User:Bioclocksvision/sandbox

= Non-Image-Forming Vision (Mammalian) =

Non-image-forming vision is a subcategory of the visual system. In contrast to the visual perception system, which is responsible for the perception of shape, color and motion, non-image-forming vision relays the overall ambient light level of the external environment. Mechanisms involved in this type of vision are subconscious and independent of visual perception. Non-image-forming vision is responsible for entrainment of an organism to the daily light cycle as well as pupillary response to light and regulation of pineal melatonin secretion. Recently, additional functions have been discovered such as modulation of vision, neonatal light aversion, and associative learning. These pathways are functional even in individuals who are lacking rods and cones in the retina. The non-image-forming visual subsystem receives information from intrinsically photosensitive retinal ganglion cells, or ipRGCs, located in the retina. ipRGCs also receive information from rods and cones, thus indirectly linking the conscious, image-forming visual system to the subconscious visual system in a one-way connection. The ipRGCs allow for the entrainment of visually-impaired individuals to the daily light-dark cycle, despite their lack of image-forming vision.

Discovery
In Foster et al. 1993, mice with vision loss demonstrated the ability to entrain to the daily light cycle. In 1995 the Czeisler lab at Harvard found that humans who were diagnosed as lacking visual perception were able to react to the presence of light. The individuals in the study were found to be able to synchronize their biological clocks to the daily light cycles even with non-functional rods and cones. Before this discovery, the model for vision only held included rods, cones, and their signals. These inputs were believed responsible for the control of all visual reactions. After this data was reported researchers began looking for another photopigment that worked independent of rods and cones. This lead to the discovery of melanopsin in frogs in 1998 by Ignacio Provencio and his colleagues at Uniformed Services University of Health Sciences in Bethesda. Not long after Provencio's lab found retinal ganglion cells in mammals that contained a protein very similar to the frog melanopsin. Melanopsin is the photopigment responsible for perception of light and is the pigment primarily responsible for non-image-forming vision. The cells that contain melanopsin are ipRGCs. These are the cells primarily responsible for non-image-forming vision.

Mechanism
Expression of the photopigment melanopsin (Opn4) in intrinsically photosensitive retinal ganglion cells (ipRGCs) is the basis for non-image-forming vision in vertebrates. The ipRGCs most commonly reside in the ganglion cell layer and are dispersed across the retina, forming a large photosensitive region that detects light incident upon the retina.

Knockouts of melanopsin confirm its role in photoentrainment and pupillary response; however, loss of melanopsin does not prevent photoentrainment. Synaptic inputs to ipRGCs from rods and cones partially compensate for the loss of melanopsin and allow for responses to light-based stimuli.

The melanopsin pigment closely resembles invertebrate rhodopsins, and is thought to have intrinsic photoisomerase activity through a similar mechanism to seven-helix opsin photopigments. The absorption of a photon by melanopsin triggers a conformational change in the protein, which activates a G protein and signals the opening of a transient receptor channel. Through a phosphoinositide signaling cascade, this then leads to the induction of an action potential. The putative molecular players of the melanopsin response pathways are labelled in this diagram.

Labeling experiments in mice have shown that ipRGCs innervate many areas of the brain involved in circadian rhythm generation, photic response, and pupillary constriction [2]. Further studies indicate that there exist multiple populations of morphologically distinct ipRCGs that innervate different brain regions and form connections in different areas of the retina. The ipRGCs in the retina form the retinohypothalamic tract that projects to the suprachiasmatic nucleus (SCN), a region of the brain which is responsible for circadian rhythm generation and is considered to be the “master pacemaker” of the body.

ipRGCs release the neurotransmitters glutamate and pituitary adenylate cyclase activating polypeptide (PACAP) from their axon terminals. These neurotransmitters interact with the neurons in the SCN, activating a CREB-mediated pathway that shifts the circadian clock by inducing expression of period genes. Connections to other regions of the brain allow ipRGCs to govern unconscious responses to light, including the pupillary light reflex.

