Ординатура / Офтальмология / Английские материалы / Eye, Retina, and Visual System of the Mouse_Chalupa, Williams_2008

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CHRISTIAN-ALBRECHT MAY

This chapter introduces structural and developmental aspects of the murine optic nerve. After an initial consideration of general morphological features, the first section describes the development of the optic nerve, with additional discussion of the optic nerve head region and myelinogenesis. The second section introduces the different cellular components of the optic nerve, namely, axons and glial cells (astrocytes, oligodendrocytes, microglia), while the third section focuses on connective tissue in the different optic nerve sections. The fourth section discusses the vascular supply of the murine optic nerve.

General morphological features

Four distinct sections of the optic nerve can be differentiated in the mouse orbit (figure 16.1): (1) The optic nerve head: efferent (axonal) processes of the retinal ganglion cells (RGCs) forming the nerve fiber layer of the retina accumulate toward the intraocular portion of the optic nerve. (2) The lamina cribrosa region: at the level of the choroid and sclera, the optic nerve fibers leave the eye. (3) The unmyelinated portion: the murine optic nerve first remains unmyelinated in the extraocular course. (4) The myelinated portion: in the posterior orbit, the optic nerve contains myelinated axons.

As part of the CNS, the extraocular portion of the optic nerve in the orbit is surrounded by three meningeal sheaths:

(1) The pia mater covers the surface of the nerve and contains the small pial vessels. (2) A delicate arachnoid mater forms the subarachnoidal space containing cerebrospinal fluid. (3) The dura mater is the outermost sheath and merges anteriorly with the sclera.

Development

Next to the optic stalk, about 50–100 μm behind the eye, the first bundles of axons from the RGCs are seen on embryonic day 12.5 (E12.5) as a mixture of thin axons, thicker growth cones, and fine filopodial and foliopodial extensions (Colello and Guillery, 1992). Over the next 2 days, these bundles increase in size and number, and contain growth cones in all parts of the bundles. Toward the chiasm, the structure of the optic nerve pathway changes significantly: the growth

cones become located predominantly close to the pial surface, and the deeper regions are filled by fine axons (Colello and Guillery, 1992). At the molecular level, the axon guidance molecule netrin-1 is necessary locally at the optic disc for proper pathfinding of the RGC axons (Deiner et al., 1997). The homebox gene Vax1 and the sonic hedgehog protein seem to regulate the interaction between sprouting axons and optic nerve glia (astrocytes) deriving from the optic stalk (Bertuzzi et al., 1999; Wallace and Raff, 1999; Dakubo et al., 2003). At the level of the optic chiasm, Vax1 and the paired homebox transcription factor Pax2 are required for proper formation of contralateral projections (Torres et al., 1996; Bertuzzi et al., 1999), while homebox gene Vax2 is necessary for the formation of ipsilateral retinocollicular projections (Barbieri et al., 2002). Another crucial factor at the level of the optic chiasm is the growthassociated protein 43 (Strittmatter et al., 1995).

The optic nerve head/optic disc develops at the interface between the optic stalk and the retina. The initial step is the formation of the optic fissure on E10, which enables ganglion cell axons to exit the eye and mesenchymal cells to form hyaloid vessels. A crucial factor for this event seems to be the bone morphogenetic protein-7 (Bmp7), a factor known also to stimulate Pax2 in an early phase of optic nerve head formation (Morcillo et al., 2006). Pax2, together with other homebox genes (e.g., Vax2), is necessary for guidance of the sprouting ganglion cell axons and for proper closure of the optic fissure (Torres et al., 1996; Otteson et al., 1998; Barbieri et al., 2002). Besides Bmp7, Pax2 expression is also induced by other cytokines, among them Bmp4 and sonic hedgehog protein (Weston et al., 2003), but at a slightly later stage of the development. Closure of the optic fissure begins on E11 and is usually completed 2 days later (Hero, 1990; Ozeki et al., 2000). At birth (normally E21–E23), the optic nerve head is completely developed, showing a twoto threefold increase in the number of axons, which falls to the adult value within 1 week (Sefton et al., 1985; Strom and Williams, 1998).

