Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79

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Autonomic Neuroscience: Basic and Clinical

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u

Autonomic control of the eye and the iris

Winfried Neuhuber a,⁎, Falk Schrödl a,b
a
Institute of Anatomy, University of Erlangen-Nuremberg, Krankenhausstrasse 9, D-91054 Erlangen, Germany
b
Departments of Anatomy and Ophthalmology, Paracelsus Medical University, Salzburg, Austria

a r t i c l e i n f o a b s t r a c t

Article history: The vertebrate eye receives innervation from ciliary and pterygopalatine parasympathetic and cervical
Received 10 February 2010 sympathetic ganglia as well as sensory trigeminal axons. The sympathetic and parasympathetic pathways
Received in revised form 8 August 2010 represent the classical “core” of neural regulation of ocular homeostasis. Sensory trigeminal neurons are also
Accepted 13 October 2010
involved in autonomic regulation by both providing the afferent limb of various reflexes and exerting their
peptide-mediated local effector function. This arrangement is remarkably conserved throughout vertebrate
Keywords:
Parasympathetic
classes although significant modifications are observed in anamniotes, in particular their irises. In higher
Sympathetic primates and birds, intrinsic choroidal neurons emerged as a significant additional innervation component.
Intrinsic neurons They most likely mediate local vascular regulation and other local homeostatic tasks in foveate eyes. This
Cornea review across the vertebrate classes outfolds the complex neuronal regulatory underpinnings across
Iris vertebrates that ensure proper visual function.
Ciliary body © 2010 Elsevier B.V. All rights reserved.
Choroid
Comparative neuroanatomy

1. Introduction muscle as well as immune functions through local release of various

Autonomic innervation of the eye, as presented in most textbooks
of anatomy and physiology, is mainly conceived as sympathetic and
parasympathetic nerves controlling pupil size and accommodation.
The eye, in particular the iris, is readily used as a didactic paradigm to
demonstrate the antagonistic action of these two autonomic systems,
and pupillography is a convenient method for diagnosis of lesions of
the autonomic nervous system (Kawasaki, 1999; Dütsch et al., 2004).
However, regulation of ocular blood flow, aqueous humor production
and intraocular pressure (IOP) are also important tasks for autonomic
neurons. Moreover, thin calibre primary afferent nerve fibers of the
trigeminal nerve, long considered as purely sensory mediating
protective reflexes, influence intraocular blood vessels and smooth
Abbreviations: ACAID, anterior chamber associated immune deviation; CCK,
cholezystokinin; CGC, choroidal ganglion cells; CGRP, calcitonin gene-related peptide;
ChAT, choline acetyl transferase; FRAP, fluoride resistant acid phosphatase; ICN,
intrinsic choroidal neurons; IOP, intraocular pressure; NADPHd, nicotinamide adenine
dinucleotide phosphate diaphorase; NKA, neurokinin A; nNOS, neuronal nitric oxide
synthase; NO, nitric oxide; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase
activating peptide; pChAT, peripheral choline acetyl transferase; SP, substance P; TH,
tyrosine hydroxylase; VAChT, vesicular acetyl choline transporter; VIP, vasoactive
intestinal peptide; VMAT, vesicular monoamine transporter.
⁎ Corresponding author. Tel.: + 49 9131 8522264; fax: + 49 9131 8522863.
E-mail address: winfried.neuhuber@anatomie1.med.uni-erlangen.de
(W. Neuhuber).
peptides, thus representing an additional autonomic neuronal
component. In addition, recent studies have revealed intrinsic
neurons of the middle layer of the eye bulb, i.e., the uvea as a
significant component of autonomic ocular innervation. This review
will provide an overview of autonomic innervation of the vertebrate
eye from cyclostomes to human, although emphasis will be put on
mammals and birds as most of the more recent data have been
brought about in these classes.
2. Extrinsic autonomic innervation
Like most organs, the eye receives innervation from both cranial
and spinal autonomic systems, conventionally referred to as para-
sympathetic and sympathetic, respectively (Fig. 1). However, there
are significant modifications of this pattern established in mammals in
other vertebrate classes in terms of location of preganglionic neurons,
pathways to ganglionic relays and targets for the respective systems.
2.1. Cranial autonomic system
2.1.1. IIIrd cranial nerve pathway
Preganglionic neurons of the IIIrd cranial nerve pathway reside in
the accessory oculomotor nucleus Edinger–Westphal in the rostral
mesencephalon (Figs. 1 and 2). This nucleus is present in virtually all
vertebrate classes (Matesz and Székely, 1977; Wathey, 1988b;
Gamlin, 2000; Horn et al., 2008), although its identification is difficult
in cyclostomes (Fritzsch et al., 1990; Pombal et al., 2001) and some

1566-0702/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.autneu.2010.10.004
68 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79

Fig. 1. Schematic of autonomic innervation of the eye in non-primate mammals. The same or a similar basic pattern also applies to teleost fish, amphibia and reptiles. The cranial
autonomic system is represented by preganglionic neurons of the Edinger–Westphal (III) and superior salivatory (VII) nuclei and their related ciliary (Cil) and pterygopalatine (PtP)
ganglia, respectively. The intermediolateral nucleus (IML) and the superior cervical ganglion (SCG) stand for the spinal autonomic system. Neurons of the trigeminal ganglion (Trig)
subserve both afferent and efferent “local effector” functions. Major transmitters of the respective ganglionic neurons are indicated in italics. Targets are structures in the anterior eye
segment as well as both extra- and intraocular branches of the ophthalmic artery. ACh—acetylcholine; bv—blood vessels; C—cornea; CGRP—calcitonin gene-related peptide; CNS—
central nervous system; NA—noradrenaline; NO—nitric oxide; NPY—neuropeptide Y; P—pupil; TK—tachykinins; VIP—vasoactive intestinal peptide.

elasmobranch (Anadón et al., 2000) and urodele species (Naujoks-
Manteuffel et al., 1986). The Edinger–Westphal nucleus as defined
cytoarchitectonically does not always represent a homogenous group
of neurons in terms of projections and neurochemistry, as shown by
recent studies on the perioculomotor area (Horn et al., 2008). Besides
cholinergic preganglionic neurons projecting to the ciliary ganglion,
which in goldfish and pigeon also contain neuronal nitric oxyde
synthase (nNOS; Cuthbertson et al., 1999; Giraldez-Perez et al., 2009)
and substance P (SP; Cuthbertson et al., 1999), in several mammalian
species it also harbours tecto-spinal and tecto-cerebellar neurons as
well as nerve cell groups projecting to dorsal raphe nuclei and lateral
septum. Some of these cells contain urocortin (May et al., 2008a,b;
Ryabinin et al, 2005), SP (Maciewicz et al., 1983) or cholecystokinin
(CCK; Maciewicz et al., 1984; Horn et al., 2008 for further references).
This mismatch is particularly pronounced in cat (Sugimoto et al.,
1977) and rabbit (Johnson and Purves, 1981), where cholinergic
preganglionic neurons are not even within the confines of Edinger–
Westphal nucleus proper but rather scattered in the perioculomotor
reticular formation. In human, cholinergic preganglionic neurons are
located dorsomedially to the Edinger–Westphal nucleus (Horn et al.,
2008). It appears that only in monkey and birds, cholinergic pre-
ganglionic neurons projecting to the ciliary ganglion are within the

