Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

Glossary

Circadian clock – A cell-autonomous, cyclical autoregulatory molecular mechanism, involving genes – clock genes and their proteins that generate circadian molecular oscillations.

Clock genes – The cyclically, with a cycle about a day, expressed genes engaged in molecular mechanism of circadian clock.

Cryptochrome – A blue-light absorbing protein, which contains a flavin-binding domain and functions as a circadian photoreceptor and an element of the molecular clock in the central and peripheral clocks of Drosophila, respectively. In the mammalian circadian clock, cryptochromes are the core clock elements.

Electroretinogram – A record of electric activity of cells, measured by inserting an electrode into the eye.

Entrainment – The synchronization of circadian oscillations of the clock to the external daily changes of day and night or to other cyclically changing environmental cues.

Green fluorescent protein (GFP) – A green-light- emitting protein originally found in Aquorea victoria and used, after insertion of its gene in transgenic animals, as a reporter of selected proteins and cell types.

Pigment-dispersing hormones – A family of peptides that regulates migration of pigment granules in the crustaceans’ eye and in chromatofores of their body surface and also plays the role of neurotransmitters in circadian systems of crustaceans and insects. In insects, these peptides are called pigment-dispersing factors. Rhabdomere – A light-absorbing part of the compound eye photoreceptor.

Subjective day – A part of the circadian cycle under constant darkness (DD) or in continuous light (LL) in which previously, in the day/night cycle (LD), was the day.

Subjective night – A part of the circadian cycle under constant darkness (DD) or in continuous light (LL) in which previously, in the day/night cycle (LD), was the night.

Zeitgeber time – A time of the 24-h day/night cycle in the environment measured in hours. Usually ZT0 means the beginning of the day.

The Fly’s Visual System

The visual system is a major sensory system for flies and includes the large compound eyes, the ocelli – simple eyes located on the vertex of the head and the optic lobes of the brain. The compound eyes are image-forming eyes, while the ocelli play a role in orientation. In addition to the photoreceptors in the compound eyes and ocelli, light stimuli can be received by extraocular photoreceptors and deep brain photoreceptors.

The most external layer of the compound eye is the retina, which overlies three optic neuropils of the optic lobe: lamina, medulla, and lobula (Figures 1(a) and 1(b)). In flies, the lobula is divided into the lobula and the lobula plate. The retina of the compound eye is composed of many single units called ommatidia whose number depends on the size of the eye. In the housefly Musca domestica, the compound eye is composed of 3000 ommatidia, while the fruit fly, Drosophila melanogaster, has about 800 ommatidia in each eye. Each ommatidium is composed of eight photoreceptors and six of them, R1–R6, terminate in the first optic neuropil or lamina. The other two photoreceptors, R7 and R8, have axons that bypass the lamina and terminate in the medulla. The light-sensitive pigment in the R1–R6 is the blue-sensitive rhodopsin Rh1, while the visual pigments in R7 and R8 are ultraviolet (UV)-sensitive: Rh3, Rh4, or Rh5.

The lamina also has a modular structure and is composed of cylindrical modules called cartridges (Figures 1(c), 1(d) and 2). Each cartridge contains 12 cell types and is surrounded by three epithelial glial cells. Elements of the cartridge include the terminals of photoreceptors R1–R6, the axons and dendrites of the lamina monopolar cells L1–L5, amacrine cell processes, processes of cells located in the medulla, and processes of tangential neurons with cell bodies located in other parts of the brain. The structure and synaptic contacts of the medulla have not been as extensively studied as in the lamina; however, the medulla is known to consist of columns each of which contains 35 cells. The lobula and the lobula plate are centers for processing motion information, and they contain, among others, 10 individually identifiable vertical system neurons that respond to visual wide-field motions of arbitrary patterns.

The function of the retina is to receive photic and visual information, transduce this information into receptor potentials, then transmit the information to the lamina by regulating the release of the neurotransmitter

histamine at synaptic contacts called tetrad synapses. At these tetrad synapses, photoreceptors R1–R6 contact two large monopolar cells (LMCs), L1 and L2, the major output neurons of lamellar cartridges, and two other post-

synaptic elements which may include processes of amacrine cells, epithelial glial cells, and L3 monopolar cell (Figure 2). L2 also forms feedback synapses back onto the photoreceptor terminals.