Myelinogenesis of the optic nerve axons begins by the end of the first week of postnatal life, starting selectively with the largest axons and in the direction of brain toward the eye (Bernstein et al., 1983; Dangata and Kaufman, 1997). At the

Figure 16.1 Optic nerve, sagittal section, showing four distinct sections: the optic nerve head (ONH), lamina cribrosa region (LCR), unmyelinated optic nerve (NMN), and myelinated optic nerve (MN). In the inner region of the optic nerve head several central retinal vessels (CRV) are visible. At the level of the sclera (S), no collagen bundles penetrate the optic nerve head; therefore, no lamina cribrosa is present. The extraocular optic nerve is surrounded by the pia mater (PM) and the dura mater (DM), separated by the subarachnoidal space.

end of the fifth week, about 73% of the fibers are myelinated, and by the 16th week virtually all axons enclose a myelin sheath (Dangata and Kaufman, 1997). The process of myelin sheath formation and differentiation continues even in adult animals, though on a very reduced scale. Quantification of optic nerve axons revealed that only about 1.2% of axons are unmyelinated in the optic nerve of the adult mouse (Honjin et al., 1977). Specific factors for oligodendrocyte morphogenesis and myelin formation in the optic nerve include the following: (1) for precursor cell numbers and cell spreading: brain-derived neurotrophic factor (Cellerino et al., 1997), gap junction proteins connexin 47 and connexin 32 (Menichella et al., 2003; Odermatt et al., 2003), laminin- 2 (Chun et al., 2003), and Wiskott-Aldrich syndrome protein family verprolin homologous protein 1 (Kim et al., 2006); and (2) for axonal ensheathment and myelin compaction: myelin-associated glycoprotein (Biffiger et al., 2000), proteolipid protein (Thomson et al., 2005), and matrix metalloproteinases 9 and 12, which regulate insulin-like growth factor 1 (Larsen et al., 2006). Interestingly, myelination of the murine optic nerve stops 0.6–0.8 mm behind the eye globe. The precise mechanism is unknown, but potential molecular factors that might actively stop myelination at this level include tenascin C (Bartsch et al., 1994) and the poly-

sialylated neural cell adhesion molecule (Charles et al., 2000).

Neuronal and glial tissue

The neuronal tissue in the optic nerve head and optic nerve consists of axons from the RGCs. Their number reveals profound variations in different mouse strains: in 60 inbred strains, the number of axons varies between 32,000 and 87,000, with distinct modes centered at 55,000 and 64,000 axons (Williams et al., 1996). The two most popular mouse strains represent the two modes, the lower (C57BL/6J) and the higher (Balb/cJ) mode, respectively. This difference is mainly due to a difference in RGC generation rather than apoptosis postpartum (Strom and Williams, 1998).

At birth, the unmyelinated axons have an average diameter of 0.4 μm (Strom and Williams, 1998). They are located next to each other without being separated by glial cell processes. In adult optic nerve sections, the myelinated nerve fibers (axons, including the myelin sheath) range in diameter from 0.3 to 4.2 μm, with a single peak at 0.7–0.9 μm. In the peripheral area of the murine optic nerve on cross section, the nerve fibers are relatively small and uniform in diameter, whereas the larger nerve fibers are mainly located in the central area (Honjin et al., 1977). In the optic nerve head, the axons remain unmyelinated and are clustered in bundles without glial separation of each single axon within the bundle. At the ultrastructural level the axons contain neurofilaments, neurotubuli, and mitochondria.

The presence and distribution of glial cells is different in the optic nerve head and the optic nerve: while the first contains only astrocytes, the latter contains astrocytes and oligodendrocytes. Microglia cells occur in both parts in rather small number (Wong et al., 1979; Lawson et al., 1994) and express MAC-1, but not Fc gamma II/III receptor, F4/80, or MAC-2 (Reichert and Rotshenker, 1996). Cell numbers of all three types of glial cells—astrocytes, oligodendrocytes, and microglia—show a distinct proportion to the number of axons: relating to 1,000 axons in a myelinated optic nerve cross section, one can detect 1.7–2.1 nuclei of oligodendrocytes, 0.9–1.2 nuclei of astrocytes, and 0.05– 0.07 nuclei of microglia cells (adjusted from Burne et al., 1996).

Optic nerve astrocytes, stimulated by the ganglion cell axons to proliferate and differentiate (Burne and Raff, 1997), initially express vimentin (from E12 to E16) and then gradually change to their specific glial filament acidic protein (GFAP) expression. GFAP staining is first seen at the border of the nerve (beginning on E17) and spreads into the central optic nerve until birth. Astrocytes develop and express GFAP from the eye toward the optic tract (Bovolenta et al., 1987). In the mature myelinated optic nerve, astrocyte processes form multiple contacts with the nodes of Ranvier, blood

vessels, and subpial glia limitans. They appear uniform, and there is no evidence for a specialized subpopulation of astrocytes in this part of the murine optic nerve (Butt et al., 1994).

