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date: 12 December 2019

Autonomic Regulation of the Eye

Summary and Keywords

The functions of the eye are regulated by and dependent upon the autonomic nervous system. The parasympathetic nervous system controls constriction of the iris and accommodation of the lens via a pathway with preganglionic motor neurons in the Edinger-Westphal nucleus and postganglionic motor neurons in the ciliary ganglion. The parasympathetic nervous system regulates choroidal blood flow and the production of aqueous humor through a pathway with preganglionic motor neurons in the superior salivatory nucleus and postganglionic motor neurons in the pterygopalatine (sphenopalatine) ganglion. The sympathetic nervous system controls dilation of the iris and may modulate the outflow of aqueous humor from the eye. The sympathetic preganglionic motor neurons lie in the intermediolateral cell column at the first level of the thoracic cord, and the postganglionic motor neurons are found in the superior cervical ganglion.

The central pathways controlling different autonomic functions in the eye are found in a variety of locations within the central nervous system. The reflex response of the iris to changes in luminance levels begins with melanopsin-containing retinal ganglion cells in the retina that project to the olivary pretectal nucleus. This nucleus then projects upon the Edinger-Westphal preganglionic motoneurons. The dark response that produces maximal pupillary dilation involves the sympathetic pathways to the iris. Pupil size is also regulated by many other factors, but the pathways to the parasympathetic and sympathetic preganglionic motoneurons that underlie this are not well understood. Lens accommodation is controlled by premotor neurons located in the supraoculomotor area. These also regulate the pupil, and control vergence angle by modulating the activity of medial rectus, and presumably lateral rectus, motoneurons. Pathways from the frontal eye fields and cerebellum help regulate their activity. Blood flow in the choroid is regulated with respect to systemic blood pressure through pathways through the nucleus of the tractus solitarius. It is also regulated with respect to luminance levels, which likely involves the suprachiasmatic nucleus, which receives inputs from melanopsin-containing retinal ganglion cells, and other areas of the hypothalamus that project upon the parasympathetic preganglionic neurons of the superior salivatory nucleus that mediate choroidal vasodilation.

Keywords: lens, accommodation, pupil, iris, choroidal blood flow, sympathetic, parasympathetic, intraocular pressure, ciliary ganglion, pterygopalatine ganglion, superior salivatory nucleus, Edinger-Westphal, near response, light reflex, melanopsin

Introduction

Autonomic Regulation of the Eye

Figure 1. Anatomy of the anterior segment of the eye. A. Low-magnification view of section through the eye. Blue square shows area of interest illustrated in B and C. The intermediate magnification (B) shows major components of the anterior segment and the higher-magnification view (C) shows details of this region that contains major targets of the autonomic innervation of the eye, including: the ciliary and sphincter pupillae muscles (in red), the trabecular meshwork and stratum vasculosum in the ciliary processes. The high-magnification view of the iris shown in the right insert shows the anterior iridial epithelium, which includes the dilator pupillae muscle, another target. A high-magnification view of the retina shown in the left insert illustrates the choroidal vessels in red, another autonomic target.

Like most organs, the eye is innervated by the autonomic nervous system. However, the autonomic innervation of the eye is particularly specialized to support the unique requirements of the eye as the organ of vision (Figure 1). In the anterior segment, the iris acts to control the amount of light falling on the retina. While photoreceptors have specializations that allow the retina to maintain function in the face of large differences in ambient luminance, the iris can much more quickly respond to luminance changes through the autonomic innervation of its muscles. Encircling the edge of the pupil is a muscle band (smooth muscle in mammals, skeletal in many non-mammals), the sphincter pupillae muscle, that constricts the pupil (miosis) in response to increased luminance levels (the pupillary light reflex). In addition, small myoepithelial extensions of the anterior irideal epithelium, a layer that stretches across the back of the iris, work together as the dilator pupillae muscle. This muscle opposes the actions of the sphincter and dilates the pupil (mydriasis). The activated dilator produces a maximally expanded pupil in the dark (the pupillary dark reflex), and with sympathetic arousal. Together, these two muscles control pupillary diameter, so loss of activity in the dilator muscle of one eye by interruption of its cranial sympathetic innervation (Horner’s syndrome) produces uneven pupils (anisocoria) due to pupillary constriction by the unopposed sphincter muscle on the affected side.

Behind the iris is the lens, which focuses the visual world on the retina. Its shape is regulated by tension in the zonule of Zinn (suspensory ligament of the lens), such that one can focus either near or far targets on the retina. The tension in the zonule is in turn regulated by the ciliary muscle, a smooth muscle (skeletal muscle in birds) found within the ciliary body. Contraction of the ciliary muscle releases tension in the zonule of Zinn, allowing the anterior surface of the lens to become more spherical, in order to focus nearby targets on the retina. Focusing on nearby targets is generally accompanied by contraction of the pupil through the action of the sphincter pupillae muscle to increase depth of field, and convergence of the eyes to point them at the near target through the actions of the medial and lateral rectus muscles. Together these three actions are commonly referred to as the near response or near triad.