The Fly’s Circadian System

Circadian rhythms are self-sustaining oscillations with a period of about 24 h that are maintained in constant conditions, such as constant darkness (DD). These rhythms are not only entrained to the external day/night cycle primarily by light, but they also can be entrained by other environmental cues. The eyes of flies and of other insect species provide light input to the circadian system which controls circadian rhythms in behavior and in physiological and biochemical processes, including those within the visual system. The circadian system in flies is composed of a central clock (pacemaker) located in the brain as well as peripheral clocks located in many tissues throughout the body. All circadian rhythms in the body are synchronized to each other and maintain the

organism’s homeostasis in time. As will be described in greater detail below, the circadian system controls structural changes within the lamina of the visual system and the numbers of specific synapse, and these changes are correlated with the animal’s locomotor activity rhythm.

In D. melanogaster, clock genes are expressed in approximately 100 neurons in the brain belonging to seven groups on each side of the brain: small and large ventral lateral neurons (s-LNvs and l-LNvs), dorsal lateral neurons (LNds), lateral posterior neurons (LPNs), and three groups of dorsal neurons (DN1, DN2, and DN3). These cell groups constitute the main circadian pacemaker. Four of five s-LNvs and four l-LNvs express the neuropeptide pigment-dispersing factor (PDF), the only output neurotransmitter of the circadian system known so far. Peripheral clocks, distributed throughout the animal,

generate circadian rhythms in peripheral organs, including antennae, Malpighian tubules, testes, and the retina photoreceptor cells. In contrast to the pacemaker neurons, in which the circadian oscillations of clock gene expression are self-sustained for many days in DD, oscillations in the peripheral clocks decline after several cycles in DD. Thus, the molecular mechanisms underlying central and peripheral clocks may be different.

Circadian clocks are cell autonomous, and a cell is said to contain a circadian clock if it expresses clock genes, those that show circadian expression and control the expression of a large population of other genes (so-called clock-controlled genes). In clock cells, clock genes and their proteins form transcriptional/translational negativeand positive-feedback loops that are the molecular basis of circadian clocks. Much of our understanding of molecular clocks comes from studies of D. melanogaster, and our ideas about how these molecular clocks are regulated and entrained continue to be refined. A basic model is presented below and in Figure 3.

In central pacemaker clock cells, two cyclically expressed core clock genes are period (per) and timeless (tim). When their proteins PERIOD (PER) and TIMELESS (TIM) accumulate in cytoplasm, they form heterodimers and enter the nucleus. In the nucleus, they bind to heterodimers of the transcription factors CLOCK(CLK)/ CYCLE(CYC) encoded by Clock (Clk) and cycle (cyc) genes, respectively, and PER, and possibly TIM, repress their own transcription. This is the negative-feedback loop of the molecular clock. CLK/CYC also control the cyclical expression of two other core clock genes, vrille (vri) and Par domain protein 1e (Pdp1e) and their protein products, VRI and Pdp1e, respectively, regulate the transcription of clk. VRI represses the transcription of Clk while Pdp1e enhances it. The increase in clk transcription is a positivefeedback loop of the molecular clock. The level of PER and the transition of PER and TIM from the cytoplasm to the nucleus is controlled by phosphorylation so that the transcriptional feedback occurs at a particular time of the day.

Light entrainment of the molecular clock in central pacemaker neurons depends on an intracellular blue- light-photosensitive protein CRYPTOCHROME (CRY). CRY is involved in the light-dependent degradation of TIM. When the light is on, TIM does not accumulate in the cytoplasm, the negative-feedback loop that represses per and tim transcription is delayed and, as a result, the phase of the clock will be delayed. However, if TIM is degraded, while it is in the nucleus, the repression of CLK/CYC will be removed early, the transcription of per and tim will be advanced and the phase of the clock will be advanced.

The molecular mechanism in the peripheral clocks is also based on per and tim cyclical expression; however, in peripheral clocks, CRY may be a central element of the

molecular mechanism in addition to its role as a circadian photoreceptor involved in the light entrainment of the molecular clock. It has been suggested that in peripheral clocks of D. melanogaster, CRY is a transcriptional repressor playing a role similar to that of CRY proteins (mCRY1 and mCRY2) in mammalian molecular clocks.