In the optic nerve head, astrocytes also appear uniform ultrastructurally (May and Lütjen-Drecoll, 2002). However, at the level of the sclera, elongated astrocyte processes run transversally between the axon bundles, forming a meshlike frame and being extensively stuffed with intermediate glial filaments and cell organelles (Ding et al., 2002). Astrocytes are connected between each other by connexin 43, which is pronounced in the optic nerve head region (Yancey et al., 1992; May and Mittag, 2006).

The generation of oligodendrocytes and the myelin sheath was described earlier in the chapter. Mature oligodendrocytes of the murine optic nerve are characterized ultrastructurally by a dense nucleus and cytoplasm with sparse filaments (figure 16.2). Besides the production of myelin, optic nerve oligodendrocytes contain carbonic anhydrase II, presumably for local pH regulation (May and Lütjen-Drecoll, 2002; Ro and Carson, 2004).

rates the neuronal tissue. This ring is continuous with the pial connective tissue in the postbulbar portion of the nerve (figure 16.3), the bundles of collagen type I, III, and VI fibers arranged obliquely and longitudinally to the long axis of the nerve (May and Lütjen-Drecoll, 2002; May and Mittag, 2006). Toward the neuronal tissue of the optic nerve the collagen fibers of the sheath are connected to the basement membrane of the astrocyte processes surrounding the nerve. Occasionally, short, 5 μm extensions of the collagen sheath follow the basement membrane of the astrocyte processes, giving the internal surface of the ring a somewhat wavelike appearance. Elastic fibers are completely absent within the pial sheath, even at the level of the choroid (May and LütjenDrecoll, 2002). At the level of the sclera, the central retinal vessels enter the optic nerve and occupy about one-sixth of the ring.

In the murine optic nerve there are no connective tissue septa separating individual nerve fiber bundles from each other. Only some collagen fibers split from the pial connective tissue to follow the entering vessels into the myelinated part of the nerve.

Connective tissue

Although numerous species develop a lamina cribrosa at the level of the sclera, none of the different mouse strains analyzed shows any connective tissue bundles penetrating the optic nerve head in the unmyelinated portion (Tansley, 1956; Fujita et al., 2000; Morcos and Chan-Ling, 2000; May and Lütjen-Drecoll, 2002). At the level of the choroid and sclera, a smooth ring of densely packed collagen fibers sepa-

Vascular supply

The central retinal artery (CRA) derives as a branch from the ophthalmic artery before ramifying into the posterior ciliary arteries. A triangular intra-arterial cushion is regularly present in the ophthalmic artery just before the

Figure 16.2 Myelinated portion of the optic nerve. Note the morphological differences between nuclei of astrocytes (Astro) and oligodendrocytes (Oligo).

Figure 16.3 Optic nerve, sagittal section, immunostained with antibodies against collagen type III. Note the intense staining around the central retinal vessels (CRA), around the ophthalmic artery (OA), in the sclera, and around the optic nerve. No staining is present in the myelinated (MON) or unmyelinated (NON) portion of the optic nerve.

branching of the CRA. The cushion consists of smooth muscle cells and is covered by endothelial cells toward the lumen of the vessel. No nerve terminals are present in these protuberances. At the base of the cushion, the internal elastic lamina of the ophthalmic artery is interrupted, but fine elastic fibers within the cushion contact the internal elastic lamina (May and Lütjen-Drecoll, 2002). A similar cushion is also present in the rat ophthalmic artery (Lassmann et al., 1972), but does not exist in the human. The functional significance of this cushion is not clear, but it might modify blood flow in the entrance region of small branching vessels.

The CRA runs to the sclera and enters the optic nerve obliquely at the level of the sclera and choroid toward the center of the ONH (figure 16.4), where it branches further, forming the retinal arteries. The unmyelinated portion of the optic nerve is exclusively supplied by backward branches of the central retinal artery (May and Lütjen-Drecoll, 2002). These small vessels (two to three capillaries) are in direct contact with the neuronal tissue, showing a merged basement membrane of both endothelial cells and pericytes and astrocytes. The sheath of pericytes in this region is incomplete. The endothelial cells are connected by tight junctions supporting the blood–neural tissue barrier. The choroid does not contribute to the optic nerve head region blood supply in the mouse, and the arterial circle of Zinn and Haller is not present.

