neurotransmitters: 5-HT: 5-hydroxytryptamine; 5-HT2A and 5-HT2C: excitatory 5-HT receptors; ACh: acetylcholine; DA: dopamine; Glu: glutamate; H: histamine; H1: excitatory H1 histamine receptors; NA: noradrenaline; Ox: orexin. Receptors: α1: excitatory α1-adrenoceptors; α2: inhibitory α2-adrenoceptors. Wakefulness-promoting nuclei (yellow), sleep-promoting nucleus (purple). The wakefulness-promoting nuclei exert a direct activating effect on the cerebral cortex: the VLPO promotes sleep by inhibiting the TMN and the LC. The LC promotes wakefulness by stimulating the cerebral cortex and the wakefulness-promoting neurones of the PPT, and by inhibiting the VLPO. The LC also inhibits the REM-sleep-promoting neurones of the PPT. The raphe nucleus promotes wakefulness by activating the cerebral cortex; this effect is attenuated by stimulation of GABAergic interneurones, which inhibit the LC and the VTA. The GABAergic interneurones, activated by excitatory 5-HT2C receptors, are located in the VTA itself (Bubar and Cunningham, 2007; Gobert et al., 2000) and in the vicinity of the LC (Gobert et al., 2000). The VTA exerts its wakefulness-promoting effect largely via activation of the LC, and the LH/PF largely via activation of the TMN and the LC. See Section 6.1 for details. Reproduced from Samuels ER and Szabadi E (2008b) Functional neuroanatomy of the noradrenergic locus coeruleus: Its roles in the regulation of arousal and autonomic function. Part II: Physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans. Curr Neuropharmacol 6: 254–285 with permission from Bentham Science Publishers.

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Figure 4 and Section 4.1.2) and the VLPO (see Section 4.3.2.1), and of REM-promoting activities of some of the REM-active neu-rones in the PPT/LDT (see Section 4.4.5.2).

Further details of the sleep/arousal network are described in the legend to Figure 6. The interplay between excitatory choliner-gic and inhibitory GABAergic neurones in the BF, and their mod-ulation by the LC, are shown in Figure 4. Recent work has emphasized the key role of the BF, and its activation by a gluta-matergic input from the parabrachial nucleus and the subcoer-uleus area, in the maintenance of arousal (Fuller et al., 2011).

6.2 Autonomic network

The autonomic nervous system supplies smooth muscle, cardiac muscle and glandular tissue with vegetative motor fibers, and influences metabolic processes via the regulation of the release of hormones (Loewy, 1990a). Both divisions (sympathetic and para-sympathetic) of the autonomic nervous system consist of two neu-rones linked serially: a preganglionic neurone located in the CNS (brainstem or spinal cord) synapses with a postganglionic neurone located in a peripheral autonomic ganglion. Both the sympathetic and parasympathetic preganglionic neurones are cholinergic. The sympathetic postganglionic neurones are noradrenergic, with the exception of those innervating sweat glands (‘sudomotor neu-rones‘), which are cholinergic: all parasympathetic postganglionic neurones are cholinergic (Hamill, 1996; Loewy, 1990a). The activity of preganglionic neurones is controlled by a number of premotor autonomic nuclei (e.g. CR, LC (together with the A5/A7 pontine noradrenergic nuclei), PVN, RVLM) (Loewy, 1990b; Mosqueda-Garcia, 1996), which in turn are under the influence of ‘higher‘ structures, such as the suprachiasmatic nucleus (SCN) of the hypothalamus (Buijs et al., 2003), the amygdala (Fortaleza et al., 2012) and the cerebral cortex (Cechetto and Saper, 1990).

The pontine noradrenergic nuclei (A5/A7, LC) occupy a cen-tral position in the autonomic network (Figures 7 and 8), where they accomplish three separate functions. Firstly, they are impor-tant sympathetic premotor nuclei, exerting an excitatory influence on preganglionic sympathetic neurones in the IML via the stimu-lation of α1-adrenoceptors (see Section 4.6.3). Secondly, they also function as premotor parasympathetic nuclei: they project to preganglionic parasympathetic nuclei in the brainstem, such as the EWN, the salivatory and vagal nuclei, where they exert an inhibi-tory influence via the stimulation of α2-adrenoceptors (see Section 4.4.2). Thirdly, the LC modulates the activity of other sympathetic premotor nuclei, such as the CR, PVN and RVLM (see Sections 4.3.2.3 and 4.4.1). While the effect of the LC on PVN and CR neurones is excitatory via the activation of α1-adrenoceptors, the LC exerts an inhibitory influence on the vasomotor and cardio-accelerator neurones of the RVLM via the stimulation of inhibi-tory α2-adrenoceptors, thereby presumably dampening the sympathoexcitation evoked by sympathetic premotor nuclei. The central role of the LC in the control of cardiac activity is shown in Figure 8.