Similar circadian systems – consisting of many circadian clocks that are based on a transcriptional/translational feedback loop model – are probably present in other insect species. However, some aspects of the molecular mechanism of the clock may differ in even closely related dipteran species. For example, in Lucilia cuprina, the PER expression pattern is similar to that of D. melanogaster, but in the housefly, M. domestica, PER isolated from the whole head does not cycle.

As was described above, light is the major environmental cue that entrains the central pacemaker to the day/ night cycle. The light input to the central pacemaker is complex, and the fly’s compound eyes are not the only source. Ocelli photoreceptors, the extraocular photoreceptors known as the Hofbauer–Buchner (H–B) eyelet, and the intracellular blue-light-photosensitive protein CRYPTOCHROME (CRY), which is present in most cells harboring molecular circadian clocks, also provide light input. The H–B eyelet consists of four photoreceptors located between the retina and medulla. These photoreceptors contact the small LNvs pacemaker neurons and synchronize the molecular rhythms in these neurons. The small LNvs, in turn, synchronize the animal’s behavioral rhythms by the rhythmic release of PDF. Since the pacemaker comprises several groups of neurons, each group may be important for producing circadian rhythms in different cells, tissues, and systems, and receive light inputs from different photoreceptors.

The visual system receives circadian input from pacemakers; however, it is still unknown which group or groups of pacemaker neurons send the circadian input to the visual system. In addition, the visual system possesses peripheral clocks in the retina photoreceptor cells.

Circadian Rhythms in the Retina of the

Compound Eye

Most arthropods, including insects, show daily changes in the structure of photoreceptors manifested by changes in the size of the rhabdomere, the photosensitive part of photoreceptors. Moreover, daily changes in screening pigment movements have been documented in many insect and crustaceans species. The most pronounced structural changes in photoreceptors, regulated by a circadian clock, have been described in the horseshoe crab Limulus polyphemus. In contrast to crustaceans, locusts, praying mantis, and mosquitoes, the cross-sectional area

of rhabdomeres in the retina photoreceptors of flies shows no (L. cuprina) or only little (D. melanogaster) change during the day and night cycle.

However, in many species, including flies, diurnal rhythms have been detected in the amplitude of the electrical activity of the eye recorded with the electroretinogram (ERG). The ERG originates from both the retina and the lamina L1 and L2 monopolar cells and measures

changes in eye sensitivity. In D. melanogaster, cyclical changes are observed in both the amplitude of the ERG and the level of visual pigment in photoreceptors as measured by microspectrophotometry. When D. melanogaster is maintained under normal LD conditions, the ERG-measured sensitivity and the concentration of visual pigment in photoreceptors are highest during the night. Then about 8 h before lights-on, the sensitivity begins to decline and, about 2 h

after lights-on, the level of visual pigment in the eye starts to decrease. The sensitivity and the level of visual pigment continue to decrease until 4 h after the onset of the light. In white-eye D. melanogaster mutants, the level of visual pigment recovers 2–4 h later. The observations that changes in ERG sensitivity and visual pigment levels anticipate changes in illumination, and that these cyclic changes are maintained in DD conditions indicate both processes are under circadian control.

In the blowfly Calliphora vicina, a diurnal insect, three ERG components have been studied under LD and DD conditions; one component called the sustained negative potential originates at least partly from the retina photoreceptors, and two others, ON and OFF transients, originate from the lamina monopolar cells. The lamina transients exhibit circadian oscillations and increase during the subjective night in DD. The negative potential that originates from the retina changes in antiphase with the transients and becomes smaller during the subjective night, indicating that the retina and the lamina components of ERG seem to be regulated by two different circadian clocks. In the cockroach Leucophaea maderae, a nocturnal insect, the opposite changes to those recorded in the blowfly have been observed, and the negative potential of ERG in this species exhibits the highest amplitude during the subjective night. The changes in the ERG observed in these two different species indicate that the photoreceptor activity is correlated with the animal’s pattern of locomotor activity. This activity is higher during the day than at night in diurnal insects and higher at night in nocturnal insects.

