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How Vision WorksThe Physiological Mechanisms Behind What We See$

Nigel Daw

Print publication date: 2012

Print ISBN-13: 9780199751617

Published to Oxford Scholarship Online: May 2012

DOI: 10.1093/acprof:oso/9780199751617.001.0001

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(p.247) Appendix

(p.247) Appendix

How Vision Works

Nigel Daw

Oxford University Press

Circadian Rhythms and Pupillary Reflex

Some important aspects of vision do not involve seeing. Because they have to do with the perception of light rather than the seeing of objects, these are called non-image-forming aspects of vision. They include circadian rhythms of various functions in the body, and the pupillary light reflex.

Circadian rhythms are rhythms that vary daily, occurring on an approximately 24-hour cycle. They include the sleep-wake cycle, activity, feeding, drinking, body temperature, effect of liver enzymes on glycogenesis, a cycle in the pineal hormone melatonin, and sex. A particularly useful circadian rhythm for the purpose of experiments is the cycle of activity in rodents (Richter, 1967). Nocturnal rodents run at night—sometimes 30 or 40 miles per night on wheels in their cages. This activity can be monitored on an activity meter. If the rat is blinded, then it continues to run on a cycle that is approximately, but not exactly, 24 hours: some rats will start running a little earlier each day, and some a little later each day, but each one will keep a regular cycle for months after blinding. If the animal is kept continually in the dark, the same result occurs, and the cycle can be reset by a pulse of light.

These results show that there is an oscillator somewhere in the brain that keeps the approximately 24-hour cycle, and it can be reset, or entrained by light. Lesions of the adrenal glands and hypophysis do not affect the cycles, nor do starvation, dehydration, hypothermia, changes of respiration or heartbeat, or application of various drugs (Richter, 1967). The rhythm is there in congenitally blind rodents and in humans. Lesions of various parts of the image-forming visual system do not affect it either: the crucial area that does is the suprachiasmatic nucleus in the hypothalamus (SCN), demonstrated by lesions of this nucleus, or of the projections from it by a lesion just behind it, which abolish the circadian rhythm (Stephan & Zucker, 1972). The point is buttressed by experiments in Syrian hamsters, where a mutant of the tau gene changes the period from 24 hours to 20 hours. An isolated cultured SCN shows an endogenous rhythm, and deletion (p.248) of the SCN in normal hamsters, followed by implantation of a SCN from a tau mutant hamster, changes the period from normal to the tau period of 20 hours, and vice versa (Ralph, Foster, Davis, & Menaker, 1990). Thus, there must be an endogenous clock in the SCN.

The clock in the SCN consists of a number of genes that feed back on each other. The prime genes in the nucleus are the period genes (Per1, Per2, and Per3) and the cryptochrome genes (Cry1 and Cry2). These genes are activated by a heterodimer of two transcription factors, CLOCK and BMAL1 (Reppert & Weaver, 2002). The proteins produced by the period and cryptochrome genes eventually migrate from the cytoplasm back to the nucleus, where they inhibit the transcription by CLOCK and BMAL1 in a negative feedback loop (Fig. Appx–1). The system is complicated by a number of other genes and feedback loops, but this is the essential mechanism. There are some 20,000 cells in the SCN, and the clocks in each of them are synchronized by neurotransmitter interactions to produce a cycle for the whole nucleus. There are also clocks located in other tissues, such as the liver, that the SCN influences through neural or humoral effects. Some of them may keep cycling for 3 weeks or more in isolation, as long as the culture is maintained, but the rhythm is controlled by the SCN in the intact system (Nishide et al., 2006). There is also a circadian clock in the retina; it controls the


FIGURE APPX–1. Genes and proteins in the SCN clock. Period genes and cryptochrome genes are activated by a dimer Clock and Bmal1 through the Ebox enhancer. As they accumulate, the period and cryptochrome proteins return to the nucleus to inhibit this transcription. (Reprinted from Reppert & Weaver, 2002, with kind permission of MacMillan Publishers.)

(p.249) diurnal shedding of the discs in the photoreceptors, and release of dopamine and melatonin in the retina. This rhythm is not controlled by the SCN (Ruan, Allen, Yamazaki, & McMahon, 2008; Storch et al., 2007).