On the basis of the position of the pontine noradrenergic nuclei within the autonomic network, it is possible to predict changes in autonomic activity resulting from their activation. Overall, central noradrenergic activation leads to sympathoexcitation and para-sympathetic inhibition. The signs of sympathoexcitation are an increase in pupil diameter (Phillips et al. 2000a, 2000b) and mod-erate increases in heart rate and blood pressure (Drolet and

Gauthier, 1985; Stock et al., 1981) whereas the signs of parasym-pathetic inhibition are the attenuation of the light reflex response (Bakes et al., 1990; Bitsios et al., 1996) and a reduction in salivary flow (Szabadi and Tavernor, 1999).

As the pontine noradrenergic nuclei are intimately involved in the control of pupil function, it is expected that changes in LC activity would be reflected in changes in pupil diameter. Indeed, it has been shown that fluctuations in the firing rate of LC neurones are closely paralleled by fluctuations in pupil diameter (Aston-Jones and Cohen, 2005; Rajkowski et al., 1993). Furthermore, as the LC integrates arousal-related information from all wakeful-ness-promoting and sleep-promoting nuclei (see Section 6.1 and Figure 6), it is expected that LC activity at any one time would reflect the overall level of arousal, and this could be reflected in pupillary function. The relationship between level of arousal and pupillary function can be assessed by the Pupillographic Sleepiness Test (PST), based on an inverse relationship between level of arousal and pupillary fluctuations in darkness (Hou et al., 2006, 2007; Wilhelm et al., 2001; Yoss et al., 1970). It is an intriguing possibility that, as sleepiness develops, there is an increasing instability between wakefulness-promoting and sleep-promoting inputs to the LC, leading to increasing fluctuations in LC neuronal activity, and this may be detected by the PST.

6.3 Photomodulation network

Photoreceptors in the retina are responsible for two separate functions: pattern recognition and irradiance detection. Pattern recognition leads to image formation (IF), via the process of visual perception, whereas irradiance detection gauges the intensity of ambient light, modulating a number of non-image formation (NIF) functions. NIF functions include the pupillary light reflex, adjustment of the circadian cycle to the day/night cycle (photoentrainment), and acute influence of light on some physiological functions (e.g. arousal, sympathetic activity). The term ‘photomodulation‘ is used here to refer to this latter effect of light.

It is well documented that the stimulation of the photoreceptor cells of the retina, the rods and cones, leads to the activation of retinal ganglion cells, that in turn give rise to both IF and NIF projections. The IF output is to the visual cortex, via the lateral geniculate nucleus, whereas the two major NIF outputs are to the hypothalamus and the diencephalon/midbrain border (OPN) (see below).

It has been discovered recently that the rods and cones are not the only photosensitive cells in the retina: a small population of retinal ganglion cells scattered randomly over the whole area of the retina are also photosensitive (ipRGCs). It has also been shown that the photosensitivity of these ganglion cells is due to the presence of the photo-pigment melanopsin (Semo et al., 2005). Melanopsin has a distinct spectral sensitivity: it is activated by a narrow short-wavelength band (around 460 nm) of blue light (Kawasaki and Kardon, 2007; Thapan et al., 2001).

There is evidence that NIF functions are mediated almost exclusively by the ipRGCs that can be stimulated by light, both directly and indirectly, via the rods and cones (Gooley et al., 2003; Güler et al., 2008). The ipRGCs give rise to two pathways: one to the OPN and another one to the hypo-thalamus. Recent evidence indicates that the two pathways originate from separate populations of ipRGCs (Baver et al., 2008; Chen et al., 2011). The OPN is a promotor nucleus in the parasympathetic light reflex pathway: it

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projects to the preganglionic parasympathetic neurones in the EWN (see Section 4.4.2.1). The output to the hypothalamus (retino-hypothalamic tract) innervates two hypothalamic nuclei, the SCN and the VLPO (Gooley et al., 2003; Güler et al., 2008; Lu et al., 1999) (Figure 9). The SCN is responsible for the generation of circadian rhythms and is involved in the modulation of autonomic and endocrine functions (Kalsbeek et al., 2000, 2006; Van Esseveldt et al., 2000) whereas the VLPO is a major sleep-pro-moting nucleus (see Section 6.1 and Figure 6).