Fig. 2. Schematic of autonomic innervation of the eye in higher primates and birds. In addition to cranial and spinal autonomic and trigeminal sensory neurons, intrinsic choroidal
neurons (ICN) supply choroidal blood vessels and non-vascular smooth muscle (NVSM). ICN also establish intrinsic connections and receive extrinsic input from ciliary and superior
cervical ganglia and collaterals of trigeminal afferents. In birds, choroidal blood vessels are also innervated by choroid neurons of the ciliary ganglion (dashed arrow). Other
abbreviations as in Fig. 1.
 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79
Edinger–Westphal nucleus proper (Gamlin, 2000; Vasconcelos et al,
2003; Horn et al., 2008). In monkey, anterograde tracing from the
pretectum showed that the subdivision of this nucleus controlling the
size of the pupil was located in the ventromedial portion of its middle
third (May et al., 2008a,b). Subnuclei controlling the pupil and lens,
respectively, have also been defined in cat (Erichsen and May, 2002).
In most if not all vertebrate classes, Edinger–Westphal neurons
controlling pupillary size represent a minority as compared to those
devoted to accommodation (Wathey, 1988b; Gamlin, 2000). In birds,
the Edinger–Westphal nucleus is partitioned into a medial and lateral
portion that project to choroid and ciliary neurons of the ciliary
ganglion, controlling choroidal blood flow and intraocular muscles,
respectively (Gamlin, 2000). Although choroidal blood flow in
mammals is considered to be regulated via the VIIth cranial nerve
pathway, a role for the IIIrd nerve pathway cannot be ruled out
(Gamlin, 2000). Tecto-spinal projecting neurons are also detected in
the Edinger–Westphal nucleus of elasmobranchs (Cruce et al., 1999),
amphibians (Sánchez-Camacho et al., 2001) and reptiles (ten
Donkelaar et al., 1980). Edinger–Westphal neurons projecting to the
cerebellum, distinct from those innervating ciliary ganglion neurons
have also been described in teleosts (Wathey and Wullimann, 1988).
SP- and urocortin-immunoreactive neurons have been observed in
the Edinger–Westphal nucleus of elasmobranchs (Rodríguez-Moldes
et al., 1993) and amphibians (Kozicz et al., 2002), respectively. Thus,
the Edinger–Westphal nucleus of non-mammalian vertebrates may
be as heterogeneous as in mammals.
A ciliary ganglion (Figs. 1 and 2) is found in all vertebrate classes
and species examined, from elasmobranchs to human (Gibbins,
1994). Even where its absence has been noted, e.g., in cyclostomes
(Nishi, 1938), it may be represented by neurons scattered along the
oculomotor nerve as described in some gnathostomes (e.g., Latimeria,
Northcutt and Bemis, 1993). Preganglionic axons from the oculomotor
nerve enter the ganglion through the radix brevis while the radix
longa from the nasociliary nerve contributes trigeminal afferent and
postganglionic sympathetic axons. In birds, two types of neurons are
distinguished: large ciliary neurons innervating ciliary and iris
muscles and small choroid neurons innervating blood vessels and
non-vascular smooth muscle in the choroid (Marwitt et al., 1971;
Meriney and Pilar, 1987). Both types of neurons are cholinergic as
demonstrated by choline acetyltransferase (ChAT) immunoreactivity
and functional studies (Landis et al., 1987). Subpopulations contain
various peptides and nNOS, although there is considerable interspe-
cies variability (Stone et al., 1988; Hardebo et al., 1992; Sun et al.,
1994; Kirch et al., 1995; Gottanka et al., 2005; Kaleczyc et al., 2005). In
birds, choroid neurons are immunopositive for somatostatin (Epstein
et al., 1988; Coulombe and Nishi, 1991; De Stefano et al., 1993).
Although somatostatin positive neurons were also described in pig
ciliary ganglion (Kaleczyc et al., 2005), it is unknown if they are
homologous to avian choroid neurons. Preganglionic cholinergic
terminals occur in two varieties: large cup-shaped (“calyciform”)
and small varicose boutons. In birds, calyciform terminals which
display both chemical and electrical synaptic features contact the
large ciliary neurons in a 1:1 relation whereas boutons from multiple
preganglionic axons terminate on smaller choroid neurons (Cantino
and Mugnaini, 1975; Dryer and Chiappinelli, 1985). Both calyciform
and varicose endings co-stain for nNOS and SP in pigeon (Cuthbertson
et al., 1999) although only choroid neurons which are innervated by
varicose endings respond to SP (Dryer and Chiappinelli, 1985). The
reason why ciliary neurons contacted by SP-positive calyciform
endings do not respond to SP application is unclear. On the other
hand, nitric oxide (NO) appears to modulate cholinergic transmission
mainly at calyciform endings (Scott and Bennett, 1993). In addition to
cholinergic preganglionic terminals, about 15% of human ciliary
ganglion neurons are surrounded by varicosities immunoreactive for
both SP and calcitonin gene-related peptide (CGRP), most likely
collaterals of trigeminal afferents (Fig. 2; Kirch et al., 1995).
69
More than 90 % of ciliary neurons in mammals and birds are
targeted to the ciliary muscle whereas the remaining innervate the
iris and blood vessels, thus reflecting a similar bias in the Edinger–
Westphal nucleus towards accommodation neurons (for references
see Gamlin, 2000; Jumblatt, 2000).
From the distal pole of the ciliary ganglion, the short ciliary nerves
course towards the eye globe, carrying postganglionic parasympa-
thetic and sympathetic as well as trigeminal afferent axons. Within
the globe, they travel in the suprachoroid space towards the anterior
eye segment giving off small branches to the choroidal nerve plexus
(short uveal nerves; May, 2004). Accessory ciliary ganglia are em-
bedded within short ciliary nerves (Kuchiiwa et al., 1989) and receive
innervation from the Edinger–Westphal nucleus (Kuchiiwa et al.,
1994).
2.1.2. VIIth cranial nerve pathway
Cholinergic preganglionic neurons reside in the medulla oblongata
in a cell group classically termed the superior salivatory nucleus
(Figs. 1 and 2). This nucleus has been identified using tracing methods
in anurans (Oka et al., 1987), reptiles (Atobe et al., 2004), birds
(Schrödl et al., 2006) and mammals (Contreras et al., 1980; ten
Tusscher et al., 1990; Cuthbertson et al., 2003) and was shown to
represent scattered neurons dorsolateral to, and partially inter-
mingled with, the branchiomotor facial neurons rather than a solid
nucleus. It is more difficult to localize it in cyclostomes (Pombal et al.,
2001), elasmobranchs (Molist et al., 1995; Anadón et al., 2000) and
teleosts (Arévalo et al., 1995), where small cholinergic neurons
dorsomedial to the branchiomotor cell groups were suggested to
represent preganglionic parasympathetic neurons. In Rana esculenta,
these preganglionic neurons also stain for CGRP (Petkó and Sánta,
1992) while in rabbit they co-stain for ChAT and nNOS (Zhu et al.,
1997). Neurons of the superior salivatory nucleus project to
postganglionic nerve cells in the pterygopalatine ganglion and
microganglia in the orbit (Cuthbertson et al., 2003; Schrödl et al.,
2006) which in turn innervate the uvea and intraorbital glands.
However, this pathway has been convincingly shown only in birds
(Cuthbertson et al., 1997; Schrödl et al., 2006) and mammals (Ruskell,
1985a; Kuchiiwa, 1990; ten Tusscher et al., 1990; Beckers et al., 1993;
Cuthbertson et al., 2003; Ruskell, 2004) and can only be inferred for
other classes and species. For example, there is a communicating
branch from the palatine ramus of the VIIth cranial nerve to the ciliary
plexus in elasmobranchs which may carry parasympathetic pregan-
glionic fibers destined to the eye (Gibbins, 1994).
The pterygopalatine or sphenopalatine ganglion represents a
major pre-postganglionic relay in the parasympathetic VIIth cranial
nerve pathway (Figs. 1 and 2). Its postganglionic neurons innervate
blood vessels, non-vascular smooth muscle and glands in the
maxillary area, nasal cavity and orbit. In many vertebrate classes,
there are several smaller ganglia and scattered ganglion cells
embedded in small nerve branches, in addition to, or even
substituting a pterygopalatine ganglion sensu strictu (Ten Tusscher
et al., 1990; Gibbins, 1994; Cuthbertson et al., 1997). In birds, they are
located close to the Harderian gland (Cuthbertson et al., 1997; Schrödl
et al., 2006). The orbital branches of the pterygopalatine ganglion
intermingle with the retroorbital plexus (Ruskell, 1970b). Most