The ciliary body is the site of aqueous humor production, and its production rate is determined by the blood pressure in the vessels supplying the ciliary processes. Autonomic input helps regulate ciliary body blood pressure. Autonomic input also regulates outflow through the trabelcular meshwork, the conventional route, as well as through the unconventional, uveoscleral route. Glaucoma results when the rate of production does not match the rate of outflow, resulting in increased intraocular pressure (IOP) that compresses the entering retinal vessels and exiting retinal axons at the optic papilla, where they pass through an opening in the sclera. Finally, blood flow through the vessels supplying the choroid, which supports the photoreceptors and retinal pigment epithelium, must be regulated by the autonomic nervous system in order to support their functions; otherwise vision may be compromised (Fitzgerald, Jones, Cutherbertson, & Reiner, 2002). The rest of the retinal circuitry is supplied by branches of the central retinal artery. These intraretinal vessels do not receive autonomic input, and flow through them is controlled by local autoregulatory mechanisms (Delaey & Van de Voorde, 1999), although the central retinal artery is innervated. In this article, the peripheral innervation of each of the relevant target structures is dealt with independently, then the circuits that control these functions are described. More details are provided in relevant reviews (Neuhuber & Schrödl, 2011; McDougal & Gamlin, 2015; Reiner, Fitzgerald, Del Mar, & Li, 2018).

Peripheral Autonomic Pathways Influencing the Eye

Sphincter Pupillae Muscle

The parasympathetic, cholinergic postganglionic fibers that supply the sphincter (constrictor) pupillae muscle originate in the ciliary ganglion, which is located behind the eyeball, and access the iris via the short ciliary nerves. The cholinergic, preganglionic parasympathetic fibers that supply this ganglion originate in the preganglionic Edinger-Westphal nucleus, located near the oculomotor nucleus in the midbrain. These fibers travel with the oculomotor nerve and exit with its inferior division to target the ganglion (May & Corbett, 2017) (Figure 2).

Autonomic Regulation of the Eye

Figure 2. Autonomic control of pupil diameter. Daylight (photopic conditions) regulation of pupil diameter in response to luminance changes is accomplished by modulating the contraction of the sphincter pupillae muscle through the parasympathetic pathway shown in green. Pupillary response to darkness (scotopic conditions) is accomplished by regulating the activity of the dilator pupillae muscle. This is undertaken by the sympathetic pathway shown in blue. The dilator pupilae muscle is actually an extension of the anterior iridial epithelium, as illustrated in the higher-magnification insert. Details of the pathways through the hypothalamus remain to be elucidated.

Dilator Pupillae Muscle

The adrenergic, sympathetic postganglionic fibers that supply the dilator pupillae muscle originate in the superior cervical ganglion. They travel with the carotid artery to gain entry into the cranial vault, jump onto the trigeminal nerve to exit the cranial vault, then enter the orbit on the nasocillary nerve, finally accessing the iris with the long ciliary nerves. The cholinergic, preganglionic motor neurons that control the dilator muscle are found in or near the first thoracic level of the spinal cord, within the intermediolateral cell column (May & Corbett, 2017) (Figure 2).

Ciliary Body

Autonomic Regulation of the Eye

Figure 3. Autonomic pathways for control of lens accommodation. The parasympathetic pathway for lens accommodation originates in the preganglionic Ediger-Westphal nucleus. These motoneurons are controlled by midbrain near response neurons. They cause the ciliary muscle to contract toward the lens (1), decreasing tension in the zonule of Zinn (2), which allows the anterior surface of the lens to become more spherical (3). This increases the refractive power of the lens, enabling it to focus the image of near targets on the retina.

The cholinergic, parasympathetic postganglionic motor neurons supplying the ciliary muscle are found in the ciliary ganglion or in accessory ganglia located in the short ciliary nerves (Kuchiiwa, Kuchiiwa, & Suzuki, 1989). They access this muscle via the short ciliary nerves. The cholinergic, preganglionic parasympathetic motor neurons are located in the preganglionic Edinger-Westphal nucleus (EWpg) (Figure 3). The cholinergic, parasympathetic motor neurons controlling ciliary body vasculature are found in the pterygopalatine (sphenopalatine) ganglion (Figure 4). They are supplied by preganglionic motor neurons in the superior salivatory nucleus. The adrenergic, sympathetic postganglionic motor neurons that supply the vasculature of the ciliary body lie in the superior cervical ganglion (Figure 4). These two inputs, by controlling the blood pressure within the vessels of the ciliary processes, help control the rate of production of the aqueous humor (Reiner et al., 2018; Rittig, Licht, & Funk, 1993). Interestingly, the resistance of episcleral veins, into which the aqueous humor returns to the circulation after leaving the anterior chamber via the trabecular meshwork, is also regulated by sympathetic innervation (Selbach, Rohen, Steuhl, & Lütjen-Drecoll, 2005). Moreover, it has been suggested that myoid elements in the trabecular meshwork, itself, may be neurally regulated and could possibly contribute to glaucoma when functioning abnormally (Selbach, Gottanka, Wittmann, & Lütjen-Drecoll, 2000).