Light has a dual effect on arousal and sympathetic activity: it has both wakefulness-promoting and sleep-promoting functions, and sym-pathoexcitatory and sympathoinhibitory functions. The overall effect of exposure to light depends on the relationship between the two

opposing functions. Interestingly, there is a species difference relating to the overall effect of light on arousal: it is sleep-promoting in noctur-nal animals (Altimus et al., 2008; Tsai et al., 2009) whereas in diurnal animals, including man, it is wakefulness-promoting (Cajochen et al., 2005; Lockley et al., 2006; Revell et al. 2006). The overall effect of light, in both diurnal and nocturnal animals, is inhibitory on pregangli-onic sympathetic neurones of the upper thoracic spinal cord projecting to the superior cervical ganglion (Kalsbeek et al., 2000; Pereau-Lenz et al., 2003): this effect leads to pupil constriction (Passatore, 1976; Passatore and Pettorossi, 1976; Szabadi et al., 2010) and inhibition of melatonin synthesis (Kalsbeek et al., 1999; Nishino et al., 1976; Zeitzer et al., 2000). However, the overall effect of light, in diurnal animals, is

Figure 7. Noradrenergic regulation of autonomic functions. Outputs from the nuclei are indicated by arrows. Red: excitatory (+); blue: inhibitory (–).Neurotransmitters: ACh: acetylcholine; NA: noradrenaline. Nuclei: EWN: Edinger-Westphal nucleus; LC: locus coeruleus; Para ggl: parasympathetic ganglion; Preggl Para: preganglionic parasympathetic neurones; Preggl Symp: preganglionic sympathetic neurones; PVN: paraventricular nucleus; Saliv: salivatory nucleus; Symp ggl: sympathetic ganglion. Receptors: α1 and α2: adrenoceptor subtypes. Organs comprising of smooth muscle (e.g. blood vessels, iris) or glandular tissue (e.g. sweat glands, salivary glands) receive autonomic (sympathetic and parasympathetic) innervations. Both innervations consist of a chain of two neurones (preganglionic and postganglionic) joined in a synapse located in the autonomic ganglion. Preganglionic sympathetic neurones are located in the intermediolateral cell column (IML) of the spinal cord, whereas the preganglionic parasympathetic neurones are located in brainstem nuclei. Blood vessels (arterioles) and sweat glands receive sympathetic and salivary glands parasympathetic inputs, whereas the smooth muscles in the iris are controlled by opposing sympathetic and parasympathetic inputs. The preganglionic neurones are always cholinergic: the postganglionic sympathetic neurones are noradrenergic (with the exception of those innervating the sweat glands which are cholinergic) whereas the postganglionic parasympathetic neurones are always cholinergic. The preganglionic neurones are influenced by premotor autonomic nuclei of which three are shown: PVN; rostroventrolateral medulla (RVLM) containing vasomotor and cardioaccelerator neurones; and the LC. The pontine noradrenergic nuclei (LC, A5/A7) play a pivotal role in autonomic regulation, influencing the activities of preganglionic neurones both directly and indirectly via other premotor nuclei. The outputs from the pontine noradrenergic nuclei can activate either excitatory α1-adrenoceptors or inhibitory α2-adrenoceptors. The noradrenergic nuclei exert an excitatory effect on preganglionic sympathetic neurones, and an inhibitory effect on premotor sympathetic neurones (vasomotor neurones) in the RVLM and on preganglionic parasympathetic neurones. The activity of the premotor autonomic neurones (e.g. PVN) is under the influence of the cerebral cortex. The light reflex is a parasympathetically-mediated reflex consisting of the constriction of the pupil in response to a light stimulus reaching the retina. The neuronal chain in the reflex includes the pretectal nucleus, the EWN, and the ciliary ganglion (CG). See Section 6.2, for details. Reproduced from Samuels ER and Szabadi E (2008b) Functional neuroanatomy of the noradrenergic locus coeruleus: Its roles in the regulation of arousal and autonomic function. Part II: Physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans. Curr Neuropharmacol 6: 254–285 with permission from Bentham Science Publishers.

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stimulatory at the level of lower thoracic segments, leading to stimula-tion of cardiovascular activity (Cajochen et al., 2005; Michimori et al., 1997; Scheer et al., 1999). On the other hand, light seems to inhibit cardiovascular activity in nocturnal animals (Scheer et al., 2001).