In addition to regulating the content of visual pigment in insect photoreceptors, circadian clocks may regulate phototransduction by controlling the expression of some genes such as the one that encodes a transient receptor potential channel involved in this process.

Much evidence indicates that retinal photoreceptors are themselves peripheral clocks. They show daily changes in the abundance of the clock protein PER that are maintained in DD conditions and they express other clock genes, including cr y. As in the pacemaker neurons in the brain, the abundance of PER in the photoreceptors is highest at the end of the night. In photoreceptors, however, PER decays faster during the day than in the perexpressing neurons in the brain. The rhythmic changes in PER immunostaining in the photoreceptors are also affected by per mutations. For example, in flies expressing the pers mutation, in which the period of circadian locomotor activity is shorter (19 h) than 24 h, PER in photoreceptors appears earlier than in wild-type flies. Evidence that the circadian clocks in retinal photoreceptors are cell autonomous comes from experiments that used transgenic D. melanogaster in which PER was expressed only in photoreceptors. In these animals, cyclic PER expression was observed in photoreceptors in DD condition, even

though no PER expression was detected elsewhere in the animal and the animals were otherwise arrhythmic. Although the retinal photoreceptors possess autonomous circadian clocks, it is unknown to what extent these clocks control the rhythms observed in photoreceptors. Again, it is unknown if the clocks in the fly’s retina impact the rhythms in cells that are postsynaptic to the photoreceptors.

Circadian Rhythms in the First Visual

Neuropil (Lamina)

Although structural changes in the photoreceptor cell bodies of flies are not dramatic, striking circadian rhythms have been detected in the lamina of the fly’s visual system. Here, the number of synaptic contacts, the morphology of two visual interneurons, and the number of some organelles in the photoreceptor terminals change during the LD and DD conditions. These rhythms are examples of plasticity in the nervous system regulated by a circadian clock, and they may serve to gate the flow of information through the visual system to correlate with the animal’s locomotor activity.

Since clock gene expression has not been detected in the lamina neurons, circadian rhythms observed in the lamina must be driven by circadian pacemaker neurons located in the brain and/or clocks present in the retina photoreceptors. These rhythms may also be maintained by clock-gene-expressing glial cells distributed between neurons and other glial cells in the optic neuropils.

Circadian Plasticity of Synaptic Contacts

In the lamina of the housefly M. domestica, cyclic changes have been found in the frequency of two types of synaptic contacts: tetrad presynaptic profiles or the so-called T-bars, and feedback synapses (Figure 1(d)). In the housefly, which is a diurnal species, the number of tetrad presynaptic profiles is highest at the beginning of the day when the flies also show the highest locomotor activity. In contrast to the tetrads, the number of feedback synapses peak at the beginning of the night. The oscillations in the number of feedback synapses are maintained in DD and are not affected by light. Therefore, they are clearly controlled by circadian clocks. By contrast, the number of tetrad synapses does not significantly change in DD, but increases after a 1-h light pulse presented during the subjective day or subjective night in DD. This could be interpreted to mean that the number of tetrad synapses is controlled by light, not by circadian clocks. However, studies with D. melanogaster suggest that circadian clocks are important regulators of the number of tetrad synapses.

In D. melanogaster, daily oscillations have been found in the abundance of a scaffolding protein of the T-bar ribbon in presynaptic tetrad synapses, the BRP protein encoded by the Bruchpilot gene (Figure 2). As in the housefly, the number of presynaptic sites immunoreactive to BRP and the abundance of the protein in the lamina are highest at the beginning of the day. This rhythm was not detected in DD, but it was also absent in cyclic light in the arrhythmic per null mutant. Taken together, these observations indicate that although the daily rhythm in the formation of T-bar presynaptic tetrads depends on light, signals from circadian clocks are also required.

Circadian Plasticity of Second-Order Neurons

and Glial Cells

The daily oscillations in the frequency of photoreceptor tetrad synapses are correlated with morphological changes in the L1 and L2 monopolar cells of the lamina. In the housefly, both cells swell at the beginning of the day and shrink during the night, and this rhythm is maintained in DD and also in LL, a condition that disrupts circadian rhythms in behavior, causing animals to become arrhythmic. Examination of the morphology of the entire L2 cells in transgenic D. melanogaster, in which green fluorescent protein (GFP) was

expressed specifically in L2 cells (Figures 2(b) and 2(e)), has shown that circadian changes occur in the girth of axons and in the length of dendrites extending from these axons (Figure 4). The daily pattern of morphological changes of the L2 is slightly different in males than in females. Circadian changes also occur in the size of L2 nuclei but not in their cell bodies (Figure 4).