neurons in these ganglia are cholinergic and nitrergic, containing
ChAT and nNOS (Morris et al., 1993; Cuthbertson et al., 1997;
Gottanka et al., 2005) but also contain peptides, e.g., vasoactive
intestinal peptide (VIP) and neuropeptide Y (NPY; Gibbins and
Morris, 1987; Ceccatelli et al., 1994; Alm et al., 1995). In birds, a
minority of the cholinergic/nitrergic neurons is co-immunoreactive
for galanin (Schrödl et al., 2000; Stübinger et al., 2010).
Similar to the ciliary ganglion, several pterygopalatine gangli-
onic neurons are contacted by collaterals of trigeminal afferents
(Suzuki et al., 1989). However, it is not known if these neurons
innervate the eye.
70 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79
Recently, somatostatin immunoreactive nerve terminals have
been demonstrated on nitrergic neurons of the quail pterygopalatine
ganglion, suggesting input from choroid neurons of the ciliary
ganglion (Schrödl et al., 2005). In turn, nerve fibers anterogradely
labelled from the rat pterygopalatine ganglion have been detected in
the ciliary ganglion (Beckers et al., 1993); however, such a pathway is
unlikely in human (Ruskell, 1970a). Thus, there might exist reciprocal
connections between these two eye-related parasympathetic ganglia
in some species.
Again, similar to the ciliary ganglion, the pterygopalatine ganglion
is traversed by postganglionic sympathetic axons from the superior
cervical ganglion (ten Tusscher et al., 1990). Whether these axons
influence parasympathetic neurons is not known.
2.2. Spinal autonomic system
The spinal “sympathetic” autonomic system emerged with gnathos-
tomes (Funakoshi and Nakano, 2007). Although sympathetic chain
ganglia are present in elasmobranchs, there is apparently no “sympa-
thetic” pathway to the eye (Nilsson, 1994). The pattern typically seen in
mammals, birds and reptiles where postganglionic adrenergic nerves
from sympathetic chain ganglia are directed to the dilator pupillae
muscle (Nilsson, 1994; Dearworth and Cooper, 2008), does not apply to
teleosts and amphibia either (Nilsson, 1994). In teleosts, sympathetic
ganglion neurons which are cholinergic (Uranoscopus) or adrenergic
(Gadus) activate the sphincter pupillae. In contrast, in amphibia,
adrenergic sympathetic neurons inhibit the sphincter pupillae.
Preganglionic cholinergic spinal autonomic neurons are located in
the intermediolateral nucleus (IML) from the 8th cervical to the 2nd
thoracic spinal segments, the so-called centrum ciliospinale in
mammals, and the lowermost cervical, i.e., the 16th, and uppermost
thoracic segments in birds (Figs. 1 and 2). In anurans, these neurons
reside in the 2nd through 4th spinal segments (Morris, 1976; Nilsson,
1994 for references). Postganglionic neurons which are typically
adrenergic with NPY and ATP as co-transmitters reside in the superior
cervical ganglion of mammals and birds or the respective most cranial
sympathetic chain ganglia in other vertebrates (Ellison and Clark,
1975; Gibbins and Morris, 1987; Gibbins, 1994).
2.3. Trigeminal local effctor system
Small neurons in the ophthalmic portion of the trigeminal
ganglion of birds and mammals and the profundus ganglion of fish,
amphibia and reptiles innervate all layers of the eye except for the
retina (Figs. 1 and 2; guinea-pig: Kuwayama and Stone, 1987;
goldfish: Wathey, 1988a; guinea-pig and human: Uusitalo et al.,
1989; cat: Mintenig et al., 1995; duck: Schrödl et al., 2001a). By virtue
of their ability to release peptides, e.g., tachykinins such as SP and
neurokinin A (NKA), CGRP, somatostatin, galanin, CCK, pituitary
adenylate cyclase activating peptide (PACAP), secretoneurin, etc. from
their peripheral endings and collaterals, they can influence smooth
muscle and other ocular targets exerting a so-called local effector
function in addition to their sensory functions (rabbit: Wang et al.,
1995; macaques and baboons: Firth et al., 2002; human: Schmid et al.,
2005; for further references see Holzer, 1988; Jumblatt, 2000; Troger
et al., 2009). Although studies on trigeminal peptidergic innervation
of the eye are sparse in non-mammalian classes, the general
comparability of the trigeminal afferent systems of various verte-
brates enables for inferences across species (chick: Corvetti et al.,
1988; snake: Kadota et al., 1988; frog: Hernández et al., 2003; for
further references see Sneddon, 2004). Trigeminal axons are distrib-
uted through the nasociliary nerve via the long ciliary nerves and
through the sensory root of the ciliary ganglion to the short ciliary
nerves to the eye. Collaterals of trigeminal peptidergic afferents
contact ciliary (Fig. 2; Kirch et al., 1995) and pterygopalatine (Suzuki
et al., 1989) ganglionic neurons and intrinsic choroidal neurons
(Fig. 2; Schrödl et al., 2001a), thus providing a structural basis for pre-
central reflexes as known from mammalian prevertebral ganglia
(Matthews et al., 1987).
2.4. Gateways for extrinsic autonomic neurons to the eye
The superior and inferior orbital fissures (in species where they are
present) represent the main entry for autonomic nerves towards the
eye. The oculomotor nerve providing preganglionic parasympathetic
nerve fibers and the nasociliary nerve carrying both trigeminal
primary afferents and postganglionic sympathetic axons from the
internal carotid plexus are passing through the superior orbital fissure
whereas orbital branches from the pterygopalatine ganglion carrying
postganglionic parasympathetic fibers of the VIIth nerve pathway,
primary afferents of the maxillary nerve and also sympathetic
postganglionics enter through the inferior orbital fissure (Ruskell,
1970a,b, 1974).
Orbital rami of the pterygopalatine ganglion join with sympathetic
fibers from the internal carotid plexus to form the retrorbital plexus
which issues delicate nerve branches to the eye globe as well as
lacrimal and harderian glands. It also contains several microganglia
(Ruskell, 1970a,b). This ganglionic arrangement in mammals, includ-
ing primates, is similar to that in birds and reptiles where several
small ganglia connected with the facial nerve pathway are found
within the orbit (Gibbins, 1994).
In addition to the orbital fissures, in human a significant amount of
autonomic nerve fibers, mainly sympathetic from the internal carotid
plexus, enter the orbit through the optic canal, embedded in its
periosteum, the optic nerve sheath and the adventitia of the
ophthalmic artery. They join the ciliary nerves or enter the eye
directly (Ruskell, 2003).
3. Intrinsic neurons
3.1. Intrinsic choroidal neurons
Neurons in the choroid, termed intrinsic choroidal neurons (ICN;
Fig. 2; Schrödl et al., 2000) or choroidal ganglion cells (CGC; May et al.,
2004) were described more than a century ago (for review see
Schrödl, 2009). However, they were almost neglected until recently,
when modern histo- and immunohistochemical techniques enabled a
more thorough investigation of these neurons. Although they were
found in a variety of species including rat, guinea pig and rabbit, they
are present in larger numbers only in primates, in particular humans,
and in birds (Schrödl, 2009). This has been correlated to the highly
developed visual apparatus in these species. From a developmental
point of view, they may be interpreted as ectopic, peripherally
displaced parasympathetic neurons, e.g., an extreme variant of a
ciliary plexus or accessory ciliary ganglia which have been found in
many non-mammalian and mammalian species (Kuchiiwa et al.,
1989, 1994; Gibbins, 1994). Likewise, the ICN could represent an
intraocular continuation of intraorbital microganglia of the retro-
orbital plexus along the facial parasympathetic pathway. However,
ICN/CGC display some hodological and neurochemical features that
distinguish them from parasympathetic neurons.
3.1.1. ICN in human and non-human primates
The human choroid harbours about 2000 ICN per eye (Flügel et al.,
1994; May et al., 2004). This is in the same order of magnitude as
ciliary ganglion neurons which number about 3000 (Gibbins, 1990).
Lower counts of ICN (about 500/eye) have been reported for monkeys
(Flügel-Koch et al., 1994; May et al., 1997, 2006) whereas non-foveate
primates, e.g., the common tree shrew Tupaia glis and the owl monkey
Aotes trivirgatus, are lacking ICN (Flügel-Koch et al., 1994). ICN occur
singly or in groups of up to 20 cells forming ganglia at the nodes
of a nerve plexus located in the outer zone of the choroid. The
 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79 71