The dual effect of light on arousal and sympathetic activity is controlled by the photomodulation network (Figure 9). The LC occupies an important position in this network: it has a central role in mediating the stimulatory effect of light on arousal and sympathetic activity. The glutamatergic ipRGCs project to the VLPO (Lu et al. 1999): this pathway is respon-sible for mediating the sleep-promoting effect of light. The ipRGCs also project to the SCN where they can stimulate separate populations of GABAergic inhibitory and gluta-matergic excitatory output neurones (Mistlberger, 2005). An inhibitory GABAergic output from the SCN to the PVN, an important premotor sympathetic nucleus, can switch off the sympathoexcitatory drive from the PVN to the preganglionic sympathetic neurones in the IML, leading to

sympathoinhibition (Kalsbeek et al., 2000). On the other hand, an excitatory glutamatergic output form the SCN (Perreau-Lenz et al., 2003) can activate orexinergic neurones in the dor-somedial hypothalamus (DMH) which, in turn, exert an excitatory influence on the LC (Aston-Jones, 2005; Aston-Jones et al., 2001; Gonzalez and Aston-Jones, 2006). Indeed, it has been shown by functional magnetic resonance imaging (fMRI) in humans that short wavelength (blue) light, that pref-erentially stimulates the melanopsin-containing photorecep-tors of ipRGCs (Kawasaki and Kardon, 2007), activates the LC (Vandewalle et al., 2007). The activation of the LC by light via the SCN→DMH→LC route would lead to wakefulness-promoting (see Section 6.1) and sympathetic activating (see Section 6.2) effects. Interestingly, another pathway mediating the stimulatory effect of light on arousal has been described recently: light can activate the orexinergic neurones of the LH/PF area of the hypothalamus which in turn activate wake-fulness-promoting serotonergic neurones in the DR

Figure 8. Schematic diagram of the neuronal network regulating cardiac activity.Cellular groups (nuclei and ganglia): CG: cardiac ganglia; CR: caudal raphe; IML: intermedial lateral column; LC: locus coeruleus; PVN: paraventricular nucleus; RVLM: rostral ventrolateral medulla; StG: stellate ganglion; V: vagal nuclei (dorsal nucleus, nucleus ambiguous). Outputs from nuclei and ganglia: arrows (red, excitatory; blue, inhibitory). Neurotransmitters: 5-HT: 5-hydroxytryptamine (serotonin); ACh: acetylcholine; Glu: glutamate; NA: noradrenaline; VP: vasopressin. Adrenoceptors: α1 (excitatory), α2 (inhibitory), β1 (excitatory). Cardiac activity is under dual sympathetic/parasympathetic control: sympathetic output to the heart stimulates it, whereas the parasympathetic output inhibits it. Sympathetic output: sympathetic preganglionic cholinergic neurones in the (IML) of the spinal cord synapse with postgangli-onic noradrenergic neurones in the stellate ganglion; the postganglionic neurones innervate the heart where they mediate a stimulatory effect (cardioacceleration) via excitatory β1-adrenoceptors. Parasympathetic output: parasympathetic preganglionic cholinergic neurones in the vagal nuclei synapse with postganglionic cholinergic neurones in the cardiac ganglia; the postganglionic neurones innervate the heart where they mediate an inhibitory effect (cardiodeceleration) via inhibitory muscarinic cholinoceptors. Premotor autonomic neurones regulate the activity of preganglionic neurones. The CR, LC, PVN (together with the other pontine noradrenergic nuclei) and RVLM send excitatory outputs to preganglionic sympathetic neurones in the IML, and the LC sends an inhibitory output to preganglionic parasympathetic neurones in the vagal nuclei, thereby promoting sympathoexcitation. The pontine noradrenergic nuclei play a central role in cardiac regulation: apart from controlling the activity of preganglionic sympathetic and parasympathetic neurones, they also modulate the activity of other premotor autonomic nuclei. The LC promotes sympathetic activity via excitatory outputs to the CR and PVN but also attenuates it via an inhibitory output to the RVLM. Further attenuation of sympathetic activity is attained by the inhibi-tion of the RVLM via an inhibitory input from the vagal nuclei. See Sections 4.3.2.3, 4.4.1.1, 4.4.1.2, 4.4.2.3 and 4.6.3, for details.

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(Adidharma et al., 2012). As both the LH/PF (see Section 5.3.2) and the DR (see Section 5.4.1.3) send excitatory projec-tions to the LC, the LH/PF→DR→LC route is likely to aug-ment the activation of LC via the SC→DMH→LC route, and thus enhance the wakefulness-promoting effect of light. Light is expected to stimulate the sleep-promoting neurones of the VLPO in both diurnal and nocturnal animals: however, in diurnal animals, the wakefulness-promoting effect deriving from activation of the LC is likely to supersede the sleep-pro-moting effect arising from the activation of the VLPO.

7. Neuropathology of the LC

The functional significance of the central noradrenergic system, and in particular of the LC, is highlighted by pathological condi-tions that damage the system. The pathological conditions include chronic progressive neurodegenerative processes and acute (mainly vascular) insults.