Autonomic Regulation of the Eye

Figure 4. Autonomic control of aqueous humor production. Aqueous humor is derived from blood vessels in stratum vasculosum of the ciliary body. As indicated by the blue arrows in the low-magnification view (A), it flows from the posterior chamber, through the pupil into the anterior chamber, supplying the lens and cornea with sustenance. As shown in B, it empties through the trabecular meshwork into the canal of Schlemm in the trabecular route and through the ciliary body in the uveoscleral route. Sympathetic system pathways (B) regulate blood flow to stratum vasculosum and the aqueous output channels in the meshwork.

Choroid

The cholinergic, parasympathetic postganglionic motor neurons that supply the choroidal vasculature in mammals reside in the pterygopalatine ganglion (Cuthbertson et al., 1997, 2003) (Figure 5). In mammals, the preganglionic, cholinergic parasympathetic neurons that innervate the pterygopalatine ganglion are located in the superior salivatory nucleus, and their axons exit the brain via the facial nerve, diverge from it as the greater petrosal nerve, which continues as the nerve of the pterygoid canal to the ganglion. In birds, cholinergic neurons located in the ciliary ganglion also innervate the choroid (Reiner, Karten, Gamlin, & Erichsen, 1983) and receive input from preganglionic parasympathetic motor neurons found in the Edinger-Westphal nucleus. The choroid and ciliary body in primates and birds, and to a lesser extent other mammals, contain a nervous plexus arising from intrinsic neurons (May, Neuhuber, & Lütjen-Drecoll, 2004; Schrödl, Tines, Brehmer, & Neuhuber, 2001; Schrödl et al., 2003; Tamm, Flügel-Koch, Mayer, & Lütjen-Drecol, 1995). These intrinsic nitrergic cells can dilate the choroidal and ciliary vessels. They are supplied by sympathetic, postganglionic input, but may also be sensitive to local autoregulatory signals.

Autonomic Regulation of the Eye

Figure 5. Autonomic control of the retinal vasculature. The box contains the layers of the retina and choroid with vessels shown in red. Note that the choriocapillaris supplies retinal photoreceptors. The pathway for autoregulation of choroidal blood flow in response to luminance levels is illustrated in blue. Systemic blood pressure also influences choroidal blood flow via the pathway illustrated in green. Regulation of the blood flow to the rest of the retina via the central retinal artery occurs before the blood reaches the retina.

Ciliary Ganglion

The postganglionic motor neurons found in mammalian ciliary ganglia are multipolar cells with just a few, mostly unbranched, dendrites and numerous perisomatic appendages (May & Warren, 1993; Zhang, Tan, & Wong, 1993; 1994). Most of their input occurs within the perisomatic neuropil (Forehand & Purves, 1984). The pupillary component of the postganglionic population is quite small, and has been estimated to be around 3% in the monkey and 10% in the cat (Erichssen & May, 2002; Warwick, 1954). While these cells are cholinergic, some of them also test positive for other peptide co-transmitters or for nitric oxide (Stone, McGlinn, Kuwayama, & Grimes, 1988; Sun, Erichsen, & May, 1994; Cuthbertson et al., 1999). In mammals, there is no evidence for distributional or morphologic differences between pupil- and lens-related ganglion cells. However, in the bird, those neurons that project to the choroidal vasculature can be differentiated because they are smaller and receive boutonal endings from EWpg, while those supplying the iris and ciliary body are larger and receive cap-like endings from EWpg (Reiner et al., 1983). The presynaptic terminals in the ganglion contain clear round vesicles, but also contain scattered dense-cored vesicles suggestive of the use of peptide co-transmitters (May & Warren, 1993; Zhang et al., 1993; 1994). This agrees with evidence of peptidergic terminals in this ganglion in mammals and birds (Erichsen, Karten, Eldred, & Brecha, 1982; Grimes, McGlinn, & Stone, 1990; LeBlanc, Trimmer, & Landis, 1987; Reiner et al., 1991). There is evidence that GABA may also be present as a co-transmitter in some terminals (Barnerssoi, May, & Horn, 2017).

Superior Cervical Ganglion

While the superior cervical ganglion has been intensively studied with respect to many of its other functions, such as glandular secretion and cerebrovascular blood pressure control, relatively little is known about the motor neurons that control pupillary dilation or orbital vasculature. The cells that supply the eye show a sparse distribution that is concentrated within the rostral two thirds of the ganglion (Flett & Bell, 1991), and up to 10% of the motor neurons in the ganglion may supply the eye (Rødahl & Haarr, 2000). These eye-related cells can contain neuropeptides as co-transmitters and they are contacted by CGRP-positive terminals. (Grkovic, Edwards, Murphy, & Anderson, 1999; Headley, Suhan, & Horn, 2005). The cholinergic, preganglionic motor neurons that supply these sympathetic autonomic motor neurons are concentrated in the first three thoracic segments of the spinal cord, within the intermediolateral cell column (Strack & Lowey, 1990).

