Circadian rhythm dysfunction in glaucoma: A hypothesis

Numerous experimental studies have convincingly shown that light is the most important synchronizer of circadian rhythms [1]. On a daily basis, light sets and resets the timing of the circadian time-keeping system, to ensure its proper functioning. Consistent with established phase response curves, light exposure early in the morning resets the circadian system to adjust for its propensity to phase-delay, and light exposure in the evening is necessary to adjust for phase-advances in the master clock [2-6].In the absence of the entraining effects of the light-dark cycle, the circadian system free-runs [7]. According to time-isolation studies, the circadian system can gradually shift and may even become completely desynchronized with respect to external environmental cycles [7,8]. Thus, failure to achieve such necessary adjustments in the timing of the circadian system, either because of deprivation of light cues, knowledge of time, or societal pressures [9,10], could lead to circadian misalignment (see below), which could engender circadian disorders. Paradoxically, the ability of organisms to free-run is considered an advantage, as it allows them to maintain a stable phase relation with the environmental cycles and/or to adapt to seasonal variations in day length [11].Research conducted with visually intact adults has shown that the photosensory brightness-sensing system provides direct photic input to the suprachiasmatic nuclei (SCN, the master circadian clock in mammals), using pathways that are distinct from the standard retinal radiations to the visual system [12-14]. Studies distinguish between two entraining photic pathways. The primary pathway uses the retinohypothalamic tract that transmits photic cues to the SCN and the pineal gland [15,16]. The secondary pathway referred to as the geniculohypothalamic tract stems from the intergeniculate leaflet of the lateral hypothalamus [17-19].Much of the literature in human chronobiology has focused on studies of agin