The neuromelanin-containing catecholaminergic neurones of the brainstem, including the noradrenergic neurones of the LC, are susceptible to degeneration in progressive neurodegenerative

Figure 9. Schematic diagram of the neuronal network responsible for mediating the acute effects of light on arousal and sympathetic activity (‘photomodulation‘).Adrenoceptors: α1 (excitatory), α2 (inhibitory), β1 (excitatory).Cellular groups (nuclei and ganglia): CG: ciliary ganglion; DMH: dorsomedial hypothalamus; EWN: Edinger-Westphal nucleus; IML: intermedial lateral column; LC: locus coeruleus; OPT: olivary pretectal nucleus; PVN: paraventricular nucleus; SCG: superior cervical ganglion; SCN: suprachiasmatic nucleus; StG: stellate ganglion; TMN: tuber-omammillary nucleus; VLPO: ventrolateral preoptic area.Neurotransmitters: ACh: acetylcholine; GABA: γ-aminobutyric acid; Glu: glutamate; H: histamine; NA: noradrenaline; Ox: orexin; VP: vasopressin. Outputs from nuclei and ganglia: arrows (red: excitatory; blue: inhibitory). Light, either directly or indirectly, via rods and cones, stimulates intrinsically photosensitive retinal ganglion cells (ipRGCs) in the retina, that project to the SCN and VLPO (retino-hypothalamic tract) and OPT (light reflex pathway). Light has a dual effect on arousal. By stimulating sleep-promoting GABAergic neurones in the VLPO, it is sleep-promoting. Light, however, also has a wakefulness-promoting effect via activation of glutamatergic neurones in the SCN which in turn stimulate, via the DMH, the wakefulness-promoting neurones in the LC. The sleep-promoting effect of light seems to predominate in nocturnal animals, which, however, is superseded by the wakefulness-promoting effect in diurnal animals. Light also exerts a dual effect on sympathetic activity. Light can inhibit sympathetic outflow by stimulating GABAergic inhibitory neurones in the SCN, which in turn inhibit premotor sympathetic neurones in the PVN. The withdrawal of the stimulatory influence of the PVN on preganglionic sympathetic neurones in the IML leads to sympathoinhibition in the spinal segments projecting to the superior cervical ganglion, manifesting as pupil constriction and suppression of melatonin synthesis. Light, however, can also stimulate sympathetic activity at lower thoracic levels of the spinal cord, leading to increased cardiac activ-ity. The LC is involved in mediating this effect. The stimulation of glutamatergic excitatory neurones in the SCN by light leads to the activation of the LC, via the DMH. The LC, in turn, can activate preganglionic sympathetic neurones in the IML projecting to the stellate ganglion, leading to cardiostimulation. See Section 6.3, for details.

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disorders, such as the synucleinopathies (e.g. Parkinson‘s disease (PD), Lewy body dementia) (Puschmann et al., 2012) and the tau-pathies (e.g. Alzheimer‘s disease (AD)) (Lee et al., 2001).

It has been shown that neurodegenerative changes in PD ascend from the lower brainstem to the cerebral cortex (Braak et al., 2003). It has also been shown that the noradrenergic neu-rones in the LC get involved earlier than the dopaminergic neu-rones in the midbrain, the degeneration of which is responsible for the characteristic motor symptoms of PD (Del Tredici et al., 2002). There is evidence of loss of noradrenergic neurones in the LC in the brains of PD patients, as shown by both post-mortem examination (Bertrand et al., 1997; Zarow et al., 2003) and meas-urement of the neuromelanin signal in vivo by nuclear magnetic resonance (Sasaki et al., 2006).

Progressive degeneration of the LC in PD is likely to be responsible for a number of non-motor symptoms of PD which may appear before the onset of the motor symptoms. The loss of the noradrenergic input to the neocortex, especially to the prefron-tal cortex, has been implicated in early cognitive changes in PD (Vazey and Aston-Jones, 2012) and the development of dementia in more advanced disease (Chan-Palay, 1991; Zweig, 1993). Deficient noradrenergic function may underlie, at least partly, the sleep disorders observed in PD, such as excessive daytime sleepi-ness (Arnulf et al., 2002) and REM sleep behavior disorder (Barber and Dashtipour, 2012; Dugger et al., 2012). The loss of the noradrenergic input to the limbic system has been implicated in the emotional changes, such as depression, often observed in PD (Remy et al., 2005).