Pterygopalatine Ganglion

The cholinergic, postganglionic motor neurons of the pterygopalatine ganglion that supply the choroidal vasculature also use the peptide co-transmitter VIP and in many cases they are nitrergic (Cuthbertson et al., 1997). The cholinergic, preganglionic motor neurons that supply these cells are located within the superior salivatory nucleus, adjacent to the facial nucleus, and those that supply the choroid-innervating neurons of the pterygopalatine ganglion are nitrergic as well (Cuthbertson et al., 2003).

Functional Circuits

Neural Control of the Pupil

Pupillary Light Reflex

Constriction of the pupil in response to light is produced by a reflex arc that begins with melanopsin containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) (Hannibal et al., 2014; Hattar, Liao, Takao, Berson, & Yau, 2002; Schmidt et al., 2011) (Figure 2). These cells have extremely broad dendritic fields, allowing them to receive input from retinal photoreceptors as a supplement to their intrinsic capacity to react to light levels. The axons of ipRGCs mediating the pupil light reflex terminate within the olivary pretectal nucleus (Güler et al., 2008; Hannibal et al., 2014). The pattern of retinal termination in this nucleus varies with species, with many lateral-eyed animals displaying an entirely crossed projection, while frontal-eyed species provide it with bilateral input (Scalia, 1972; Reiner et al., 1983; Hutchins & Weber, 1985; Sun and May, 2014a). The presence of a bilateral projection provides a substrate for the presence of both direct (in the ipsilateral, illuminated eye) and consensual (in the contralateral, unilluminated eye) pupillary responses in animals with frontally placed eyes. In some species, this capacity may be augmented by connections between the two olivary pretectal nuclei (Gamlin, Reiner, Erichsen, Karten, & Cohen, 1984; Sun & May, 2014b). Ablation studies have demonstrated that the olivary pretectal nucleus is crucial to the occurrence of the pupillary light reflex (Magoun & Ranson, 1935; Gamlin et al., 1984; Young & Lund, 1994), and electrical stimulation of this region produces pupilloconstriction (Distler & Hoffman, 1989; Gamlin, Zhang, & Clarke, 1995). The cells in this nucleus are principally responsive to luminance levels, and are not regulated by other visual properties (Clarke & Ikeda, 1985a, 1985b; Clarke, Blanks, & Giolli, 2003). However, there is increased sensitivity to centrally located stimuli in many cells. Olivary pretectal neurons display extremely broad visual receptive fields, often encompassing both hemifields. This suggests there is input from non-retinal sources, as direct retinal input is confined to one hemifield (Clarke et al., 2003).

The premotor cells within the olivary pretectal nucleus project to pupillary preganglionic motor neurons within the Edinger-Westphal nucleus. The mammalian Edinger-Westphal nucleus contains both ocular and nonocular subdivisions based on transmitters and connectivity: the preganglionic Edinger-Westphal nucleus (EWpg) contains cholinergic motor neurons and supplies the ciliary ganglion, while the centrally projecting Edinger-Westphal nucleus (EWcp) contains peptidergic, especially urocortin-1 neurons and provides a relatively diffuse projection to much of the neuraxis (Horn, Eberhorn, Härtig, Ardeleanu, Messoudi, & Büttner-Ennever, 2008; Kozicz et al., 2011; May, Reiner, & Ryabinin, 2008). There are species-specific variations in the organization of these divisions. In primates and birds, the EWpg is a well-delimited nucleus found near the midline, dorsal to the oculomotor nucleus. In non-primate mammals, EWpg neurons are scattered dorsal, anterior and ventral to the oculomotor nucleus (for further details, see Kozicz et al., 2011).

In animals lacking a consensual pupillary response, the olivary nucleus projection to EWpg is an entirely crossed one, so that the preganglionic motor neurons supplying the illuminated eye are activated. Most authorities believe that the olivary pretectal nucleus projection to EWpg in animals with a consensual response is a bilateral one, with decussating axons crossing in the posterior commissure (Benevento, Rezak, & Santos-Anderson, 1977; Sun & May, 2014b, but see Steiger & Büttner-Ennever, 1979). There is evidence that the pupillary light reflex is modulated by higher centers (e.g., Binda & Gamlin, 2017). For example, pupillary responses to sinusoidal illumination are slowed with lesions of the fastigial nucleus and units with pupillomotor signals are found within this nucleus (Hultborn, Mori, & Tsukahara, 1978; Ijichi, Kiyohara, Hosoba, & Tsukahara, 1977). An inhibitory circuit connecting the superior colliculus to pupillary preganglionic motor neurons has also been proposed, that causes pupillary dilation in conjunction with saccades (Wang & Munoz, 2015).

Pupillary Dilation

Descending projections to the pupillary preganglionic motor neurons in the spinal cord are believed to subserve the dark reflex (Loewy, Araujo, & Kerr, 1973) (Figure 2). Since the dilator pupillae muscle is supplied by the sympathetic nervous system, it appears that many factors that influence sympathetic tone also cause pupillary dilation. Thus, pupillary size is often monitored under controlled luminance condition in studies of cognitive load, drowsiness, interest and attention, as a convenient way to monitor and quantify autonomic activity (e.g., Lick, Cortland, & Johnson, 2016; van den Brink, Murphy, & Nieuwenhuis, 2016; Zekveld, Heslenfeld, Johnsrude, Versfeld, & Kramer, 2014).