Changes in the size of monopolar cell axons are correlated with the pattern of the locomotor activity of fly species. In typically diurnal species such as M. domestica and C. vicina, L1 and L2 monopolar cell axons are largest at the beginning of the day when flies show highest locomotor activity. The sizes of these axons can be further increased, by 20–30%, when insects are additionally stimulated to fly intensively. In D. melanogaster the daily pattern of changes in sizes of L1 and L2 axons is different. Under LD, D. melanogaster has two peaks in locomotor activity, one in the morning and a second one in the evening, and in this species, the L1 and L2 cell axons enlarge twice during the day, in the morning and in the evening. Changes in size of L1 and L2 monopolar cell axons are offset by changes in size of the surrounding epithelial glial cells, which shrink during the day and swell during the night. Changes in the girth of L1 and L2 interneuron axons seem to be correlated with the perimeter of their dendritic trees. Studies of transgenic

D. melanogaster, in which GFP is expressed specifically in L2 monopolar cells, revealed that the L2 dendrites postsynaptic to tetrad synapses are longest at the beginning of the day. This rhythm is absent in arrhythmic per null mutant flies (per0), and its pattern is changed from wild-type in mutant flies harboring a mutation in the CRY protein (cryb). These findings indicate that circadian plasticity of the L2 cells depends on cyclical expression of per and involves cry in maintaining the phase of the rhythm.

In contrast to L1 and L2 monopolar cells, photoreceptor terminals in the lamina do not change their girth. It is unknown, however, if other monopolar cells in the lamina show similar morphological circadian changes.

Circadian Rhythms in Organelles inside Photoreceptor Terminals

Although photoreceptor terminals in the lamina do not show circadian changes in their size, circadian structural changes have been detected in some organelles inside the terminals. For example, in the housefly, there is a vertical migration of pigment granules into and out of photoreceptor terminals. Radial movements of screening pigment within the cell bodies of photoreceptors R1–R6 are well documented. These movements are driven by light. Pigment granules move horizontally toward the rhabdomeres during light adaptation and away from the rhabdomeres during dark adaptation providing an important pupillary mechanism. However, the vertical migration of pigment granules in the housefly photoreceptors appears regulated by a circadian clock. Fewer pigment granules are present in photoreceptor terminals during the day compared to the night. This rhythm is maintained in DD, thereby indicating its endogenous, circadian regulation. These vertical movements of pigment granules may play a role in light adaptation providing more pigment granules to the photoreceptor cell bodies during the day.

Other organelles in the housefly photoreceptor cell terminals are formed from the invaginations of neighboring cells in the lamina: from other photoreceptor terminals and glial cells. Among these two types of invaginations, only the number of inter-receptor invaginations changes during the subjective day and subjective night in DD, and the number is greatest at the end of the subjective night. These organelles are rare in the photoreceptor terminals in flies reared in LD conditions, but increase in darkreared flies. Their functions remain to be discovered.

Neurotransmitter Regulation of Circadian

Rhythms in the Visual System

The lamina is invaded by several sets of wide-field tangential neurons with processes directed at right angles to

the lamellar cartridges; thus, they are appropriately suited for the global regulation of visual processing. In the housefly’s lamina, the most numerous of these processes are immunoreactive for serotonin (5-hydroxytryptamine, 5-HT). They originate from two giant ventral protocerebral neurons called LBO5-HT that project ipsiand contralaterally to the optic lobes. Another group of processes is immunoreactive for PDF and originates from the LNvs. Still other processes are immunoreactive for the neuropeptide Phe- Met-Arg-Phe-NH2 (FMRFamide). The neurotransmitter chemistry of remaining processes remains to be identified.