There is also a loss of noradrenergic neurones from the LC in another neurodegenerative disease, AD (Busch et al., 1997; Lyness et al., 2003; Tomlinson et al., 1981; Yang et al., 1999; Zarow et al., 2003). The degeneration of LC neurones in AD has been implicated in cognitive changes in this disorder, both at an early stage (Grudzien et al., 2007) and also later as manifest dementia supervenes (Bondareff et al., 1987; Chan-Palay, 1991; Matthews et al., 2002). Depression is a common concomitant of AD, and the depression appears to be related to neuronal loss in the LC (Chan-Palay and Asan, 1989; Forstl et al., 1994).

There are some physiological changes observed in patients suffering from AD that can be attributed to compromised LC function. There is evidence of reduced sympathetic activity and alertness in AD patients (for review, see Samuels and Szabadi, 2008b) consistent with the roles of the LC in the regulation of autonomic activity (see Section 6.2) and arousal (see Section 6.1). Both smooth pursuit and saccadic eye movements have been reported to be impaired in AD patients (for review, see Samuels and Szabadi, 2008b): this may reflect a deficit of the noradrener-gic regulation of motoneurones in the oculomotor complex (see Section 4.4.3.1).

Loss of noradrenergic neurones from the LC has also been found in some other neurodegenerative diseases, such as Down‘s syndrome (German et al., 1992; Lockrow et al., 2011, 2012; Mann et al., 1983), Pick‘s disease (Arima and Akashi, 1990; Takauchi et al., 1995), progressive supranu-clear palsy (Arima et al., 1992; Mann et al., 1983; Wang et al., 2006) and corticobasal degeneration (Gibb et al., 1989).

Recently it has been reported that the LC is damaged in mul-tiple sclerosis (Polak et al., 2011). The damage of the LC in mul-tiple sclerosis may contribute to the clinical picture: it has been

suggested that compromised LC function may be responsible for the deficit of arousal in this condition, manifesting as fatigue (Niepel et al., 2013). Furthermore, the identification of a noradr-energic deficit in multiple sclerosis may open new therapeutic avenues (McSharry, 2011).

Acute, mainly vascular, lesions can also compromise central noradrenergic function. It has been reported that a patient with a focal lesion in the dorsomedial pontine tegmentum, involving the LC, developed both narcolepsy and REM sleep behavior dis-order (Mathis et al., 2007) and this highlights the importance of the LC in mediating the influence of the orexinergic system on wakefulness and muscle tone. It has been shown that brainstem stroke leads to coma only if a well-defined area of the upper pontine tegmentum, including the LC, is affected (Parvizi and Damasio, 2003). This observation suggests that the coma may be due to destruction of the LC, and is consistent with the role of the LC in the maintenance of wakefulness. However, it has been reported recently that damage to some other structures in the vicinity of the LC (parabrachial nucleus, precoeruleus area) may play a major role in the causation of brainstem coma (Fuller et al., 2011).

8. Pathophysiology of the LCThe activity of the LC is altered in a number of pathological and drug-induced states when changed LC activity contributes to the clinical manifestation of these conditions.

The LC plays an important role in both the processing and modulation of pain. The LC is an important relay nucleus in the pain-processing system: it receives nociceptive inputs from both the sensory trigeminal nuclei and the dorsal horn of the spinal cord (Craig, 1992). The LC projects to higher pain-processing centers, such as the somatosensory thalamus (Voisin et al., 2005) and the somatosensory cerebral cortex (Levitt et al., 1984). There is extensive evidence that noxious stimulation leads to an increase in LC activity (for review see Szabadi, 2012). The LC not only receives an input from nociceptive afferents but it also projects to primary pain-sensitive/pain-processing sensory neurones in the trigeminal sensory nuclei of the brainstem (Tsuruoka et al., 2003), the dorsal horn of the spinal cord (Liu et al., 2007), and secondary pain-processing neurones in the somatosensory thalamus (Voisin et al., 2005). Through these projections the LC exerts an inhibi-tory influence on pain sensation (for reviews see Ossipov et al., 2010; Pertovaara and Almeida, 2006; Szabadi, 2012; Willis and Westlund, 1997).

Anxiety is generally defined as an emotional state evoked by threatening stimuli (Szabadi and Bradshaw, 1988), when the threat is direct or immediate, and fear as anticipation of threat (Grillon et al., 1991). The LC is closely involved with both the generation of the emotional states of fear and anxiety and the pro-duction of the behavioral syndrome characteristic of anxious states (Millan, 2003). The basis of this dual role of the LC in fear and anxiety is its two-way relationship to the amygdala, the struc-ture that is critical for the generation of anxiety and anxious responses (Canteras et al., 2010; Charney et al., 1998; Damasio, 1998; LeDoux, 1998; Pare and Duvarci, 2012). As discussed above, the LC sends an excitatory projection to the central and basal nuclei of the amygdala (see Section 4.2.1) and the same nuclei of the amygdala receive an excitatory input from the LC (see Section 5.2). Stimulation of the LC can evoke anxiety

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(McDougle et al., 1995; Redmond and Huang, 1979) and lesions of the central noradrenergic system lead to attenuation of fear-related responses (Redmond, 1987; Verleye and Bernet, 1983). On the other hand, there is evidence that anxious states lead to the activation of the LC (Charney et al., 1990; Cullinan et al., 1995; Rasmussen and Jacobs, 1986).