Presumably, many of the signals accessing sympathetic pupillary preganglionic motor neurons in the spinal cord must transit the hypothalamus. Within the hypothalamus, the paraventricular nuclei, the tuberomammillary nuclei and suprachiasmatic nucleus all have been associated with the autonomic innervation of the eye by use of trans-neuronal transport of pseudorabies virus, as has the intergeniculate leaflet of the ventral thalamus (Smeraski, Sollars, Ogilvie, Enquist, & Pickard, 2004). Of these, the suprachiasmatic nucleus and intergeniculate leaflet receive input from ipRGCs signaling luminance levels, and so could be a source of a spinally projecting pathway subserving the dark reflex. However, in view of the role these nuclei play in setting circadian rhythms, it may be that these structures regulate pupillary responsiveness and intraocular pressure with respect to daily rhythms (Del Sole, Sande, Bernades, Aba, & Rosenstein, 2007; Liu, Gallar, & Loving, 1996).

Tracer studies suggest that the primary sources of hypothalamo-spinal projections are the paraventricular and lateral hypothalamic nuclei (Don Carlos & Finkelstein, 1987; Youngstrom & Nunez, 1992). However, it is difficult to determine which of these inputs to preganglionic sympathetic motor neurons is related to pupillary control, as opposed to control of the ocular vasculature. There is evidence that the hypothalamus also sends inhibitory input to the preganglionic Edinger-Westphal nucleus to suppress the activity of the sphincter pupillae muscle (Cassady, 1996; Silllito & Zbozyna, 1970b). The locus coeruleus was also labeled in studies using retrograde transneuronal methods to assess circuits supplying the eye (Smeraski et al., 2004). Furthermore, pupillary dilation has been used to assess noradrenergic tone in the brain (Joshi, Kalwani, & Gold, 2016). However, these dilation effects may be due to noradrenergic influences spread across premotor centers, not by direct inputs to preganglionic motor neurons (Costa & Rudebeck, 2016).

Neural Control of Lens Accommodation

Physiological investigations of the control of eye movements have described a set of cells located in the midbrain adjacent to the oculomotor nucleus that often display activity in conjunction with vergence eye movements, as well as lens accommodation (Bando, Yamamoto, & Tsukahara, 1984b; Judge & Cummings, 1986; Mays, 1984) (Figure 3). Many of these neurons display tonic activity related to eye position or accommodative drive, but others also show phasic activity at the onset of the near response (Mays, Porter, Gamlin, & Tello, 1986). Most fire in response to near targets (convergence), but some fire in response to far targets (divergence). Their activity is modified in individuals with strabismus (Das, 2011, 2012). They are premotor neurons whose axons target medial rectus motor neurons within the oculomotor nucleus and lens- and pupil-related preganglionic motor neurons within the Edinger-Westphal nucleus (Zhang, Mays, & Gamlin, 1992). Premotor near response neurons are concentrated at the caudal end of the oculomotor nucleus, within the supraoculomotor area (May, Warren, Gamlin, & Billig, 2018). Their EWpg targets have been physiologically characterized. Stimulation of the Edinger-Westphal nucleus in primates produces lens accommodation and pupilloconstriction (Clarke, Coimbra, & Alessio, 1985; Crawford, Terasawa, & Kaufman, 1989; Gamlin et al., 1994). Furthermore, the firing of the preganglionic neurons is closely correlated with lens accommodation velocity during target changes, and static accommodative state while viewing the target (Gamlin, Zhang, Clendaniel, & Mays, 1994).

The decision to shift the line of sight between targets in space requires the construction of a three dimensional view of the visual scene. This is a complex problem that likely involves much of visual cortex and the use of concepts like size constancy (Richter, Costello, Sponheim, Lee, & Pardo, 2004). However, a number of visual features play particularly important roles in determining target distance, including retinal disparity (the difference between the two eyes in the location on the retina where the target falls) and focus (Richter, Lee, & Pardo, 2000). There is evidence for the existence of regions in the cerebral cortex that formulate a command for the near response that would modulate accommodative tone. Stimulation of areas of the posterior suprasylvan cortex (Clare-Bishop Area) in the cat produces lens accommodation and disjunctive eye movements (Bando, 1985; Bando, Tsukuda, Yamamoto, Maeda, & Tsukahara, 1981; Toda, Takagi, Yoshizawa, & Bando, 1991). Within this region, neurons whose activity correlates with convergence, lens accommodation, pupillary constriction and pupillary dilation were encountered (Bando et al., 1981, 1984b; Takagi et al., 1992).