The clock in the SCN is entrained by input from the retina. This is direct via the retinohypothalamic tract (RHT) and also indirect through the intergeniculate leaflet within the lateral geniculate nucleus, via the geniculohypothalamic tract. Interestingly, this entrainment continues in the absence of the rod and cone photoreceptors (Freedman et al., 1999). This persistent photic influence on the SCN is mediated by a special class of ganglion cells, about 1%–2% of the total, called ipRGCs, that are capable of independent phototransduction (Berson, Dunn, & Takao, 2002). This sensitivity arises from their unique photopigment, melanopsin. Rods and, to a smaller extent, cones also excite these ganglion cells and contribute to the circadian entrainment. However, all photic influence on the clock seems to pass through the ipRGCs: ablating them abolishes entrainment altogether (Altimus et al., 2009; Guler, 2008). These ganglion cells give very sustained and sluggish responses with a long latency, and they have large receptive fields. The cells in the SCN have similar responses, and the intensity range of the response is narrow, from daylight to 100 times that, appropriately for their function (Groos & Mason, 1980). Both these points may be modified when the rod and cone input is active.

One of the targets of the SCN is the pineal gland, which produces melatonin (Moore & Klein, 1974). Melatonin rises in the evening and declines in the morning (Illnerova, 1991). Thus, melatonin is a component in several sleep medicines and jet lag pills. Melatonin in turn affects the SCN in another feedback loop. Other targets of the SCN are various regions of the hypothalamus nearby, which affect feeding, drinking, and sex (Rosenwasser, 2009). Thus, changes in the photoperiod from 16 hours light and 8 hours dark to 8 hours light and 16 hours dark affect sexual activity and the clock genes in the SCN (Tournier, Birkenstock, Pevet, & Vuillez, 2009).

Different animals have different sexual cycles, from short ones in rodents to annual ones in sheep. This is of particular interest to sheep breeders, who move their animals from the northern hemisphere to the southern hemisphere, for example from England to Australia. Such animals must change their breeding cycle by 6 months if they wish to continue to conceive in the fall and deliver in the spring. Changes in melatonin levels, as the day length shortens in the fall and lengthens again in the spring, control this cycle by acting on the pituitary (Dupre et al., 2008; Karsch et al., 1991).

Pupillary Light Reflex

The pupillary light reflex is also abolished by ablation of the ganglion cells containing melanopsin (Guler et al., 2008). This occurs through projections of these cells to the olivary pretectal nucleus (OPN) in the pretectum (Hattar et al., 2002). (p.250) Experiments in a variety of animals, including humans, show that there are different components to the pupillary light reflex, depending on the level of illumination (Gamlin et al., 2007; Lucas et al., 2003). In dim light this is due to rods, in moderate light levels to melanopsin as well as rods and cones, and at bright light levels to cones. When melanopsin is involved, it leads to a slow component to the reflex, because melanopsin is an invertebrate photopigment (Mure et al., 2009; Young & Kimura, 2008) and also because there is a different action spectrum (Lucas, Douglas, & Foster, 2001).

Human Disorders

The importance of circadian rhythms controlled by the SCN is emphasized by the variety of disorders that occur in disruptions of circadian rhythms (Moore, 1991). First, of course, is jet lag and “graveyard” work shifts. These lead to a feeling of sleepiness, fatigue, periods of inattentiveness during the waking period, and partial insomnia during the sleep period. Some individuals also tend to go to sleep early, like rodents with cycles less than 24 hours, and some go to sleep late, like rodents with cycles greater than 24 hours. Others have irregular sleep periods, like rodents that do not entrain to a 24-hour period. Moreover, retinally blind subjects who are missing the ipRGCs have free running circadian rhythms, leading to a mismatch between their clocks and the rest of society, which is a major complaint of the blind population.

Another problem is seasonal affective disorder (SAD). Individuals with SAD exhibit sadness, anxiety, irritability, and decreased energy in the winter. Exposure of such individuals to a bright light during the daytime can improve the symptoms.

Finally, older people tend to go to sleep earlier than younger ones, awaken earlier, and nap during the daytime. Whether this is related to a change in their SCN clock is not known.


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