The effect of threat (anticipatory anxiety) has been studied extensively using the paradigm of ‘fear conditioning‘. Fear condi-tioning involves the association of a noxious (unconditioned) stimulus with a neutral (conditioned) stimulus, leading to the abil-ity of the conditioned stimulus to evoke the response to the uncon-ditioned stimulus (usually pain). Fear conditioning leads to the activation of both the amygdala (Davis et al., 1993; Pascoe and Kapp, 1985) and the LC (Ishida et al., 2002; Rasmussen and Jacobs, 1986). It has been shown that fear-conditioning can modu-late physiological reflexes: the acoustic startle response, involv-ing the contraction of striated muscles, is potentiated whereas the pupillary light reflex, involving the contraction of smooth muscles in the iris, is inhibited by conditioned fear (for review see Szabadi, 2012). In both cases, the activation of the LC, via the amygdala, is involved: increased LC activity enhances the startle response via facilitating motoneurone activity (see Sections 4.4.3 and 4.6.2) and attenuates the pupillary light reflex via enhancing the noradr-energic inhibition of the parasympathetic output to the iris (see Section 6.2) (Szabadi, 2012).

Post-traumatic stress disorder (PTSD) is a clinical syndrome that arises following exposure to extreme stressful experience. Increased startle reactivity is a feature of the syndrome, and it may be related to increased LC activity (Szabadi, 2012). It has been reported that exposure to stress leads to the activation of the LC (Pacák and Palkovits, 2001; Valentino and Van Bockstaele, 2008), and there is evidence of enhanced noradrenergic activity in PTSD (Jacobsen et al., 2001; Southwick et al., 1993).

The LC has been implicated in anesthesia, due to its position in the LC ↔ VLPO → TMN → cerebral cortex circuit (see Section 6.1 and Figure 6) (Nelson et al., 2002, 2003). GABAergic anes-thetics (e.g. propofol, pentobarbitone) stimulate GABAA recep-tors on the GABAergic neurones of the VLPO: this leads to increased inhibition of the wakefulness-promoting histaminergic neurones of the TMN. The withdrawal of the histaminergic stimu-lation of the cerebral cortex results in sedation (Nelson et al., 2002). It should be noted, however, that the central role of the GABAergic inhibition of the TMN in the mode of action of GABAergic anesthetics has been challenged recently (Zecharia et al., 2012).

The LC, by inhibiting the VLPO via stimulation of α2-adrenoceptors, is expected to attenuate the effect of GABAergic anesthetics. This is demonstrated by the effects of drugs that inter-act with inhibitory α2-adrenoceptors (autoreceptors) on LC neu-rones, and thereby modulate LC activity. Thus α2-adrenoceptor agonists (e.g. clonidine, dexmedetomidine) potentiate or even induce anesthesia (Kushikata et al., 2002; Nelson et al., 2003) whereas α2-adrenoceptor antagonists (e.g. yohimbine) antagonize anesthesia (Kushikata et al., 2002). Consistent with these find-ings, potentiation of anesthesia was reported following destruc-tion of the noradrenergic output from the LC by the neurotoxin DSP-4 (Kushikata et al, 2011). It should be noted that the inhibi-tory link between the VLPO and the LC operates in both direc-tions (see Sections 5.3.1 and 6.1). Therefore GABAergic anesthetics, by increasing the activity of VLPO neurones, dampen LC activity (Hirota and Kushikata, 2001).

Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-functions mutations in the methyl-CpG-binding pro-tein-2 (MECP2) gene (Amir et al., 1999). The clinical phenotype is characterized by cognitive, motor and behavioral deficits, ste-reotype hand movements, loss of speech, autistic features, sei-zures, impairments of respiratory, cardiac and gastrointestinal functions (Chahrour and Zoghbi, 2007; Hagberg et al., 1983). Reduced levels of noradrenaline metabolites have been detected in the cerebrospinal fluid of RTT patients (Zoghbi et al., 1989) raising the possibility of a central noradrenergic abnormality. This possibility has been followed up using an animal model of the disorder (MECP2 null mutant mouse). A number of abnormalities of the central noradrenergic system have been detected, including some specifically related to the LC. The abnormalities detected include reduced noradrenaline content (Samaco et al., 2009; Viemari et al., 2005), smaller noradrenergic neurones (Taneja et al., 2009), reduced activity of the synthesizing enzymes tyros-ine hydroxylase (Roux et al., 2010; Samaco et al., 2009; Taneja et al., 2009; Viemari et al., 2005; Zhang et al., 2010) and dopa-mine β-hydroxylase (Zhang et al., 2010), and electrical hyperex-citability of LC neurones (Taneja et al., 2009). Some of the clinical features of the syndrome have been related to central noradrener-gic deficit, such as disordered respiratory control (Viemari et al., 2005; Voituron et al., 2010) and autism (Mehler and Purpura, 2009).