In monkeys, cells in the lateral intraparietal cortex have been shown to be sensitive to target distance (Gnadt & Mays, 1995). In addition, Jampel (1959, 1960) found that stimulating in the region of the middle temporal sulcus produces convergence, pupilloconstriction and lens accommodation. This region of cortex has also been associated with components of the near response in PET and fMRI studies (Richter, Costello, Sponheim, Lee, & Pardo, 2004; Ward, Bolding, Schultz, & Gamlin, 2015). In cat, it has been suggested that the suprasylvan cortex accommodation areas access the EWpg by way of a relay located in the pretectum or rostral superior colliculus (Maekawa & Ohtsuka, 1993; Sato & Ohtsuka, 1996). Studies using stimulation have shown that activating the rostral superior colliculus can produce changes in lens accommodation and disjunctive eye movements (Chaturvedi & van Gisbergen, 1999; Sawa & Ohtsuka, 1994; Suzuki & Ohtsuka, 2004). In addition, cells with vergence signals have been described in the superior colliculus (Van Horn, Waitzman, & Cullen, 2013, although see Walton & Mays, 2003). The superior colliculus is known to project to the supraoculomotor area (Edwards & Henkel, 1978).

There is also good evidence for the presence of near response neurons in the region of the frontal eye fields. Jampel (1959; 1960) observed convergence and lens accommodation changes with stimulation of this region. Cells whose activity was related to vergence eye movements are located just rostral to saccade-related populations in the arcuate sulcus (Gamlin & Yoon, 2000). One way in which these cortical areas may influence near response motor neurons is via cerebellar circuits. Neurons whose activity is correlated with both convergence and divergence have been reported within the nucleus reticularis tegmenti pontis, and stimulation of this region produces changes in convergence (Gamlin & Clarke, 1995). Within the cerebellum, neurons within the posterior interposed nucleus have activity that is correlated with divergence and focusing the lens at a far target (Bando, Ishihara, & Tsukahara, 1979; Zhang & Gamlin, 1998). Similarly, stimulation of this region produces near triad changes suitable for far targets (Zhang & Gamlin, 1998). Cells that fire during convergence movements are found within the fastigial nucleus (Gamlin, 2002) and changes in lens accommodation are found when this nucleus is stimulated (Hosoba & Tsukahara, 1976). Both the posterior interposed and the fastigial nuclei provide inputs to the supraoculomotor area, where the near response neurons reside (May, Porter, & Gamlin, 1992).

Control of Intraocular Pressure

Peripheral Factors

The intraocular pressure (IOP) of the eye is determined by the balance between aqueous humor production and aqueous humor outflow. Aqueous humor is produced by the ciliary epithelium to maintain intraocular pressure and to provide nutrients to the lens and cornea, both of which are avascular. Aqueous humor secreted by the ciliary epithelium enters the posterior chamber where it then flows around the lens and iris into the anterior chamber (Figure 4). Aqueous humor outflow is known to occur through two different pathways: 1) In the trabecular or “conventional” route, outflow is through the trabecular meshwork to Schlemm’s canal. Eventually this outflow reaches the episcleral venous circulation; 2) In the uveoscleral or “unconventional” route, outflow occurs through the connective tissue between ciliary muscle bundles at the iris root. It then exits through scleral veins. Blood flow to the ciliary body combined with the rate of secretion from the ciliary epithelium determines the overall rate of aqueous humor production (Kiel, Hollingsworth, Rao, Chen, & Reitsamer, 2011). Aqueous humor outflow is determined by: 1) by the outflow facility of the trabecular meshwork and Schlemm’s canal for the conventional route and, 2) by uveoscleral outflow facility and episcleral venous resistance for the unconventional route (Gabelt & Kaufman, 2011). In general, in vivo pharmacological stimulation and lesion studies are unable to selectively modulate any one of the following: ciliary body blood flow, ciliary epithelium secretion, the outflow facility of the conventional and unconventional routes, or the resistance of the episcleral venous circulation. Therefore, in many cases, the precise pathway(s) and structure(s) underlying any observed changes in IOP are poorly understood.

Neural Control of Ciliary Body Blood Flow

Parasympathetic and sympathetic innervation affects both aqueous humor production and outflow. In many species, the ciliary body vasculature is innervated by fibers arising from postganglionic parasympathetic neurons in the pterygopalatine ganglion (McDougal & Gamlin, 2015). Activation of the preganglionic input to the pterygopalatine ganglion causes increased blood flow in the ciliary body (Nilsson, Linder, & Bill, 1985). This increased blood flow is most likely mediated by neuronal nitric oxide synthase (nNOS) at low frequencies (2 Hz), and additionally by vasoactive intestinal peptide (VIP) at higher frequencies (5 Hz) (Nilsson, 1996, 2000). The ciliary body vasculature is also innervated by fibers that arise from noradrenergic postganglionic neurons in the superior cervical ganglion. Unilateral sympathetic nerve stimulation causes a substantial reduction in ciliary body blood flow. Overall increased sympathetic innervation of the ciliary body vasculature produces a pronounced vasoconstriction, a consequent reduction in aqueous humor production, and a decrease in IOP (Belmonte, Bartels, Liu, & Neufeld, 1987). Ciliary body blood vessels in mammals, including humans, are also innervated by trigeminal sensory fibers containing both substance P (SP) and calcitonin gene-related peptide (CGRP) (McDougal & Gamlin, 2015). When trigeminal nerve endings release the tachykinin SP and CGRP in response to noxious stimuli, temperature changes, or pressure they have a robust vasodilatory effect (McDougal & Gamlin, 2015).