The myelinated portion of the optic nerve is supplied by capillaries deriving from pial vessels (May and LütjenDrecoll, 2002). These capillaries show a similar structure as in the unmyelinated portion, with two differences: the vessels are surrounded by a small connective tissue sheath separat-

Figure 16.4 Sagittal section. The central retinal artery (CRA) and central retinal vein (CRV) enter the optic nerve obliquely at the level of the sclera (S) and choroid (Ch) toward the center of the optic nerve head. NON, unmyelinated portion of the optic nerve.

ing the basement membrane from the vessel wall and the basement membrane of the astrocytes, and the endothelial cells do not show tight junctions, indicating a somewhat less potent blood barrier. Anastomoses between both capillary beds exist at the transit from the myelinated to the unmyelinated portion of the optic nerve.

The central retinal vein runs closer to the optic nerve than the artery and is connected with the pial venous system. In contrast, the posterior ciliary veins draining blood from the posterior choroid continued to the orbital venous sinus (Pinkerton and Webber, 1964; Yamashita et al., 1980).

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Circadian rhythms are near-24-hour oscillations in behavior and physiology found in most living organisms that enable the orchestration of endogenous processes to the appropriate time of day. An endogenous timekeeping mechanism or oscillator generates and maintains these rhythms. Thus, a property of circadian oscillations is their sustenance under constant environmental conditions in the absence of any timing cue. Interestingly, most free-running circadian pacemakers oscillate with a periodicity different from that of Earth’s rotation. Therefore, the oscillator requires daily adjustment to maintain a constant phase relationship with geophysical time. Furthermore, the phase of the oscillator must be adjusted to seasonal day-length variations. Of all the potential environmental factors that fluctuate daily and can serve as an input, light is the predominant Zeitgeiber (time giver) or entrainment stimulus for the clock. Therefore, under natural conditions, the daily rhythms in behavior and physiology result from the interactions of the endogenous circadian clock and the ambient light-dark cycle.

The photopigments and the cell types that play dominant roles in entrainment of the mammalian circadian oscillator have recently become known. A small subset of retinal ganglion cells (RGCs) express a novel photopigment, melanopsin, and are intrinsically photosensitive (mRGCs or ipRGCs). These RGCs make direct synaptic contact with the hypothalamic brain center harboring a master circadian oscillator. Mouse behavior and genetics have played a major role in our understanding of how mRGCs mediate entrainment of the master oscillator to the ambient lighting conditions.

The mouse as a model system for human circadian function

A wide range of human behaviors and functions, such as maintenance of core body temperature, heart function, muscle tone, alertness, eating and drinking, insulin sensitivity, the synthesis and release of several hormones, and the sleep/wake cycle, exhibit robust circadian fluctuations (Cauter, 2000), which underscores the importance of proper circadian regulation to human health and function. For

example, transient desynchronization of circadian rhythms from local physical time, as occurs during jet lag, leads to productivity loss, while chronic desynchronization, caused by shift work, can contribute to several pathological conditions, including sleep disorders, seasonal affective disorder, metabolic syndromes, and even cancer (reviewed in Waterhouse and DeCoursey, 2004). Furthermore, various nonprimate animal species exhibit seasonal breeding behavior that arises from the interaction of the circadian oscillator and seasonal day lengths (Goldman, 2001). These pervasive effects of circadian rhythms on mammalian health and disease have been a major impetus to investigating the molecular bases of the circadian system.

Remarkably, both the circadian oscillation of different behaviors and functions and the molecular mechanisms that underlie the circadian system appear to be conserved from mice to humans (Panda, Hogenesch, et al., 2002), such that mutations that cause circadian oscillator disorders in humans have similar effects in mice (Xu et al., 2007). The circadian system is largely modular in organization and function. For simplicity, it is presumed to consist of three modules: (1) the entrainment or light input, (2) the core oscillator, and (3) the outputs. Anatomically, the master circadian oscillator in mammals is located in the hypothalamic suprachiasmatic nucleus (SCN), which receives direct retinal input and, through both synaptic and diffusible signals, orchestrates rhythmic output behavior and functions in distant brain regions and peripheral organs (Reppert and Weaver, 2002).

In general, owing to their physical size, large rodents such as hamsters and rats have traditionally been used to examine the neuroanatomy of the mammalian circadian system. However, with the strength of murine genetics and the availability of genetic techniques to label and track different cell types, mice have increasingly become the model organism of choice for the study of the circadian system.

Circadian behaviors in mice

The most obvious output of the circadian oscillator in animals is the daily rhythm of activity and rest. Thus, long-