9. ConclusionsThe central noradrenergic neurone has retained the basic charac-teristics of the peripheral sympathetic neurone. The terminal axons arborize extensively and contain both synaptic (‘bouton ter-minaux‘) and non-synaptic sites of release. The non-synaptic release of noradrenaline complements the neurotransmitter action of noradrenaline with a local hormone-like (‘paracrine‘) function. The central noradrenergic neurone has the same pharmacologi-cally-sensitive sites as the peripheral sympathetic neurones: fir-ing- and release-modulating adrenoceptors, sites for the reuptake and re-storage of noradrenaline (cellular and vesicular noradrena-line transporters), machinery of storage, synthesis and degrada-tion. Furthermore, the same types of adrenoceptor are activated by noradrenaline in the periphery and the CNS, and the same cotrans-mitters occur in both peripheral and central noradrenergic neurones.

The central neurone, however, also has some unique features. Central noradrenergic neurones aggregate in distinct nuclei in the brainstem from where they send multiple outputs to diverse struc-tures of the neuraxis. There is evidence that one single neurone may innervate different, and often quite remote structures. Furthermore, the central noradrenergic neurone is a ‘dual function neurone‘: it can exert both excitatory effects, via the activation of α1-adrenoceptors, and inhibitory effects, via the activation of α2-adrenoceptors, on follower cells. In this way the central noradren-ergic neurone does not conform to Eccles‘ principle which states that ‘in the mammalian CNS neurones are either excitatory or inhibitory and are never ambivalent‘ (see page 229 in Eccles, 1976). The duality of its function equips the central noradrenergic neurone with unique flexibility and targeted executive control that can be attained by single function neurones only via the involve-ment of interneurones. The duality of central noradrenergic func-tion is illustrated by the sleep/arousal and autonomic regulatory networks: noradrenergic neurones of the LC stimulate

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wakefulness-promoting and inhibit sleep-promoting mechanisms, and they stimulate sympathetic and inhibit parasympathetic activity.

Of the central noradrenergic nuclei, the LC is the largest and best studied. The multiple and diverse efferent and afferent con-nections of the LC indicate its involvement in the regulation of a large number of physiological functions. However, the impor-tance of central noradrenergic control is best illustrated by consid-ering some integrated physiological functions in which the LC plays a major role. The LC plays a central role in both the sleep/arousal and autonomic networks: via its connections within these networks the LC exerts a powerful wakefulness-promoting and sympathetic-activating influence. Via its position in these net-works, the LC provides an important link between arousal and autonomic activity, fulfilling the role of the ‘arousal/autonomic activity interface‘. The LC also plays a unique role in the network responsible for mediating the acute effect of light on physiological functions, such as arousal and sympathetic activity (‘photomodu-lation‘). In this network, the LC is responsible for mediating the stimulatory effects of light on arousal and sympathetic activity which oppose the inhibitory effects of light on the same functions mediated via a different route (VLPO, PVN). As the inhibitory effects of light appear to be predominant in nocturnal animals, whereas the stimulatory effects prevail in diurnal animals, LC activity seems to be necessary for the daytime functioning of diur-nal animals.

Understanding the functional neuroanatomy of the central noradrenergic system helps to interpret the effects of physiologi-cal variables (e.g. pain, anxiety and stress) and pharmacological agents (e.g. stimulants, sedatives and antidepressants) on the brain and behavior (Samuels and Szabadi, 2008a). As the central noradrenergic system, and in particular the LC, is susceptible to early and progressive degeneration in neurodegenerative diseases (e.g. PD, AD), some clinical features of these diseases (e.g. cogni-tive decline, sleep disorder and depression) can be understood on the basis of the loss of the noradrenergic control of brain areas implicated in the symptoms.

AcknowledgementsThe author is grateful to Rob Langley for drawing the figures.

Conflict of interestThe author declares that there is no conflict of interest.

FundingThis research received no specific grant from any funding agency in the public, commercial, or non-profit sectors.

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