Age-related cerebrovascular defects contribute to vascular cognitive impairment and dementia (VCID) as well as other forms of dementia. There has been great interest in developing biomarkers and other tools for studying cerebrovascular disease using more easily accessible tissues outside the brain such as the retina. Decreased circulating insulin-like growth factor 1 (IGF-1) levels in aging are thought to contribute to the development of cerebrovascular impairment, a hypothesis that has been supported by the use of IGF-1 deficient animal models. Here we evaluate vascular and other retinal phenotypes in animals with circulating IGF-1 deficiency and ask whether the retina mimics common age-related vascular changes in the brain such as the development of microhemorrhages. Using a hypertension-induced model, we confirm that IGF-1 deficient mice exhibited worsened microhemorrhages than controls. The retinas of IGF-1 deficient animals do not exhibit microhemorrhages but do exhibit signs of vascular damage and retinal stress such as patterns of vascular constriction and Müller cell activation. These signs of retinal stress are not accompanied by retinal degeneration or impaired neuronal function. These data suggest that the role of IGF-1 in the retina is complex, and while IGF-1 deficiency leads to vascular defects in both the brain and the retina, not all brain pathologies are evident in the retina.
Nighttime surges in melatonin levels activate melatonin receptors, which synchronize cellular activities with the natural light/dark cycle. Melatonin receptors are expressed in several cell types in the retina, including the photon-sensitive rods and cones. Previous studies suggest that long-term photoreceptor survival and retinal health is in part reliant on melatonin orchestration of circadian homeostatic activities. This scenario would accordingly envisage that disruption of melatonin receptor signaling is detrimental to photoreceptor health. Using in vivo CRISPR/Cas9 genomic editing, we discovered that a small deletion mutation of the Mel1a melatonin receptor (mtnr1a) gene causes a loss of rod photoreceptors in retinas of developing Xenopus tropicalis heterozygous, but not homozygous mutant tadpoles. Cones were relatively spared from degeneration, and the rod loss phenotype was not obvious after metamorphosis. Localization of Mel1a receptor protein appeared to be about the same in wild type and mutant retinas, suggesting that the mutant protein is expressed at some level in mutant retinal cells. The severe impact on early rod photoreceptor viability may signify a previously underestimated critical role in circadian influences on long-term retinal health and preservation of sight. These data offer evidence that disturbance of homeostatic, circadian signaling, conveyed through a mutated melatonin receptor, is incompatible with rod photoreceptor survival. Circadian (daily) rhythms synchronize to the natural solar cycle via photoreceptive cells in the retina of the eye that detect radiant light energy and convey that information to inner retinal cells, some of which project to the brain. Cyclic oscillations of intracellular activity occur in many cells of the body, and are especially robust in retinal cells since they need to anticipate the 12 magnitudes in ambient light intensity changes that can occur over a 24-h period 1. The key circadian signaling molecule of darkness, melatonin, is produced by retinal photoreceptors at nighttime to drive circadian events in the eye and is secreted into the cerebrospinal fluid and general circulation from the pineal gland 2. Melatonin binds to integral membrane G protein-coupled receptors (GPCRs) expressed in target cells throughout the body to harmonize cellular activities with the predictable 24-h day/night cycle 3. Melatonin receptor subtypes are designated as Mel1a, Mel1b, and Mel1c in amphibians, fish and birds 4 , and as MT1, MT2, and GPR50 (which does not bind melatonin) in mammals, respectively 3. One primary function of melatonin in the retina is to enhance visual sensitivity to light at nighttime 5. If the solar light cycle is disengaged from circadian cellular readiness, the metabolic imbalance imposed on darkadapted photoreceptors by radiant light energy causes cell damage 6. The increased vulnerability of photoreceptors to light damage during subjective night 7 is consistent with reports that melatonin receptor activation exacerbates light-induced rod cell death...
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