Postganglionic, sympathetic fibers can potentially stimulate aqueous humor formation via β‎2-adrenoreceptors and inhibit formation via α‎2- adrenoreceptors and NPY receptors on the ciliary epithelium, itself (Gabelt & Kaufman, 2011). Since postganglionic, parasympathetic fibers release acetylcholine at lower frequencies and VIP at higher frequencies, parasympathetic innervation could potentially inhibit formation of aqueous humor at low frequencies and stimulate aqueous humor formation at higher frequencies.

Neural Control of Outflow Facility

Between 50 % and 75 % of the aqueous humor leaves the eye through the conventional route, while the remainder leaves through the unconventional, uveoscleral route. Dilation of the pupil constricts the irideocorneal angle, which restricts aqueous outflow (McDougal & Gamlin, 2015). Contraction of the ciliary muscle results in a conformational change of the trabecular meshwork and likely dilation of Schlemm’s canal with both effects leading to decreased outflow resistance (Gabelt & Kaufman, 2011). In addition, noradrenaline appears to increase trabecular meshwork outflow facility, but this is an active area of research, and the role of the autonomic nervous system in directly controlling trabecular meshwork resistivity is currently unclear. Sympathomimetics produce an increase in uveoscleral drainage (Alm & Nilsson, 2009), as does prostaglandin F2-alpha, which effectively increases uveoscleral flow through relaxation of the ciliary muscle and structural changes in the extracellular matrix.

Central Control of Intraocular Pressure

Injection of the GABA antagonist, bicuculline, into the dorsomedial and perifornical hypothalamus of rats produces changes in IOP, without affecting the mean arterial pressure (Samuels et al., 2012). Thus, there appears to be clear evidence for hypothalamic control of IOP. However, it is not clear through which autonomic pathway this occurs. It may act by way of sympathetic innervation, but the specific mechanisms involved remain unclear. There is more support for hypothalamic control via parasympathetic innervation. The superior salivatory nucleus appears to control episcleral venous pressure, which would modulate IOP. Electrical stimulation of this nucleus significantly increases IOP; although part of the response is probably a result of increased choroidal blood volume (Strohmaier, Reitsamer, & Kiel, 2013).

Neural Control of Retinal Vasculature

Peripheral Aspects

The retina has two vascular supplies in most placental mammals, the choroidal vasculature and the vessels of the inner retina. The blood supply to the inner retina is via the central retinal artery (which arises from the ophthalmic artery), whose branches radiate from the optic nerve head onto the inner retinal surface and then give rise to branches that penetrate into the retina through the depth of the inner nuclear layer. These supply blood to the inner retina vitread to the photoreceptors. The outer retina, which contains the photoreceptors and retinal pigment epithelium, is supplied by the choroidal vasculature.

Retinal vessels are able to respond to the local concentrations of carbon dioxide and oxygen, and to regulate blood flow accordingly (metabolic coupling), like most vascular beds (Reiner et al., 2018). The retinal vessels of mammals are themselves not innervated, but the central retinal artery is innervated by parasympathetic, sympathetic and sensory nerve fibers (Reiner et al., 2018). Both the central retinal artery and the choroidal vessels supply blood to the optic nerve (see Reiner et al., 2018, for details). Thus, the blood supply to the optic nerve and optic nerve head are under neural influence, and blood flow in the retinal vessels themselves is thereby affected by the control exerted at this level (Strohmaier et al., 2016). A retinal vascular supply appears to be necessary for a thick retina that allows detailed form vision, given the reported limit of intraretinal oxygen diffusion from the choroid under normoxia of ~150 µm (Reiner et al., 2018). This is thought to explain why retinal thickness is only about 150 µm in mammals with so-called avascular retina, such as monotremes, most marsupials, and some placental mammals, and in the avascular fovea of foveate placental mammals (Chase, 1982).

The blood supply to the choroid in mammals arises from the ophthalmic branch of the internal carotid artery, via the long and short ciliary arteries (Reiner et al., 2018). The choroid is organized into an outer layer of large blood vessels and a middle layer of branches from these vessels that feed the choriocapillaris juxtaposed to Bruch’s membrane. The choroid is one of the most highly vascularized structures in the body (Nickla & Wallman, 2010). The choroid has also been reported to contain extravascular smooth muscle cells (Nickla & Wallman, 2010; Poukens Glasgow, & Demer, 1998). These are both supplied by the autonomic nervous system. The choroid accounts for about 85% of the blood supply to the retina, and its major role involves supplying oxygen and nutrients to the retinal pigment epithelium and photoreceptors of the outer retina (Bill, 1984). The choroid is, however, also the major or exclusive vascular supply for both outer and inner retina in regions poor in or lacking retinal vessels such as the fovea. Although it was once thought that choroidal blood flow (ChBF) so exceeds retinal requirements as to obviate the need for its regulation, it is clear that: 1) high ChBF is essential as the driving force for diffusion of oxygen and nutrients through Bruch’s membrane and the retinal pigment epithelium (RPE), into the retina; 2) ChBF must be stably matched to the thermal and metabolic needs of the retina; and 3) disturbances in ChBF impair outer retinal function (Reiner et al., 2018). Thus, the ability of ChBF to respond adaptively to variations in retinal metabolism imposed by changes in illumination level and retinal activity, and to maintain stable flow despite fluctuations in bodily state and time of day, are likely to be important for maintaining the health and proper functioning of the RPE and outer retina.