choriocapillaris is devoid of ICN. Most ICN are large, smooth contoured
multipolar cells with diameters of 20 to 40 μm whereas a minor
population measures 10 to 20 μm (Fig. 3a). ICN are concentrated in
temporal quadrants (Flügel et al., 1994) although not strictly beneath
the macula (Trivino et al., 2002; Schrödl, 2009). As the majority of ICN
stain positively for nitrergic markers, typically colocalized with VIP,
the choroidal ganglionated plexus is best demonstrated using NADPH
diaphorase (NADPHd) histochemistry (Bergua et al., 1993). However,
as neurons of the pterygopalatine ganglion and some trigeminal
sensory neurons are also NADPHd/nNOS/VIP positive (Gottanka et al.,
2005), they may also contribute to this plexus. About 50% of ICN are
immunopositive for calretinin (May et al., 2004). ICN never display
ChAT, vesicular acetylcholine transporter (VAChT), tyrosine hydrox-
ylase (TH) or vesicular monoamine transporter (VMAT) immuno-
reactivity, disproving their cholinergic or adrenergic nature (May
et al., 2004). Their nitrergic but non-cholinergic nature is a major
distinction against parasympathetic neurons of ciliary or pterygopa-
latine ganglia. Morphological and chemical heterogeneity suggests
functional differences between ICN subpopulations. Ultrastructural
studies revealed incomplete covering of choroidal ganglia by glial
processes (May et al., 2004). Thus, some ICN are separated from the
periganglionic extracellular matrix only by the basal membrane, an
arrangement resembling ganglia of the enteric nervous system.
3.1.2. ICN in non-primate mammals
There are but a few, i.e., up to 20/eye, ICN in rat, guinea pig and
rabbit (Flügel et al., 1994; Ramírez et al., 1999; Schrödl, 2009), and
none are found in cat, dog, sheep and pig (Flügel et al., 1994) using
NADPHd histochemistry. It may be assumed that those tasks which
are fulfilled by ICN are of minor significance for the respective species
or are accomplished by extrinsic autonomic neurons.
3.1.3. ICN in birds
The discovery of large amounts (about 1000/eye) of NADPHd
positive ICN in the eye of the muscovy duck (Cairina moschata; Bergua
et al., 1996) was driven by the hypothesis that ICN typically occur in
species with high visual acuity provided by foveate eyes, i.e., higher
primates and birds. Subsequently, ICN have been found in another 12
avian species including chicken although in greatly varying numbers
(Fig. 3b, c, and d; Schrödl et al., 2004; Schrödl, 2009). Highest counts
were reported for the goose (up to about 9000/eye) while the eyes of
swan and buzzard harbour a few tens only. Contrary to human, avian
ICN are rarely grouped in larger ganglia (Fig. 3b). Nevertheless, the
plexus structure with single or small groups of neurons at nodal
points is very similar in higher primates and birds. In anseriforms, ICN
are concentrated along an equatorial zone whereas in galliforms, they