Processes of LBO5-HT neurons are also present in the lamina of D. melanogaster, but in this species, processes of other wide-field neurons, including PDH-immunoreactive processes, arborize in the distal medulla and only a few reach the lamina. Since the paracrine release of both biogenic amines and neuropeptides has been reported, neuromodulators released in the medulla may reach targets in the lamina of the fruit fly through volume transmission.

Among neurotransmitters detected in the lamina and the medulla, 5-HT has been found to influence both photoreceptors and L1 and L2 monopolar cells. 5HT modulates potassium channels in the photoreceptors of D. melanogaster, and in photoreceptors of locust, a diurnal modulation of potassium channel function can be mimicked by application of 5-HT. In the lamina of the housefly, 5-HT has robust effects on the structure of L1 and L2 cells, but the effects are not the same on both cells. Injections of 5-HT into the housefly’s medulla increase the diameter of L1 but not L2 monopolar cell axons. However, when 5-HT and other biogenic amines are depleted from the lamina by injecting the drug reserpine, there is a decrease in the girth of the L2 axon but not in the axon of the L1 cell. This suggests that 5-HT influences the diameter of both L1 and L2 axons, but that the effects observed depend on its concentration.

Injections of other neurotransmitters into the medulla also affect L1 and L2 axon sizes, but their effects are less significant than that of 5-HT. PDF injections induce a small increase of both cells, while FMRFamide had the opposite effect. PDF applications also have an effect on the screening pigment granules in the photoreceptor terminals. Injections of histamine, a neurotransmitter released from photoreceptor terminals, increase the size of L1 but not L2 processes, while injections of either glutamate or gamma aminobutyric acid (GABA) decrease L1 and L2 axons. The effects of glutamate and GABA mimic the changes in L1 and L2 processes seen during the night under LD conditions and during the subjective night in flies held in constant darkness. Glutamate is a transmitter candidate for the L1 and L2 cells and amacrine cells of the lamina, and GABA is detected in cells that project from the medulla into the lamina. GABA injections also decreased the number of feedback synapses from L2 onto photoreceptors.

Larval Visual System

Circadian rhythms in the visual system exist not only in adult flies but also in larvae. The larval visual system, Bolwig’s organ (BO) is located on both sides of the head and consists of 12 photoreceptors expressing either Rh-5 or Rh-6. All these photoreceptors project to the LNs of the larval circadian system, which includes four neurons on each side of the fruit fly’s larval brain. The BO photoreceptors do not express clock genes, so they are not circadian oscillators like the retina photoreceptors; instead, the BO photoreceptors receive circadian information from the LNs as do other target neurons. The circadian input from the LNs seems to control sensitivity of the larval visual system since the per and tim null mutants are relatively insensitive to light, while mutations in the positive clock elements, Clk and cyc, increase the light sensitivity of larvae. In D. melanogaster larvae, the circadian clock regulates the light-avoidance behavior and visual sensitivity. Both are high at the end of the subjective night and low at the end of subjective day in DD conditions.

The BO photoreceptors survive metamorphosis, and in the adult fly, Rh6-expressing photoreceptors correspond to the extraocular photoreceptors of the H–B eyelet. In larvae and in adults these structures play an active, if subsidiary, role in the entrainment of circadian rhythms. In larvae, light is transmitted from the BO to the LNs where light-induced degradation of TIM is essential for the larval circadian clock entrainment. Moreover, when BO is eliminated, the LN dendrite structure is altered indicating direct interactions between the larval visual system and the larval circadian system. The larval optic nerve is also required for the development of a serotonergic arborization originating in the central brain and for the development of the dendritic tree of the circadian pacemaker neurons – the small LNvs. The larval optic nerve and adult extraocular photoreceptors sequentially associate with the small LNvs during D. melanogaster brain development.

Circadian Circuits in the Fly’s Visual

System

In flies, circadian rhythms in the visual system are correlated to the circadian rhythm in locomotor activity. This indicates that circadian oscillators, both central and peripheral, must communicate with each other, but the underlying circuitry is largely unknown. The circadian rhythms in the retina seem to depend mostly on the peripheral clocks inside the photoreceptors, although pacemaker neurons could impact rhythms in the retina by controlling the number of feedback synapses from L2 onto photoreceptor terminals. As it was described above, these synapses show robust circadian changes. However,

it is unclear if the rhythms in the lamina, and probably in the other optic neuropils, are regulated only by the LNs or by both the photoreceptor’s clocks and the LNs. It is also unknown if the dorsal neurons, DN1–DN3, have any effects on the circadian rhythms in the visual system.