The choroid and choriocapillaris are separated from the outer retina by Bruch’s membrane and the RPE (Nickla & Wallman, 2010). This barrier precludes regulation of ChBF by vasogenic metabolites derived from the outer retina. (Bill & Sperber, 1990). Instead, the choroid is primarily under neural control (Kiel & van Heuven, 1995). Three major types of nerve fibers innervate the choroid in mammals: 1) parasympathetic fibers arising from the pterygopalatine ganglion (PPG); 2) noradrenergic sympathetic fibers from the superior cervical ganglion; and 3) sensory fibers from the trigeminal ganglion (Reiner et al., 2018). These parasympathetic, sympathetic, and sensory fibers and their terminals tend to be localized to the walls of the arteries and veins of the choroid, but not the choriocapillaris. Pericytes along choroidal vessels, which exert contractile effects, have also been reported to receive terminals (Schroedl et al., 2014). In addition, cholinergic parasympathetic fibers to the choroid also arise from the ciliary ganglion in birds, and perhaps in some mammalian groups as well (Reiner et al., 2018). VIP+ and nNOS+ fibers from the pterygopalatine ganglion have a vasodilatory influence on choroidal vessels and increase ChBF, while sympathetic, adrenergic fibers have a vasoconstrictory action that decreases ChBF. The input to the choroid from the ciliary ganglion also has a vasodilatory influence, mediated by muscarinic elicitation of endothelial NO release (Reiner et al., 2018). The sensory fibers in the choroid have a vasodilatory influence as well.

The choroid in some mammalian and avian species contains intrinsic neuronal cells that contain many of the various neuroactive substances typical of parasympathetic PPG neurons. These ganglion cells are most numerous in the central retina of foveate mammals (Reiner et al., 2018). Although their precise role is not established, it seems likely they contribute to local ChBF control. Abnormalities in the intrinsic choroidal neurons accordingly may play a role in retinal disease. For example, the intrinsic choroidal neurons may be vulnerable to high IOP, since they are reduced in numbers in glaucomatous human eyes. Their loss may contribute to the reduction in ChBF observed in glaucoma (Reiner et al., 2018).

Central Circuits

The pterygopalatine ganglion receives its preganglionic parasympathetic input from the superior salivatory nucleus (SSN) subdivision of the facial motor nucleus complex (Figure 5). Studies of the inputs to the part of SSN controlling ChBF have revealed that blood pressure and blood volume signals appear to drive the ganglion’s vasodilatory effect on the choroidal vasculature. Of particular note, all of the same regions (including the nucleus of the solitary tract and the rostral ventrolateral medulla) that project to SSN also drive sympathetic constriction of the systemic vasculature in response to low blood pressure signals. The phenomenon of blood flow stability over a range of systemic blood pressures has been well documented for ChBF (Reiner et al., 2018). The combination of increased vasodilation in the choroid combined with peripheral vasoconstriction works together to maintain a stable ChBF, despite blood pressure declines. Impairments in the parasympathetic control of ChBF occur with aging, and various ocular or systemic diseases such as glaucoma, age-related macular degeneration (AMD), hypertension, and diabetes, and may contribute to retinal pathology and dysfunction in these conditions. Some studies have shown increases in ChBF in response to light-mediated increases in retinal activity (Reiner et al., 2018) (Figure 5).

Inputs to SSN from brain areas receiving visual signals, such as the paraventricular nucleus of the hypothalamus, may mediate this effect. Birds possess a well-documented central parasympathetic circuit by which the ciliary ganglion can mediate ChBF increases in response to retinal illumination. The circuit involves input from the retinorecipient suprachiasmatic nucleus to the part of EWpg controlling the neurons of the ciliary ganglion projecting to choroid. Adaptive control of ChBF for this circuit is important for retinal health, since disruptions of this circuit lead to photoreceptor loss and vision deterioration (Reiner et al., 2018).

Consistent with the sympathetic innervation of choroid and vessels supplying the choroid, cervical sympathetic stimulation decreases ChBF (Reiner et al., 2018). The sympathetic input appears to be important for maintaining stable ChBF during high systemic BP. In the absence of sympathetic choroidal vasoconstriction during high systemic BP, the resulting sustained elevations in ChBF are harmful for retinal health and function, as they lead to overperfusion and breakdown of the blood-retinal barrier (Reiner et al., 2018). The central circuitry for this sympathetic choroidal vasoconstriction has not been characterized. Of note in this regard, since low BP signals cause systemic sympathetic vasoconstriction, but it is high BP that drives choroidal vasoconstriction, there must be a difference between inputs to the central neurons giving rise to the sympathetic postganglionic outflow to the systemic versus the choroidal vasculature.

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