Fig. 3. Intrinsic choroidal neurons. a) An ICN in the human choroid containing green autofluorescent lipofuscin granules is surrounded by calretinin immunoreactive varicosities
(red) deriving from distant calretinin positive ICN, indicating intrinsic ICN-ICN connections. The ICN itself is calretinin negative and embedded in green autofluorescent connective
tissue of the choroid. Laser scanning confocal image. b) NADPHd positive ICN in chicken eye overlying choroidal veins. Note the variability of neuron size and shape. c) Three NADPHd
positive ICN in chicken choroid. Two neurons on the right are spindle-shaped with slender processes while the ICN on the left displays lamellar stem dendrites with fine emerging
branches. The processes of these ICN indicate the course of interconnecting strands of the choroidal ganglionated plexus. d) Two NADPHd positive ICN in the choroid of a turkey. Note
coarse stem dendrites of the larger neuron and the fine varicosities abutting non-vascular smooth muscle (light blue) delineating lymphatic lacunae (L). Bars are 20, 100, 10 and
10 μm in a, b, c and d, respectively.
72 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79

are predominantly found in the temporo- (dorso-) cranial quadrant. intrinsic input. Virtually nothing is known about other sources of
This preferential distribution coincides with retinal areas of high input to this particular neuron population.
visual acuity in the respective families (Schrödl, 2009). In the duck ciliary body and processes, numerous nNOS positive
Avian ICN display a broad size range from 10 up to 70 μm, although neurons are present which are contacted by TH positive varicosities,
most neurons are small (Schrödl et al., 2004). Similar to primates, suggesting sympathetic input (own unpublished observation). It
most avian ICN extensively co-stain for NADPHd, nNOS, VIP and, in remains to be determined whether these duck neurons are homol-
addition, for galanin (Figs. 2 and 3b). The chemical characterization of ogous to human ciliary muscle neurons and how they are related to
ICN was performed mostly in duck and chicken (Schrödl et al., 2000; ICN.
Stübinger et al., 2010). This extensive nNOS/VIP/galanin co-localiza-
tion renders ICN distinct from pterygopalatine neurons of the same 3.3. Neurons along intraocular ciliary nerves
species where only 30 to 50% stain for galanin (Schrödl et al., 2000;
Stübinger et al., 2010). As in primates, avian ICN stain neither for Neuronal cell bodies embedded along the intraocular course of
cholinergic nor adrenergic markers. Ultrastructurally, avian ICN are ciliary nerves were described in duck (Bergua et al., 1996), cat
incompletely ensheathed by glia, similar to their human counterparts (Kuchiiwa et al., 1989), pig and human (May et al., 2002). They were
(Schrödl et al., 2001a,b). immunopositive for NADPHd/nNOS and VIP and surrounded by VIP
and SP immunoreactive varicosities (May et al., 2002). Their axons
were directed to the trabecular meshwork and did not enter the
3.1.4. Intrinsic and extrinsic connections of ICN
choroidal nerve plexus. Although they share chemical features with
Similarities shared by the choroidal ganglionated nerve plexus and
ICN, they may represent ectopic ciliary ganglion neurons distinct from
the enteric nervous system stimulated ideas on intrinsic connections
ICN.
between ICN. Such intrinsic connectivity was suggested by varicosities
positive for NADPHd, nNOS, VIP, calretinin (Fig. 3a) and galanin
4. Ocular targets of the autonomic nervous system
apposing the ICN somata in both primates and birds (Flügel et al.,
1994; Schrödl et al., 2000; May et al., 2004). As none of these markers
4.1. Tunica externa and conjunctiva
are specific for ICN, an approach using intracellular dye injection
combined with immunohistochemistry was used to demonstrate
The tunica externa is divided into sclera and cornea. The latter
direct contacts of identified ICN onto other ICN (Fig. 2; Schrödl et al.,
receives the well known sensory innervation from the ophthalmic
2003). It remains to be determined which types and how many of ICN
nerve but also, at least in mammals including human, a modest
fulfil such interneuronal function.
contribution from the sympathetic superior cervical ganglion and
About 70% of ICN in the duck and 50% of human ICN are synap-
possibly also a sparse parasympathetic innervation from the ciliary
tically contacted by adrenergic varicosities (Fig. 2; Schrödl et al.,
ganglion (Marfurt and Ellis, 1993; Marfurt, 2000). Nerve fiber bundles
2001b; May et al., 2004). Thus, similar to enteric neurons, ICN are
consisting of both thin myelinated Aδ- and unmyelinated C-fibers
influenced by postganglionic sympathetic neurons. About 50% of duck
directed to the cornea travel in the suprachoroid space and form a
and a significant proportion of human ICN also receive direct contacts
plexus at the border of the cornea. They enter the corneal stroma
from CGRP positive trigeminal afferents (Fig. 2; Schrödl et al., 2001a,
losing their perineurium shortly thereafter. Upon penetrating Bow-
2003). This indicates possible involvement of ICN in local pre-central
man's membrane, corneal nerves lose their Schwann cell sheath
reflex arcs. In quail, somatostatin positive boutons were found on ICN
forming more or less radially oriented “leashes” (Marfurt, 2000) from
(Schrödl, 2009) and VAChT positive varicosities were detected on
where short branches enter the corneal epithelium (Beckers et al.,
human ICN (May et al., 2004) indicating a third extrinsic source from
1992). Innervation density is highest near the center of the cornea
cholinergic (and in quail somatostatin-containing) ciliary ganglion
which nicely parallels mechanosensitivity levels (Marfurt, 2000).
neurons (Fig. 2). However, the possibility of direct cholinergic pro-
Corneal afferents in mammals, birds and presumably also in
jections from brainstem parasympathetic preganglionic neurons in
reptiles, amphibia and fish contain SP (about 20%), CGRP (around
the Edinger–Westphal area cannot be excluded (Kuchiiwa et al.,
50%) and several other peptides (NKA, galanin, PACAP). However, a
1994). Likewise, early observations of chromatolytic changes in
sizeable fraction is non-peptidergic and is characterized by fluoride
Edinger–Westphal neurons upon surgical removal of the eyeball
resistant acid phosphatase (FRAP) and binding of the lectin IB4 from
may be interpreted as indication for direct preganglionic projection to
the plant Griffonia simplicifolia, both of which are markers for thin
ICN (Bernheimer, 1900). On the other hand, anterograde tracing of
calibre afferents (for review see Marfurt, 2009). Most of corneal
preganglionic VIIth cranial nerve fibers failed to label axons within the
afferents are mechanosensors and polymodal nocisensors while
choroid which argues against direct preganglionic input via the facial
others serve as thermo- and chemosensors. Remarkably, corneal
nerve (Schrödl et al., 2006).
cold sensors are absent in teleosts (Ashley et al., 2006). Sympathetic
ICN appear to form an intrinsic network and are targeted by
corneal nerves contain noradrenaline and NPY while VIP might be
postganglionic sympathetic, parasympathetic and afferent trigeminal
contained in axons from the ciliary ganglion (Marfurt, 2009).
neurons. In turn, they innervate intraocular blood vessels and non-
In the conjunctiva which covers the inner aspect of the eyelid and
vascular smooth muscle (as will be discussed in the later part). These
the anterior part of the sclera, innervation is mainly perivascular and
structures are innervated also by sympathetic, parasympathetic and
originates from sympathetic (TH/NPY-immunoreactive), parasympa-
trigeminal neurons. Thus, ICN may represent a sideline in extrinsic
thetic (pterygopalatine, some ciliary ganglion neurons: nNOS/VIP/
pathways, modulating their effects.
NPY-immunoreactive) and trigeminal (SP/CGRP-immunoreactive)
ganglia as indicated by degeneration and retrograde tracing studies
3.2. Neurons in the ciliary body combined with immunohistochemistry (human and cynomolgus
monkey: Ruskell, 1985b; rat: Elsås et al., 1994; cynomolgus monkey:
The human ciliary muscle contains about 1000 ganglion cells per van der Werf et al., 1996).
