Melatonin in the mammalian retina: Synthesis, mechanisms of action and neuroprotection.

Melatonin is an important player in the regulation of many physiological functions within the body and in the retina. Melatonin synthesis in the retina primarily occurs during the night and its levels are low during the day. Retinal melatonin is primarily synthesized by the photoreceptors, but whether the synthesis occurs in the rods and/or cones is still unclear.

Hyperglycemia and circadian disruption lead to retinal dysfunction in a stabilized colony of the fat sand rat Psammomys obesus.

Purpose: The Fat Sand Rat (Psammomys obesus) recapitulates several features of human pre-proliferative diabetic retinopathy, but data are restricted to wild animals, incompatible with stringent biomedical research criteria. To overcome this barrier, we characterized retinal changes in a colony of P. obsesus maintained under strictly controlled housing conditions.

Aryl Hydrocarbon Receptor Involvement in the Sodium-Dependent Glutamate/Aspartate Transporter Regulation in Cerebellar Bergmann Glia Cells.

Glutamate, the major excitatory neurotransmitter in the vertebrate brain, exerts its functions through the activation of specific plasma membrane receptors and transporters. Overstimulation of glutamate receptors results in neuronal cell death through a process known as excitotoxicity. A family of sodium-dependent glutamate plasma membrane transporters is responsible for the removal of glutamate from the synaptic cleft, preventing an excitotoxic insult.

Aryl Hydrocarbon Receptor in Glia Cells: A Plausible Glutamatergic Neurotransmission Orchestrator.

Glutamate is the major excitatory amino acid in the vertebrate brain. Glutamatergic signaling is involved in most of the central nervous system functions. Its main components, namely receptors, ion channels, and transporters, are tightly regulated at the transcriptional, translational, and post-translational levels through a diverse array of extracellular signals, such as food, light, and neuroactive molecules.

mutation enhances masking responses in mice.

Light can restrict the activity of an animal to a diurnal or nocturnal niche by synchronizing its endogenous clock (entrainment) which controls the sleep wake cycle. Light can also directly change an animal's activity level (masking). In mice, high illumination levels decrease activity, i.

Enhanced Robustness of the Mouse Retinal Circadian Clock Upon Inherited Retina Degeneration.

Daily biological rhythms are fundamental to retinal physiology and visual function. They are generated by a local circadian clock composed of a network of cell type/layer-specific, coupled oscillators. Animal models of retinal degeneration have been instrumental in characterizing the anatomical organization of the retinal clock.

Circadian clocks, retinogenesis and ocular health in vertebrates: new molecular insights.

Circadian clocks are cell-autonomous, molecular pacemakers regulating a wide variety of behavioural and physiological processes in accordance with the 24 ​h light/dark cycle. The retina contains a complex network of cell-specific clocks orchestrating many biochemical and cellular parameters to adapt retinal biology and visual function to daily changes in light intensity. The gene regulatory networks controlling proliferation, specification and differentiation of retinal precursors into the diverse retinal cell types are evolutionary conserved among vertebrates.

Dark-adapted light response in mice is regulated by a circadian clock located in rod photoreceptors.

The retinal circadian system consists of a network of clocks located virtually in every retinal cell-type. Although it is established that the circadian clock regulates many rhythmic processes in the retina, the links between retinal cell-specific clocks and visual function remain to be elucidated. Bmal1 is a principal, non-redundant component of the circadian clock in mammals and is required to keep 24 h rhythms in the retinal transcriptome and in visual processing under photopic light condition.

Major role of MT receptors in the beneficial effect of melatonin on long-term recognition memory in C57BL/6J male mice.

Melatonin, a major signal of the circadian system, is also involved in brain functions such as learning and memory. Chronic melatonin treatment is known to improve memory performances, but the respective contribution of its central receptors, MT and MT, is still unclear. Here, we used new single receptor deficient MT and MT mice to investigate the contribution of each receptor in the positive effect of chronic melatonin treatment on long-term recognition memory.

Melatonin and the circadian system: Keys for health with a focus on sleep.

Melatonin (MLT), secreted during the night by the pineal gland, is an efferent hormonal signal of the master circadian clock located in the suprachiasmatic nucleus (SCN). Consequently, it is a reliable phase marker of the SCN clock. If one defines as "chronobiotic," a drug able to influence the phase and/or the period of the circadian clock, MLT is a very potent one.

Core circadian clock genes Per1 and Per2 regulate the rhythm in photoreceptor outer segment phagocytosis.

Retinal photoreceptors undergo daily renewal of their distal outer segments, a process indispensable for maintaining retinal health. Photoreceptor outer segment (POS) phagocytosis occurs as a daily peak, roughly about 1 hour after light onset. However, the underlying cellular and molecular mechanisms which initiate this process are still unknown.

Core-clock genes Period 1 and 2 regulate visual cascade and cell cycle components during mouse eye development.

The retinas from Period 1 (Per1) and Period 2 (Per2) double-mutant mice (Per1Per2) display abnormal blue-cone distribution associated with a reduction in cone opsin mRNA and protein levels, up to 1 year of age. To reveal the molecular mechanisms by which Per1 and Per2 control retina development, we analyzed genome-wide gene expression differences between wild-type (WT) and Per1Per2 mice across ocular developmental stages (E15, E18 and P3). All clock genes displayed changes in transcript levels along with normal eye development.

The circadian clock regulates RPE-mediated lactate transport via SLC16A1 (MCT1).