Applications to Clock Entrainment
Non-image-forming vision has been shown to photoentrain circadian rhythms and subsequently sleep cycles. Gene ablation studies in mice where the melanopsin protein is knocked out (Opn4−/−) showed significant impairment in photoentrainment confirming the role of ipRGCs and non-image-forming vision in circadian entrainment. Unlike rods and cones, ipRGCs' effect on photoentrainment is more subtle projecting signals to the mammalian master clock: the suprachiasmatic nucleus (SCN). It is notable that there is redundancy in the system such that rods and cones are still functional in Opn4-/- animal models and can still have functional, but impaired photoentrainment.

Dysfunctions in circadian photoentrainment from non-image-forming vision has significant implications for overall health. Studies have shown that circadian disruptions are associated with a decline in overall health, numerous psychiatric and neurodegenerative disorders, and is hypothesized to be a potential mechanism for Alzheimer’s Disease.

Clinical Implications
The discovery of non-image-forming vision has led to many changes in how the scientific and medical communities understand, investigate, and treat relevant pathologies. Recent finding and newfound insight into the underlying functions of the non-image-forming system has implicated a much broader involvement of the system in physiology than previously thought. Current research has found many connections to human pathology and disease states such as: seasonal affective disorder, migraine, glaucoma, inherited mitochondrial optic neuropathy, and sleep dysregulation of aging.

Pupillary Light Response
The pupillary light response is a common diagnostic produce performed by physicians to assess the pupillary light reflex and brainstem functionality. Specifically, in the pupillary light reflex, pupils dilate and constrict to regulate the intensity of light entering the eye. As light intensity decreases, the pupil dilate to let more light into the retina.

In 1927, Dr. Clyde E. Keeler’s research team at Harvard University discovered that the pupillary light response persisted in visually blind mice (lacking rods and cones). In 2001, Dr. Robert J Lucas’s team at the Imperial College School of Medicine in the UK confirmed Keeler’s research that mice with rod and cone double knockouts. Later experiments found that in ipRGC deficient mice show no pupillary light response at high light intensities despite having a competent visual system. Specifically, researchers suggest that rods and cones are responsible for the pupillary light response under low(scotopic) and moderate (mesopic) light conditions, while ipRGCs responsible for non-image-forming vision is responsible for the pupillary light response at high (photopic) light levels.

Seasonal Affective Disorder:
Seasonal Affective Disorder (SAD) is a depressive disorder related to light variation associated with seasonal changes. SAD is chronic and begins and ends at consistent times throughout the year. Most commonly, depressive symptoms begin in late fall or early winter. SAD is prevalent in 5% of the US population. Given the role of ipRGCs in photoentrainment, non-image-forming vision is suspected of playing a role in SAD and is a focus of current research.

Sleep Dysregulation in Aging:
Recent research has shown a decline in circadian regulation in the aging populations. Circadian phase markers such as core body temperature, melatonin, and cortisol secretion have been shown to decline. As non-image-forming vision is implicated in sleep circuitry, investigating deterioration of the melanopsin-dependent regulation of the circadian rhythms could provide insight to the dysregulation of sleep in aging populations.

Glaucoma
Glaucoma is a group of eye disorders, common in older adults, that involve damages (most commonly intraocular hypertension) in the optic nerve and/or impairment to the neuronal visual pathway. Initial research from rat models demonstrated rats suffering glaucoma have significantly reduced cone and melanopsin mRNA suggesting the role of non-image-forming vision in Glaucomas. Current research is ongoing with ipRGC knockout models for studying Glaucoma.

Photophobia in Migraine:
Clinical observations suggest blind patients suffer from intensified photophobia and migraine exacerbation compared to matched controls. In animal models, the thalamic nuclear group activated in response to dural stimulation, involved in the trigeminovascular pathway for migraines, were also involved in the signal transduction in the ipRGCs of non-image-forming vision. This suggest that the non-image-forming visual pathway is relevant to migraines. However, further human studies found no statistically significant difference in severity nor frequency of migraines following ipRGC stimulation.