eye which stain for NADPHd/nNOS but not VIP (Tamm et al., 1995a). A Episcleral blood vessels, both arterioles and venules as well as the
subpopulation of these cells is immunoreactive for calretinin (Flügel- prominent arterio-venous anastomoses which play a significant role
Koch et al., 2009). About two thirds of nitrergic intraciliary neurons in IOP regulation, receive rich innervation from nitrergic (pterygopa-
are contacted by SP and CGRP positive nerve endings, others by latine ganglion), adrenergic (sympathetic) and SP/CGRP peptidergic
calretinin positive processes, suggesting trigeminal afferent as well as (trigeminal ganglion) neurons (Selbach et al., 2005b; Selbach, 2009).
 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79
4.2. Tunica media
The major intraocular targets for autonomic nerves reside in the
tunica media or uvea. This includes the iris, ciliary body, outflow tract
and choroid.
4.2.1. Iris
The iris controls the entrance of light towards the retina by
adjusting the diameter of the pupil. This prerequisite for proper vision
is mediated by iris muscles, innervated by autonomic nerves in all
vertebrates from elasmobranchs to human, although significant
differences between classes and species have been observed. In
addition, in many fish, amphibian and reptile species the sphincter
pupillae muscle's cell membrane is equipped with rhodopsin which
enables contraction in response to light without intervening neural
mechanisms (Barr, 1989). Although their irises are also innervated,
the photomechanical response predominates over any neuronally
mediated reaction. Innervation by sympathetic neurons inhibits
myogenic sphincter pupillae contraction, resulting in pupillodilation
(Rubin and Nolte, 1984).
Basically, both sphincter and dilator pupillae muscles are inner-
vated by neurons in both ciliary and sympathetic ganglia. However,
which component prevails in the respective muscles depends on
species (summarized in Fig. 4).
In the elasmobranch species Scyllium catulus, Scyllium canicula,
Mustelus laevis and Trygon violaceus, the cholinergic innervation from
the ciliary ganglion contracts the dilator pupillae muscle while the
sphincter contracts through photomechanical response (Young,
1933).
Fig. 4. Diagram of iris muscle innervation in various vertebrate classes. Sphincter and
dilator pupillae muscles are indicated by circles and radial lines, respectively. Dashed
lines and concentric circles symbolize mixed striated and smooth fiber components in
both reptile and avian iris muscles. “Light” indicates photomechanical stimulus of
sphincter pupillae. α+—α adrenergic excitation; β−—β adrenergic inhibition; Cil—
ciliary ganglion; m+—muscarinic cholinergic excitation; n+—nicotinic cholinergic
excitation; SC—spinal cord; Sy—sympathetic ganglion; III—oculomotor nerve; V—
trigeminal ganglion. For references see text.
73
In teleosts, the pattern is more variable. In Uranoscopus scaber,
cholinergic neurons in ciliary and sympathetic ganglia innervate
dilator and sphincter pupillae muscles, respectively. In Gadus morhua,
adrenergic neurons in both sympathetic and ciliary ganglia innervate
the sphincter pupillae while a dilator is absent (Nilsson, 1994). The
sphincter displays also a photomechanical response. Some teleost
species, e.g., of the genus Paralabrax, are lacking a pupillary reflex to
light although some ciliary ganglion neurons innervate the iris,
probably for mediating the accommodation reaction of the pupil
(Wathey, 1988a).
In amphibia, the sphincter pupillae contracts upon illumination
through the photomechanical response which is inhibited by
sympathetic neurons. There is apparently no cholinergic innervation
of the sphincter from the ciliary ganglion, and a dilator pupillae is
absent (Nilsson, 1994).
The iris muscles of reptiles are mainly striated although smooth
muscle or myoepithelial components are also found (Reger, 1966).
Cholinergic neurons of the ciliary ganglion innervate the sphincter
pupillae while adrenergic sympathetic neurons innervate the dilator.
In addition, the sphincter is directly sensitive to light (Nilsson, 1994;
Dearworth et al., 2007; Dearworth and Cooper, 2008).
In adult birds, the situation is similar. In addition to striated muscle
fibers in both the sphincter and dilator pupillae (Zenker and
Krammer, 1967), there are myoepithelial cells (Ehinger, 1967b;
Gabella and Clarke, 1983). Striated muscle which replaces smooth
muscle during embryogenesis (Gabella and Clarke, 1983) is innervat-
ed by cholinergic neurons of the ciliary ganglion through motor
endplates (Zenker and Krammer, 1967; Nilsson, 1994 for references)
whereas the myoepithelial cells receive both cholinergic and
adrenergic innervation (Ehinger, 1967b; Nilsson, 1994). In addition,
there is innervation by peptidergic trigeminal afferents (Corvetti et al.,
1988; Nilsson, 1994 for references).
In mammals, both the sphincter and dilator muscles are densely
innervated by cholinergic neurons of the ciliary ganglion and
adrenergic neurons of the superior cervical ganglion (Ehinger,
1967a; Jumblatt, 2000). In guinea pig, the latter are co-labeled for
NPY and dynorphin (Gibbins and Morris, 1987). There is also dense
innervation by axons containing SP and CGRP, mainly of trigeminal
afferent origin (Gibbins and Morris, 1987; Kuwayama and Stone,
1987; Beckers et al, 1992; Firth et al., 2002). In guinea pig, nerve fibers
containing SP only may derive from neurons embedded along ciliary
nerves (Gibbins and Morris, 1987). Trigeminal afferent axons in the
rat iris contain peripheral (p) ChAT, a splice variant of ChAT (Yasuhara
et al., 2004). In addition, both sympathetic and sensory fibers
terminate on blood vessels (Uusitalo et al., 1989; Sandow et al.,
1998), melanocytes (Sandow et al., 1998; Jumblatt, 2000) and in the
stroma, sometimes associated with immune cells (Adamek-Kotowicz
and Lütjen-Drecoll, 2003). Iridial blood vessels in rabbit, cat and
monkey appear to be innervated also by neurons of the ciliary
ganglion (Nilsson, 2009).
4.2.2. Ciliary body
The ciliary body receives its innervation from ciliary, pterygopa-
latine, sympathetic and trigeminal ganglia and in addition from
intrinsic neurons. Cholinergic neurons of the ciliary ganglion
innervate the smooth ciliary muscle of mammals and its striated
counterpart in birds and reptiles or the lens retractor and protractor
muscles in teleosts and amphibia, respectively (Wathey, 1988a;
Jumblatt, 2000; Gamlin, 2000). The mammalian, in particular primate
ciliary muscle is also innervated by adrenergic sympathetic neurons
(Ruskell, 1973), trigeminal peptidergic afferents (Stone et al., 1987;
Firth et al., 2002) and nitrergic and calretinin positive intrinsic
neurons (Tamm et al., 1995a; Flügel-Koch et al., 2009). Blood vessels
of the ciliary body are innervated by sympathetic adrenergic and
trigeminal afferent peptidergic neurons and also by nitrergic and
VIPergic neurons of the pterygopalatine ganglion and cholinergic
74 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79
neurons of the ciliary ganglion (Ehinger, 1967b; Jumblatt, 2000;
Nilsson, 2009). Ciliary processes receive innervation from adrenergic
sympathetic neurons containing NPY, peptidergic trigeminal afferents
and NPY/VIP containing pterygopalatine ganglion neurons (Ehinger,
1967b; Gibbins and Morris, 1987; Rittig et al., 1993; Jumblatt, 2000;
Firth et al., 2002).
4.2.3. Outflow tract
Innervation of the region of the trabecular meshwork and the
scleral spur has been studied in primates (Ruskell, 1994; Tamm et al.,
1995b; Selbach et al., 2000), pig (May et al., 2005) and rat (Selbach
et al., 2005a). Common to all species are numerous SP positive axons
many of which co-stain for CGRP thus representing trigeminal
afferents. Axons of pterygopalatine ganglionic or intrinsic origin
staining for nitrergic markers, VIP or NPY prevail in human while
adrenergic innervation is prominent in monkey. Cholinergic axons are
most likely of ciliary or pterygopalatine ganglionic origin (Selbach,
2009). In the human scleral spur, immunohistochemical and electron
microscopic studies revealed large neurofilament-positive, large
nerve endings derived from myelinated axons. These terminals
were negative for SP, CGRP, NPY and VIP as well as for adrenergic