In the housefly, severing the optic lobe from the rest of the brain abolishes circadian changes in the sizes of the L1 and L2 monopolar cell axons. This suggests that circadian information is transmitted to lamina monopolar cells from central pacemaker neurons by neurotransmitters. So far, the only neurotransmitter identified in the pacemaker neurons is PDF, which is present in the LNvs of D. melanogaster and in a similar set of neurons in M. domestica. In the housefly, this peptide is cyclically released from PDF varicosities in a paracrine fashion. In this species, the circadian changes of PDF varicosity sizes have been observed in LD and DD, and the daily release of PDF from the dense-core vesicles of PDF-immunore- active processes have been detected. If PDF, which has been detected in dense arborizations in the medulla of all fly species studied and clearly in the lamina of larger flies, transmits circadian information from the LNvs, then PDF receptors should be present in neurons in this part of the visual system. However, PDF receptors have not been detected in the distal part of the medulla or in the lamina, but in the proximal medulla and in the lobula. In D. melanogaster, however, the processes of PDFimmunoreactive l-LNvs terminate in the distal medulla next to per-expressing glial cells, which may intermediate between the pacemaker neurons and neurons in the lamina cartridges showing circadian plasticity. Thus, glial cells in the optic lobe might be the third player in the regulation of circadian rhythms in the visual system. In the lamina, the epithelial glial cells change their sizes, decreasing during the day and increasing during the night, completely opposite to the neurons. Disrupting glial metabolism and closing gap-junction channels in the lamina have an effect on L1 and L2 monopolar cell sizes and their circadian morphological plasticity.

The Role of Circadian Clocks in the Visual

System

The autonomous circadian oscillators located in retina photoreceptors, and clocks in the pacemaker neurons and in glial cells of the optic lobe, provide a circadian gating of visual information. This gating changes during the day and night and differs between diurnal and nocturnal animals. The activity of the visual system is the highest during the day in diurnal species and during the night in nocturnal species. Furthermore, this pattern correlates with the pattern of locomotor activity in each species. Because of the circadian gating of visual information, light stimuli received during the night in diurnal species

do not disrupt its daily rhythm of activity and the daily pattern of animal behavior, but light stimuli can shift the phase of these rhythms. On the other hand, stressful conditions in the environment and a temporary increase in locomotor activity can result in an increase of the flow of information through the visual system, but only when this stimulation is correlated with the active period of the daily rest (sleep)/activity rhythm. Locomotor stimulation, however, may also shift the phase of the rhythm.

In addition to the gating visual information, the circadian system allows an organism to predict daily changes in the environment, and to prepare the visual and other sensory systems for a proper reception of sensory stimuli and efficient transmission of sensory information. The circadian clocks in the photoreceptors control the reception of light stimuli, while the transmission of sensory information is controlled by clocks in several types of cells, including the retina photoreceptors, the pacemaker neurons, and glial cells. These properties of the circadian and visual systems are typical not only for flies but also for other animals.

See also: The Circadian Clock in the Retina Regulates Rod and Cone Pathways; Circadian Metabolism in the Chick Retina; Circadian Regulation of Ion Channels in Photoreceptors; Fish Retinomotor Movements; Genetic Dissection of Invertebrate Phototransduction; Limulus Eyes and Their Circadian Regulation; Retinal Degeneration through the Eye of the Fly.

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Further Reading

Battelle, B. A. (2002). Circadian efferent input to Limulus eyes: Anatomy, circuitry, and impact. Microscopy Research and Techniques 15: 345–355.

Collins, B. and Blau, J. (2007). Even a stopped clock tells the right time twice a day: Circadian timekeeping in Drosophila. Pflu¨gers Archives – European Journal of Physiology 454: 857–867.

Relevant Websites

http://flybase.org – FlyBase: A Database of Drosophila and Genomes. http://flybrain.neurobio.arizona.edu – Flybrain: An Online Atlas and

Database of the Drosophila Nervous System.