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RETINAL GANGLION CELLS RETINL RESPONSE, AND THE INVOLVEMENT WITH CIRCADIAN RHYTHM AND NEURODEGENTERATIVE DISEASES
LONG TERM REPEATED DISRUPTIONS TO THE CIRCADIAN RHYTHM AND INCREASED OXIDATIVE STRESSORS MAY LEAD TO DISEASE AND RETINAL GANGLION DAMAGE
Projections of light and visual information on the retina is what allows us to interpret and see the world around us. The retina is composed of 5 different neurons in the retina, but photoreceptor cells are the heaviest involved cells which interpret photons of light creating image and non-image forming vision.
This review will focus on current knowledge of the interaction of retinal ganglion cells and phototransduction and its possible role and contribution to other neuropathic diseases.
Neuroanatomy of retinal ganglion cells and other photoreceptors in the mammalian circadian system
The interpretation of the light stimulus is done by the projection of light through the pupil projected onto the retina known as retinal illumination. Photosensitive retinal ganglion cells (ipRGCs) are responsible for the interpretation from the light stimulus, thus, play a role in non-image-forming vision by the suprachiasmatic nucleus (SCN) (Ketema et al., 2009). External light stimuli entrain the light/dark cycle via a monosynaptic pathway known as the Retinohypothalamic tract (RTH). The RTH tract contains pituitary adenylate cyclase activating polypeptide (PACAP) which is another signaling pathway contributing to circadian timing regulation, as well as retinal ganglion cells with the photopigment melanopsin, whose axons form the optic nerve, optic chiasm, and optic tract to the SCN (Hannibal et. al, 2002). Melanopsin is a photopigment of the light-sensitive retinal proteins which are g-protein coupled receptors that change shape upon detection of light, triggering the RTH tract cascade as well as signals the olivary pretectal nucleus (OPN) responsible for the pupillary light reflex which functions to allow the optimal amount of light entering the retina. The SCN of the hypothalamus coordinates the bodies timing system, acting as a “master pacemaker” with peripheral oscillators located in the tissues/organs of the body through humoral stimulus, neural signaling, and indirectly through activity and feeding behavior (Yamazaki, 2000), coordinating other physiological responses such as the sleep wake cycle, hormone levels, core body temperature, and other biological activities (Klein, 1991). The external light stimulus acts as a daily re-synchronization of circadian oscillators (zeitgeber) (Pierson et al., 2009).
The other two main photoreceptors found in the retina are Rods and Cones, which are more classically known as image-forming vision which allows for differentiation, interpretation, and tracking of visual object shapes, colors, motions, and patterns (Schmidt and Kofuki, 2008; Hattar et al., 2002). Rods and cones take in light with the other light-sensitive retinal proteins rhodopsin and photopsin which convert light stimuli into a neuronal impulse projecting to the SCN.
The circadian rhythm is a 24-hour biological clock responsible for different physiological processes such as the sleep/wake cycle, feeding behavior, brain wave activity, hormone production, cell regeneration, and others which are modulated by external clues such as light. Internal circadian time is entrained by light-induced resetting (photoentrainment mechanisms) (Moore and Lenn, 1972) but requires repeated and exposure on a regular basis in order to establish the light/dark cycle (Duffy et al., 2009).
With the introduction of artificial light, increased lighting exposure result in the suppression of the secretion of melatonin. These disruptions can lead to adverse effects on the physiological responses centered around the circadian rhythm (Duffy et al., 2009). The hormone melatonin ((N-acetyl-5-methoxytryptamine) synthesized in the pineal gland is released in the nocturnal setting in the absence of light stimulus which is observed by the optic nerve sending a melatonin secretion signal. The release of melatonin induces tiredness and fatigue as an indication to the body to rest, however, prolonged exposure to light at night inhibits melatonin release, which can contribute towards difficulty sleeping. The melatonin pathway also acts as a zeitgeber due to it’s ability to stimulate the SCN, but is considered an internal feedback regulator compared to light which is a primary circadian rhythm initiator (Pfeffer et al., 2012).
Studies examining the effects of gene ablation in mice knocking out the melanopsin gene (Opn4 -/-) found that mice deficient in melanopsin were still able to have circadian entrainment and pupillary light reflex to some degree, however, this result was only seen at high luminance levels (Hattar et al., 2002; Panda et al., 2002). Mice lacking rods, cones, and both still remain entrained to changing light stimuli which suggested that both photoreceptors are not directly necessary for circadian rhythm regulation (Freedman, 1999). Continuation of these findings found that mice lacking rods, cones, and melanopsin (Opn4 -/-) lost all retinal response to light (Hattar et al., 2003), and thus cannot suppress melatonin production pathway or entrain the circadian rhythm. The comparison of these studies suggested that rods and cones are not directly responsible for photoentrainment, however, are able to compensate up to a degree when melanopsin is lost, but losing all photoreceptors result in complete loss of retinal response to light. Similarly, blind people with no conscious perception of visual light still exhibit normal photic entrainment of the circadian rhythm (Czeisler et al., 1995), but damage to the Opn4 gene producing melanopsin has been suggested to be associated with Seasonal Affective Disorder.
Research has also found that neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s, Huntington’s, and more can also be characterized by degeneration of the optic nerve and loss of retinal ganglion cells production resulting in the loss of circadian rhythm entrainment (Hinton et al., 1986,Yu et al., 2014, and Andrade et al., 2016).
Retinal ganglion cells are unique compared to other neurons or cells in the body, where they are not able to duplicate, however, this means that damage and loss of retinal ganglion cells are permanent. Wilkiing et al., 2013 suggests a connection between circadian rhythms (and disruptions) to oxidative stress due to both processes essential function to maintain homeostasis in physiological processes in health and disease. The adverse physiological effects associated with a disrupted circadian rhythm and oxidative stress are linked to neurodegenerative diseases shown by plaques in the brains, neuronal death, and late onset (Donmez, 2012), along with cancer, heart disease, and aging (Wilking et al., 2013).
(Wilkiing et al., 2013’s conclusion of the direct relationship between circadian rhythm disruption and oxidative stress’ effect on health is not supported by a direct comparison/interaction, however, has evidence supporting the importance of circadian rhythm regulation and oxidative stress processes in proper functioning cellular activity. The conclusion also suggests the impairment of proper cellular/physiological health when the circadian rhythm is disrupted. The evidence from cumulative studies supports that long term continuous disrupted circadian rhythms and the cumulative environmental/physiological stressors resulting from the continuous disruptment could have an impact on retinal function and lead to irreparable damage to retinal ganglion cells. Long term disruptions of this 24 hour biological clock makes those susceptible to repetitive jet lag and shift work especially at a high risk for detrimental human health implications.
Interestingly, the symptoms caused by the loss of retinal ganglion cells can be reduced by synthetic melatonin treatments in individuals with Alzheimer’s disease (Venkataramanujan et al., 2009).
Long term continual disruptions of the circadian rhythm due to artificial light at night may support retinal ganglion damage
(if protective measures are not enough due to exposure to environmental stresses such as UV light, chemical pollutants, or heat, or physiological reasons such as poor diet life style etc, cells go into a state of oxidative stress which can result in DNA damage, lipid peroxidation, oxidation of amino acids, and can result in cell death
Reactive species are produced in the mitochondria as a byproduct of metabolism or due to environmental stressors. ROS
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