and cholinergic markers and displayed ultrastructural features of
mechanosensors (Tamm et al., 1994).
4.2.4. Choroid
Choroidal innervation has been thoroughly studied only in birds
and mammalian species.
In birds, cholinergic choroid neurons of the ciliary ganglion
innervate choroidal blood vessels and the sponge-like non-vascular
smooth muscle cells delineating lymphatic lacunae typical for the
avian eye (Meriney and Pilar, 1987; Cuthbertson et al., 1996; De
Stefano and Mugnaini, 1997). In pigeon, this innervation is preferen-
tially directed to superior and temporal parts of the eye involved in
high visual acuity (Cuthbertson et al., 1996). Cholinergic/nitrergic/
VIPergic pterygopalatine ganglion cells represent another parasym-
pathetic source of vascular innervation preferentially in the nasal part
of the choroid (Cuthbertson et al., 1997). There is also adrenergic
sympathetic and trigeminal afferent peptidergic innervation of the
choroid. A major source of choroidal innervation is provided by ICN
(Figs. 2, 3b, c, and d). Axons of ICN densely innervate choroidal
arteries and the non-vascular smooth muscle cells delineating
lymphatic lacunae (Schrödl et al., 2000).
Choroidal innervation in mammals originates mainly in the
superior cervical (adrenergic), pterygopalatine (nitrergic/choliner-
gic/VIPergic) and to a minor extent in trigeminal (SP/CGRP peptider-
gic) ganglia (Fig. 2; Ruskell, 1971; Anders, 1991; Nilsson, 2000). The
respective axons terminate mainly on arteries and arterioles whereas
veins and the choriocapillaris are devoid of nerve fibers. In higher
primates and human, there is in addition the significant contribution
by nitrergic/VIPergic non-cholinergic ICN (Figs. 2 and 3a; Lütjen-
Drecoll, 2006; Schrödl, 2009). Cholinergic input to ICN from ciliary
ganglion (May et al., 2004) or even from the Edinger–Westphal
nucleus suggest the possibility that the IIIrd cranial nerve pathway
may influence choroidal blood flow also in primates. As demonstrated
by intracellular dye injection, human ICN innervate not only choroidal
blood vessels but also non-vascular smooth muscle (Schrödl et al.,
2003). As in the anterior eye segment, there is also sympathetic and
parasympathetic innervation of melanocytes (Schrödl, 2009 for
references).
4.2.5. Tunica interna/retina
Innervation of the central retinal artery by adrenergic sympathetic,
nitrergic/VIPergic parasympathetic and SP/CGRPergic trigeminal
neurons is dense along its course within the optic nerve. However,
axons can hardly be followed beyond the optic disc; blood vessels in
the retina and in the pecten of the avian eye almost completely lack
extrinsic innervation (Ehinger, 1967b; Ye et al., 1990; Bergua et al.,
2003). However, the concept of their intrinsic innervation, possibly by
SP and nitrergic neurons has been repeatedly proposed (Büssow,
1974; Greenwood et al., 2000).
5. Functional aspects
At face value, autonomic neuronal regulation in the eye can be
divided into visual and homeostatic parts. By controlling pupil size,
accommodation and choroidal thickness, autonomic pathways enable
proper vision. However, through regulation of blood flow, intraocular
pressure and immune responses, autonomic neurons contribute
significantly to ocular homeostasis which, in turn, maintains visual
function. In the following, neuronal mechanisms which regulate these
various functions are summarized, emphasizing interaction and
collaboration of cranial, spinal and intrinsic autonomic neurons.
5.1. Control of the pupil
Neuronal and non-neuronal mechanisms regulating pupil size are
summarized in Fig. 4. Cholinergic neurons of the ciliary ganglion
induce contraction of the smooth muscle pupillary sphincter of
mammals through M3 muscarinic, atropin-sensitive receptors while
the striated sphincter of birds contracts via a nicotinic, curare-
sensitive mechanism (Zenker and Krammer, 1967; Nilsson, 1994;
Jumblatt, 2000). Noradrenaline from sympathetic varicosities induces
β-mediated relaxation of the smooth sphincter. However, in mam-
mals miosis can also be induced by tachykinins (via neurokinin 1 and
3 receptors) and other peptides, e.g., CGRP, released from trigeminal
afferents and occurs typically in inflammation (Jumblatt, 2000; Troger
et al., 2009). The dilator is not affected by SP and CGRP in rat (Hill
et al., 1996). However, it is relaxed by CGRP in rabbit which may
reflect a direct effect of CGRP or interaction between sensory and
sympathetic neurons (Yousufzai and Abdel-Latif, 1998). In rabbit,
cholinergically induced miosis can be inhibited by nitric oxide (NO)
whereas SP induced miosis is NO insensitive (Chuman et al., 1996).
Contraction of the dilator pupillae is mediated via α1 adrenergic
receptors while β adrenergic mechanisms result in relaxation. NPY
potentiates alpha adrenergic effects. There is a cholinergic inhibition
through M3 receptors in several species including human. Acetylcho-
line also inhibits noradrenaline release through preterminal M2
receptors. Prostaglandins act prejunctionally, inhibiting noradrena-
line while facilitating acetylcholine release (Jumblatt, 2000).
Dilation of the pupil upon somatic nerve stimulation is mediated
via the Edinger–Westphal nucleus and ciliary ganglion and not via
sympathetic nerves as it persists upon transection of the cervical
sympathetic trunk (Ohsawa et al., 1997; Tanaka et al., 2005). The
exact transmitter mechanisms remain to be established.
In reptiles, both nicotinic (turtle: Dearworth et al., 2007) and
muscarinic (alligator: Iske, 1929) sphincter contractions have been
described. These contradictory results can be explained by species-
dependent variable distribution of striated and smooth muscle com-
ponents (Reger, 1966; Dearworth et al., 2007). In turtle, contraction of
the dilator is mediated through α1 adrenergic receptors (Dearworth
and Cooper, 2008). Nicotinic blockade by vercuronium and applica-
tion of the α1 agonist phenylephrin had additive effects on pupil
dilation. This nicely demonstrates interaction of cholinergic and
adrenergic components in balancing pupil size.
In amphibia, miosis is induced by photomechanical contraction
of the sphincter which can be inhibited by β adrenergic action
(Morris, 1976; Nilsson, 1994). In the teleost Uranoscopus, cholin-
ergic muscarinic contractions of sphincter and dilator muscles are
mediated by sympathetic and ciliary ganglion neurons, respective-
ly, whereas in Gadus, adrenergic neurons in both ciliary and
sympathetic ganglia add to the photomechanical contraction of the
sphincter via α adrenoreceptors (Nilsson, 1994). In elasmobranchs,
 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79
the photomechanical contraction of the sphincter is counteracted
by cholinergic muscarinic innervation of the dilator from the ciliary
ganglion (Nilsson, 1994).
The central pathways mediating pupilloconstriction have only
been studied in mammals and birds. In primates, the pretectal olivary
nucleus relays the light stimulus to the Edinger–Westphal nucleus
which in turn projects to the ciliary ganglion (Pong and Fuchs, 2000).
In birds, the area pretectalis accomplishes this relay function and
projects to the lateral division of the Edinger–Westphal nucleus.
Miosis during accommodation may be mediated by a different
premotor relay in the nucleus of the posterior commissure to the
Edinger–Westphal nucleus (Gamlin, 2000).
5.2. Accommodation
The ciliary muscle of mammals, and its homologues in fish and
amphibia are contracted via cholinergic muscarinic mechanisms
while in birds and reptiles, acetylcholine acts via nicotinic receptors
(Gamlin, 2000; Ott, 2006). In addition, there is inhibitory adrenergic
innervation in mammals, in particular primates, and autonomic
imbalance between cholinergic and adrenergic components may
play a role in development of myopia (Chen et al., 2003; Mallen et al.,
2005; Vasudevan et al., 2009). It remains to be determined which role
intrinsic neurons in the human ciliary muscle play in accommodation.
It has been proposed that they contribute to disaccommodation via
release of NO (Tamm et al., 1995a) and form part of a local
proprioceptive mechanism (Flügel-Koch et al., 2009).
Peptidergic trigeminal afferent fibers in the ciliary muscle, besides