Multiple retinal cells harbor a circadian oscillator, including retinal pigment epithelial cells (RPE). However, little is known about the functions that are regulated by the RPE clock. The aim of this study was to investigate whether the circadian clock in the RPE regulates the transport of glucose and its glycolytic metabolic by-product - lactate.

Does the circadian clock make RPE-mediated ion transport "tick" via (NKCC1)?

The presence of a circadian clock in the retinal pigment epithelium (RPE) was discovered recently. However, little is known about mechanisms or processes regulated by the RPE clock. We cultured ARPE-19 monolayers in a transwell culture system, and we found rhythmic mRNA expression of the sodium-potassium-chloride co-transporter .

Rev-Erbα and Photoreceptor Outer Segments modulate the Circadian Clock in Retinal Pigment Epithelial Cells.

Retinal photoreceptor outer segments (POS) are renewed daily through phagocytosis by the adjacent retinal pigment epithelial (RPE) monolayer. Phagocytosis is mainly driven by the RPE circadian clock but the underlying molecular mechanisms remain elusive. Using ARPE-19 (human RPE cell-line) dispersed and monolayer cell cultures, we investigated the influence of cellular organization on the RPE clock and phagocytosis genes.

Circadian Analysis of the Mouse Cerebellum Proteome.

The cerebellum contains a circadian clock, generating internal temporal signals. The daily oscillations of cerebellar proteins were investigated in mice using a large-scale two-dimensional difference in gel electrophoresis (2D-DIGE). Analysis of 2D-DIGE gels highlighted the rhythmic variation in the intensity of 27/588 protein spots (5%) over 24 h based on cosinor regression.

MT1 and MT2 melatonin receptors are expressed in nonoverlapping neuronal populations.

Melatonin (MLT) exerts its physiological effects principally through two high-affinity membrane receptors MT1 and MT2. Understanding the exact mechanism of MLT action necessitates the use of highly selective agonists/antagonists to stimulate/inhibit a given MLT receptor. The respective distribution of MT1 and MT2 within the CNS and elsewhere is controversial, and here we used a "knock-in" strategy replacing MT1 or MT2 coding sequences with a LacZ reporter.

Rods contribute to the light-induced phase shift of the retinal clock in mammals.

While rods, cones, and intrinsically photosensitive melanopsin-containing ganglion cells (ipRGCs) all drive light entrainment of the master circadian pacemaker of the suprachiasmatic nucleus, recent studies have proposed that entrainment of the mouse retinal clock is exclusively mediated by a UV-sensitive photopigment, neuropsin (OPN5). Here, we report that the retinal circadian clock can be phase shifted by short duration and relatively low-irradiance monochromatic light in the visible part of the spectrum, up to 520 nm. Phase shifts exhibit a classical photon dose-response curve.

Ocular Clocks: Adapting Mechanisms for Eye Functions and Health.

Vision is a highly rhythmic function adapted to the extensive changes in light intensity occurring over the 24-hour day. This adaptation relies on rhythms in cellular and molecular processes, which are orchestrated by a network of circadian clocks located within the retina and in the eye, synchronized to the day/night cycle and which, together, fine-tune detection and processing of light information over the 24-hour period and ensure retinal homeostasis. Systematic or high throughput studies revealed a series of genes rhythmically expressed in the retina, pointing at specific functions or pathways under circadian control.

A suprachiasmatic-independent circadian clock(s) in the habenula is affected by Per gene mutations and housing light conditions in mice.

For many years, the suprachiasmatic nucleus (SCN) was considered as the unique circadian pacemaker in the mammalian brain. Currently, it is known that other brain areas are able to oscillate in a circadian manner. However, many of them are dependent on, or synchronized by, the SCN.

Circadian rhythms of hedonic drinking behavior in mice.

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the main circadian clock, synchronized by the light-dark cycle, which generates behavioral rhythms like feeding, drinking and activity. Notwithstanding, the main role of the SCN clock on the control of all circadian rhythms has been questioned due to the presence of clock activity in many brain areas, including those implicated in the regulation of feeding and reward. Moreover, whether circadian rhythms of particular motivated behaviors exist is unknown.

Rev-Erbα modulates retinal visual processing and behavioral responses to light.

The circadian clock is thought to adjust retinal sensitivity to ambient light levels, yet the involvement of specific clock genes is poorly understood. We explored the potential role of the nuclear receptor subfamily 1, group D, member 1 (REV-ERBα; or NR1D1) in this respect. In light-evoked behavioral tests, compared with wild-type littermates, Rev-Erbα mice showed enhanced negative masking at low light levels (0.

Circadian organization of the rodent retina involves strongly coupled, layer-specific oscillators.

Rhythmic physiology is central to retinal function and survival and adapts vision to daily light intensity changes. Mammalian retina rhythmically releases melatonin when cultured under constant conditions, and the occurrence of clock gene [e.g.

Circadian clocks in rat skin and dermal fibroblasts: differential effects of aging, temperature and melatonin.

As a peripheral tissue localized at the interface between internal and external environments, skin performs functions which are critical for the preservation of body homeostasis, in coordination with environmental changes. Some of these functions undergo daily variations, such as temperature or water loss, suggesting the presence of time-keeping mechanisms. Rhythmic functions are controlled by a network of circadian oscillators present virtually in every cell and coordinated by the central clock located in the suprachiasmatic nuclei.

Rat retina shows robust circadian expression of clock and clock output genes in explant culture.

Purpose: Circadian rhythms are central to vision and retinal physiology. A circadian clock located within the retina controls various rhythmic processes including melatonin synthesis in photoreceptors. In the present study, we evaluated the rhythmic expression of clock genes and clock output genes in retinal explants maintained for several days in darkness.