Circadian organization of the mammalian retina

Abstract

The mammalian retina contains an endogenous circadian pacemaker that broadly regulates retinal physiology and function, yet the cellular origin and organization of the mammalian retinal circadian clock remains unclear. Circadian clock neurons generate daily rhythms via cell-autonomous autoregulatory clock gene networks, and, thus, to localize circadian clock neurons within the mammalian retina, we have studied the cell type-specific expression of six core circadian clock genes in individual, identified mouse retinal neurons, as well as characterized the clock gene expression rhythms in photoreceptor degenerate rd mouse retinas. Individual photoreceptors, horizontal, bipolar, dopaminergic (DA) amacrines, catecholaminergic (CA) amacrines, and ganglion neurons were identified either by morphology or by a tyrosine hydroxylase (TH) promoter-driven red fluorescent protein (RFP) fluorescent reporter. Cells were collected, and their transcriptomes were subjected to multiplex single-cell RT-PCR for the core clock genes Period (Per) 1 and 2, Cryptochrome (Cry) 1 and 2, Clock, and Bmal1. Individual horizontal, bipolar, DA, CA, and ganglion neurons, but not photoreceptors, were found to coordinately express all six core clock genes, with the lowest proportion of putative clock cells in photoreceptors (0%) and the highest proportion in DA neurons (30%). In addition, clock gene rhythms were found to persist for >25 days in isolated, cultured rd mouse retinas in which photoreceptors had degenerated. Our results indicate that multiple types of retinal neurons are potential circadian clock neurons that express key elements of the circadian autoregulatory gene network and that the inner nuclear and ganglion cell layers of the mammalian retina contain functionally autonomous circadian clocks.circadian clock ͉ clock gene ͉ mouse retina ͉ photoreceptor ͉ real-time PCR T he mammalian retinal circadian clock exerts extensive control over retinal physiology and function, regulating a wide variety of retinal circadian rhythms, including rod disk shedding (1-3), melatonin release (4-6), dopamine synthesis (7, 8), electroretinogram (ERG) b-wave amplitude (9), extracellular pH (10), visual sensitivity (11, 12), and intraocular pressure (13,14). The retinal circadian clock and its dopamine-and melatonin-signaling molecules also influence pathological processes in the eye, including the susceptibility of photoreceptors to degeneration from light damage (15, 16), photoreceptor survival in animal models of retinal degeneration (17), and the degree of refractive errors in primate models of myopia (18). Despite its widespread influence, the cellular origin and organization of the circadian clock in the mammalian retina remain unclear.Neural circadian clocks generate endogenous circadian rhythms through cell-autonomous autoregulatory transcriptiontranslation feedback loops comprised of a defined set of ''clock genes'' in subsets of circadian pacemaker neurons. Gene targeting has demonstrated that, in mammals, the genes Period (Per) 1 and 2 and Cr...

Functional Heterogeneity of Retinal Dopaminergic Neurons Underlying Their Multiple Roles in Vision

“…They demonstrate distinct functional modes of DA cell spike activity regulation in the dark and in the light that can subserve the observed sustained, transient, and light-independent circadian modes of dopamine release (Bauer et al, 1980;Mangel and Dowling, 1985;Umino et al, 1991;Weiler et (Ruan et al, 2006). Variations in the precise balance of these mechanisms likely account for the range of experimental results previously observed across adaptation conditions and species.…”

“…Recently, dopaminergic neurons in the ventral tegmental area were found to exhibit four distinct classes of spiking patterns that were modulated differentially by pharmacological inputs (Mameli-Engvall et al, 2006). In addition, midbrain dopaminergic neurons exhibit substantial neuropeptide phenotype heterogeneity (Seutin, 2005), as do retinal DA neurons for gene expression (Ruan et al, 2006). The precise extent to which distinct functional output groups represent intrinsic subpopulations of dopaminergic cells versus distinct functional states driven by synaptic input is unknown at this point.…”

Visual evoked potential changes among security guards of Government Medical College and New Civil Hospital, Surat

“…[16] Their input synchronizes the SCN to maintain the circadian rhythm near a 24 h cycle by driving the nocturnal synthesis of the pineal hormone National Journal of Physiology, Pharmacy and Pharmacologymelatonin and feedback loops to mediate clock information to the peripheral tissues and induce circadian phase, sleep, and maintenance of pupil diameter. [17,18] Hence, melanopsin which has a role in the maintenance of pupil diameter [19][20][21][22] and providing the primary environmental light input to the SCN for photoentrainment of the circadian rhythm might be affected. A constricted pupil may decrease the area of retinal illumination and increase the average latency of P100.The average decrease in pupillary diameter of 1.75 mm increases the average latency by 4.6 ms. [1] Our finding also supports the result of Jackson et al, [23] who observed the increase in P100 latency and reduction in amplitude in professional drivers with sleep deprivation.…”

Influence of Rotating Shift Work on Visual Reaction Time and Visual Evoked Potential

“…Recently discovered intrinsically photosensitive melanopsin retinal ganglion cells contribute to the maintenance of pupil diameter [6,[28][29][30][31][32] and provide the primary environmental light input to the suprachiasmatic nucleus for photoentrainment of the circadian rhythm.…”