contributing to reflex modulation via collaterals to ciliary ganglion
neurons (Kirch et al., 1995), may also have pathophysiological sig-
nificance because SP released during ocular inflammation may lead to
accommodation spasm (Duke-Elder and Scott, 1971).
Premotor neurons projecting to Edinger–Westphal nucleus con-
trolling accommodation reside in the cerebellar fastigii and inter-
positus nuclei of monkey and cat, respectively. The reticular formation
lateral to the oculomotor nucleus, harbours premotor neurons
projecting to medial rectus muscle motor neurons and possibly also
to the Edinger–Westphal nucleus. Other premotor neurons related to
accommodation are found in the nucleus of the posterior commissure
of mammals and the lateral mesencephalic reticular formation of
birds (Gamlin, 2000).
5.3. Blood flow control and vasculogenesis
Ocular blood flow is regulated through a complex interplay of
autonomic neuronal and autoregulatory mechanisms. The latter
prevail in the retina (Delaey and Van De Voorde, 2000) whereas in
the uvea, sympathetic and parasympathetic extrinsic neurons and ICN
play a major role (Figs. 1 and 2; Kiel, 1999; Chou et al., 2002; Lütjen-
Drecoll, 2006; Nilsson, 2009).
In mammals, the entire uvea is supplied with sympathetic
adrenergic nerves which mediate vasoconstriction through α recep-
tors while the effects of the co-transmitters NPY and ATP are less clear
(Nilsson, 2009). Neurons of the pterygopalatine ganglion provide
prominent vasodilatory innervation mainly through release of NO and
VIP (Nilsson, 2000). In higher primates, ICN may fulfil the same
function (Lütjen-Drecoll, 2006; Schrödl, 2009). In the anterior uvea,
there is in addition vascular innervation from the ciliary ganglion. This
is partly mediated by muscarinergic mechanisms and produces
vasoconstriction in rabbit whereas in cat and monkey, there is
vasoconstriction in the iris and vasodilation in the ciliary body
(Nilsson, 2009).
In birds, there is significant innervation of choroidal arteries by
cholinergic choroid neurons of the ciliary ganglion, in addition to
sympathetic and pterygopalatine innervation as described for mammals
(Fig. 2; Cuthbertson et al., 1996). Retinal input to the hypothalamic
75
suprachiasmatic nucleus is relayed to the medial portion of the Edinger–
Westphal nucleus which in turn stimulates choroid neurons, thus
mediating light induced increase in choroidal blood flow (Fitzgerald
et al., 1996). This pathway links retinal activity to choroidal vasoregula-
tion in particular in the temporo-cranial quadrant, an area of high visual
acuity, where this choroid innervation is targeted to (Cuthbertson et al.,
1996). As in primates, nitrergic ICN in the avian choroid are most likely
involved in blood flow regulation (Fig. 2). They are preferentially located
beneath retinal areas of high visual acuity and may be involved in the
same pathway as described previously, by virtue of their input from
choroid neurons of the ciliary ganglion (Schrödl, 2009).
Autonomic neurons also play a role in choroidal vascular re-
modeling. Cervical sympathectomy in rat leads to increased expres-
sion of vasculogenic factors and apoptosis of photoreceptors (Steinle
et al., 2005; Steinle and Lashbrook, 2006). These processes require the
presence of capsaicin sensitive sensory neurons (Steinle and Smith,
2003). In pigeon, lesioning the medial Edinger–Westphal nucleus
which regulates choroidal blood flow leads to significant upregulation
of glial fibrillary protein expression in retinal Müller cells (Kimble
et al., 2006). These examples illustrate the profound influence of auto-
nomic neurons on retinal homeostasis.
5.4. Aqueous humor production and intraocular pressure control
The influence of autonomic neurons on aqueous humor production
is complex. It occurs not only through innervation of ciliary processes
by sympathetic adrenergic, parasympathetic cholinergic/peptidergic
and sensory peptidergic neurons but also through blood flow
regulation. The level of cAMP in the ciliary epithelium plays a pivotal
role. Transmitters which increase cAMP levels, e.g., β adrenergic
agonists and VIP, lead to increasing production of aqueous humor
while α2 adrenergic agonists, NPY and ATP decrease cAMP levels and
consequently also humor production. Cholinergic effects are ambig-
uous (Jumblatt, 2000; Nilsson, 2009).
The level of IOP results as a balance between aqueous humor
production and outflow and choroidal perfusion. Both, the trabecular
meshwork and the episcleral vasculature as key components of the
outflow apparatus, are densely innervated by sympathetic, parasym-
pathetic, sensory and intrinsic neurons (May et al., 2002; Selbach,
2009). However, there are significant differences in the relative
contribution of the respective components even among primates
(Tamm et al., 1995b). Of particular interest are peptidergic and non-
peptidergic sensory fibers and terminals in the trabecular meshwork
and scleral spur, suggesting detection of IOP and flow dynamics and
their reflex regulation (Tamm et al., 1995b, 1994).
5.5. Control of choroidal thickness and bulbus growth
Experimental defocus in birds triggers compensation by changing
choridal thickness and bulbus length (Wallman and Winawer, 2004).
Myopic defocus induced rapid choroidal thickening most likely
mediated by relaxation of the non-vascular smooth muscle “sponge”
of the choroid and a more slowly change in extracellular matrix
synthesis in the sclera leading to a shorter eyeball. It has been shown
that ocular parasympathetic innervation plays an important role in
these processes (Schmid et al., 1999; Wildsoet, 2003) and NO released
from pterygopalatine ganglion neurons or ICN is the key molecular
mediator (Nickla et al., 2009). Also in primates, it is conceivable that a
similar choroidal accommodation mechanism compensates for shift-
ing of the macula by tension forces during contraction of the ciliary
muscle. Non-vascular smooth muscle cells innervated by ICN may
provide the structural basis for such a mechanism (Schrödl, 2009).
Local regulation of blood flow may also influence choroidal thickness
(Lütjen-Drecoll, 2006).
76 W. Neuhuber, F. Schrödl / Autonomic Neuroscience: Basic and Clinical 165 (2011) 67–79
5.6. Modulation of inflammation and immune responses
The vulnerable surface of the cornea requires a variety of
complementary protective mechanisms. Innervation of the epitheli-
um by SP containing trigeminal afferents contributes significantly by
stimulating epithelial cell proliferation and migration, in synergy with
insulin growth factor-1 (Nishida and Yanai, 2009). Tachykinins and
CGRP are also key mediators of neurogenic inflammation resulting
from stimulation of trigeminal afferents. In inflammatory conditions
of the anterior eye segment, this results in miosis, breakdown of the
blood-aqueous barrier and sometimes in accommodation spasm
(Duke-Elder and Scott, 1971; Troger et al., 2009). This neurogenic
inflammatory response can be suppressed by NPY (Grundemar et al.,
1993). CGRP released from trigeminal afferents and VIP from
parasympathetic nerve fibers which could act on antigen presenting
cells and lymphocytes also appear to play a role in immune function,
e.g., the anterior chamber associated immune deviation (ACAID;
Streilein et al., 2000; Taylor, 2009).
6. Concluding remarks
The major significance of autonomic innervation of the vertebrate
eye is to maintain proper visual function. This is accomplished by
regulation of the refractive apparatus and intraocular homeostasis.
Although the general innervation pattern of cranial and spinal
autonomic and trigeminal sensory neurons is fairly constant through-
out vertebrate classes, there is significant variability as to the precise
wiring and the targets for the respective neuronal components, in
particular in anamniotes. Even in mammals, considerable interspecies
differences exist in the chemical coding of autonomic neurons, i.e., in
their repertoire of co-transmitters and the effects of neuropeptides on
the respective targets. Moreover, higher primates and birds possess
numerous intrinsic choroidal neurons which represent an additional
autonomic innervation component devoted to local homeostatic
regulation.
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