Circadian rhythms, refractive development, and myopia

Abstract

Purpose: Despite extensive research, mechanisms regulating postnatal eye growth and those responsible for ametropias are poorly understood. With the marked recent increases in myopia prevalence, robust and biologically-based clinical therapies to normalize refractive development in childhood are needed. Here, we review classic and contemporary literature about how circadian biology might provide clues to develop a framework to improve the understanding of myopia etiology, and possibly lead to rational approaches to ameliorate refractive errors developing in children.

Recent findings: Increasing evidence implicates diurnal and circadian rhythms in eye growth and refractive error development. In both humans and animals, ocular length and other anatomical and physiological features of the eye undergo diurnal oscillations. Systemically, such rhythms are primarily generated by the 'master clock' in the surpachiasmatic nucleus, which receives input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) through the activation of the photopigment melanopsin. The retina also has an endogenous circadian clock. In laboratory animals developing experimental myopia, oscillations of ocular parameters are perturbed. Retinal signaling is now believed to influence refractive development; dopamine, an important neurotransmitter found in the retina, not only entrains intrinsic retinal rhythms to the light:dark cycle, but it also modulates refractive development. Circadian clocks comprise a transcription/translation feedback control mechanism utilizing so-called clock genes that have now been associated with experimental ametropias. Contemporary clinical research is also reviving ideas first proposed in the nineteenth century that light exposures might impact refraction in children. As a result, properties of ambient lighting are being investigated in refractive development. In other areas of medical science, circadian dysregulation is now thought to impact many non-ocular disorders, likely because the patterns of modern artificial lighting exert adverse physiological effects on circadian pacemakers. How, or if, such modern light exposures and circadian dysregulation contribute to refractive development is not known.

Summary: The premise of this review is that circadian biology could be a productive area worthy of increased investigation, which might lead to the improved understanding of refractive development and improved therapeutic interventions.

Keywords: circadian rhythms; clock genes; dopamine; melanopsin; myopia; refractive development.

Figure 1

Molecular mechanism of the circadian clock. Modified from Iuvone et al., with permission from Elsevier, Ltd.

Figure 2

Circadian processes in the retina and the retinal pigment epithelium, with their approximate location identified by retinal layer. RPE, retinal pigment epithelium; ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer. Modified from McMahon et al., with permission from Elsevier, Ltd.

Figure 3

Mean rhythms in axial length (black circles; left axis) and choroidal thickness (white circles; right axis) in normal chick eyes measured at 6 h intervals over 24 h. For axial length, the slope of the data for each eye (i.e., the underlying eye growth rate) was subtracted out to yield the ‘cyclic component.’ The curves are the sine waves with a fixed 24 h period fit to the data. From Nickla, with permission from Springer.

Figure 4

Rhythms in axial length (AL, blue), choroidal thickness (CT, green) and intraocular pressure (IOP, red) in human subjects measured at 10 different times over 2 consecutive days (symbols), fit with fixed 24 h period sine waves. Note that the rhythms in axial length and choroidal thickness are in approximate anti-phase to one another. From Chakraborty, et al., with permission from Association for Research in Vision and Ophthalmology^©.

Figure 5

Axial length (normalized to the mean) at 6 h intervals for chicks exposed to 2 h myopic (open symbols) or hyperopic (closed symbols) defocus in the morning (7 am–9 am), vs control eyes (dotted lines and sine wave fit). Note that data from both of the morning defocus conditions cannot be fit to a 24-h sine function (data from Nickla et al.).^,

Figure 6

The rhythms in IOP (black symbols) and axial length (open symbols), fit with fixed 24 h period sine waves. The data for the two parameters are from different sets of chicks (n = 10 in each group). Note that the rhythms in IOP are similar (almost in-phase) to the rhythms in axial length. Black bars indicate darkness. Nickla, et al., with permission from Academic Press Limited.

Figure 7

Schematic of the ON and OFF pathway circuits in the mammalian retina. Open circles indicate sign-inverting synapses, closed circles indicate sign-conserving synapses, and zig-zag arrows indicate photosensitive cells. BC: bipolar cells; AII: type II amacrine cell, GC: ganglion cell; ipRGC: intrinsically photosensitive retinal ganglion cell. Modified from Soucy et al., 1998.

Figure 8

A proposed pathway that incorporates the retinal clock and eye growth rhythms in the regulation of postnatal eye growth and refraction. Modified from Stone, et al., with permission from Elsevier.