Light sensitive cells in the fetal retina communicate as part of an interconnected network

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Brightfield light micrograph showing the retina in an eye of a human fetus. Magnified 100x.

By the second trimester, long before a baby’s eyes can see images, they can detect light.

But the light-sensitive cells in the developing retina — the thin sheet of brain-like tissue at the back of the eye — were thought to be simple on-off switches, presumably there to set up the 24-hour, day-night rhythms parents hope their baby will follow.

University of California, Berkeley, scientists have now found evidence that these simple cells actually talk to one another as part of an interconnected network that gives the retina more light sensitivity than once thought, and that may enhance the influence of light on behavior and brain development in unsuspected ways.

In the developing eye, perhaps 3% of ganglion cells — the cells in the retina that send messages through the optic nerve into the brain — are sensitive to light and, to date, researchers have found about six different subtypes that communicate with various places in the brain.

Some talk to the suprachiasmatic nucleus to tune our internal clock to the day-night cycle. Others send signals to the area that makes our pupils constrict in bright light.

But others connect to surprising areas: the perihabenula, which regulates mood, and the amygdala, which deals with emotions.

In mice and monkeys, recent evidence suggests that these ganglion cells also talk with one another through electrical connections called gap junctions, implying much more complexity in immature rodent and primate eyes than imagined.

“Given the variety of these ganglion cells and that they project to many different parts of the brain, it makes me wonder whether they play a role in how the retina connects up to the brain,” said Marla Feller, a UC Berkeley professor of molecular and cell biology and senior author of a paper that appeared this month in the journal Current Biology.

“Maybe not for visual circuits, but for non-vision behaviors. Not only the pupillary light reflex and circadian rhythms, but possibly explaining problems like light-induced migraines, or why light therapy works for depression.”

Parallel systems in developing retina

The cells, called intrinsically photosensitive retinal ganglion cells (ipRGCs), were discovered only 10 years ago, surprising those like Feller who had been studying the developing retina for nearly 20 years. She played a major role, along with her mentor, Carla Shatz of Stanford University, in showing that spontaneous electrical activity in the eye during development — so-called retinal waves — is critical for setting up the correct brain networks to process images later on.

Hence her interest in the ipRGCs that seemed to function in parallel with spontaneous retinal waves in the developing retina.

“We thought they (mouse pups and the human fetus) were blind at this point in development,” said Feller, the Paul Licht Distinguished Professor in Biological Sciences and a member of UC Berkeley’s Helen Wills Neuroscience Institute. “We thought that the ganglion cells were there in the developing eye, that they are connected to the brain, but that they were not really connected to much of the rest of the retina, at that point. Now, it turns out they are connected to each other, which was a surprising thing.”

UC Berkeley graduate student Franklin Caval-Holme combined two-photon calcium imaging, whole-cell electrical recording, pharmacology and anatomical techniques to show that the six types of ipRGCs in the newborn mouse retina link up electrically, via gap junctions, to form a retinal network that the researchers found not only detects light, but responds to the intensity of the light, which can vary nearly a billionfold.

This shows rgcs

An intrinsically photosensitive retinal ganglion cell (ipRGC) as it would appear if you looked at a mouse’s retina through the pupil.

The white arrows point to the many different types of cells with which it networks: other subtypes of ipRGCs (red, blue and green) and retinal cells that are not ipRGCs (red).

The white bar is 50 micrometers long, approximately the diameter of a human hair. The image is credited to Franklin Caval-Holme, UC Berkeley.

Gap junction circuits were critical for light sensitivity in some ipRGC subtypes, but not others, providing a potential avenue to determine which ipRGC subtypes provide the signal for specific non-visual behaviors that light evokes.

“Aversion to light, which pups develop very early, is intensity-dependent,” suggesting that these neural circuits could be involved in light-aversion behavior, Caval-Holme said.

“We don’t know which of these ipRGC subtypes in the neonatal retina actually contributes to the behavior, so it will be very interesting to see what role all these different subtypes have.”

The researchers also found evidence that the circuit tunes itself in a way that could adapt to the intensity of light, which probably has an important role in development, Feller said.

“In the past, people demonstrated that these light-sensitive cells are important for things like the development of the blood vessels in the retina and light entrainment of circadian rhythms, but those were kind of a light on/light off response, where you need some light or no light,” she said.

“This seems to argue that they are actually trying to code for many different intensities of light, encoding much more information than people had previously thought.”

Funding: The research was supported by the National Institutes of Health (NIH F31EY028022-03, RO1EY019498, RO1EY013528, P30EY003176).


The retina is a layer of photoreceptors cells and glial cells within the eye that captures incoming photons and transmits them along neuronal pathways as both electrical and chemical signals for the brain to perceive a visual picture. The retina is located in the posterior segment and forms the innermost boundary among the other major layers of the eye that include the vascular choroid and the fibrous sclera. Disease manifestations can occur in the retina at different stages of life, many of which severely compromise visual ability and consequently the quality of life.

Structure and Function

The following topics relating to the structure and function of the retina appear below:

  • Photoreceptor cells
  • Layers of the retina
  • Macula

Photoreceptor Cells

Photoreceptor cells include rods and cones and are uniquely located towards the posterior aspect of the retinal sublayers, further away from the pupil where light enters the eye. Rods are more sensitive in dim light (scotopic vision) and reside in the periphery of the retina.

Cones are more sensitive in daylight (photopic vision) and capture wavelengths of colored light. Cones localize in the center of the retina at the fovea. There are approximately 6 million cones and often more than 100 million rods within the retina.[1] 

There exist three types of cones including tritans, deutrans, and protans, named for detecting short, medium, and long wavelengths, respectively. In terms of sensing colored light, each type of cone cell can respectively characterize as detecting blue, green, and red wavelengths.

The overlap of detectable wavelength spectrums between the three types of cones results in the visible light spectrum perceived by humans. Rod cells contain rhodopsin, which is a light-sensitive pigment made of retinal that allows for the absorption of photons. Retinal is vitamin A aldehyde, making vitamin A an essential dietary component for the facilitation of the phototransduction pathway.

Vitamin A deficiency is a significant risk factor for blindness in young children and remains prominent in under-developed regions, including South Asia and sub-Saharan Africa.[2]

Layers of the Retina

The retina, more specifically, subdivides into ten distinct layers that are described in order from the innermost layers closer to the pupil to the layers further towards the posterior and periphery of the eyeball:

  • Inner Limiting Membrane – the innermost layer of the retina that forms a smooth boundary against the vitreous humor which fills the vitreous chamber of the eye. The peripheral boundary of this layer consists of Müller glial cells, which function to maintain retinal homeostasis by upholding retinal lamination and by supporting other cells.[3]
  • Retinal Nerve Fiber Layer – the layer composed of retinal ganglion cell axons mixed with astrocytes and the processes of the Muller cells. The inner limiting membrane serves as the basal lamina for the cells of the retinal nerve fiber layer.[4]
  • Ganglion Cell Layer – the layer of ganglion cell bodies that project their axons, eventually to form the optic nerve.
  • Inner Plexiform Layer – this layer is where the axons of bipolar cells synapse onto the ganglion cells. The dendrites of amacrine cells also synapse at this zone and function in modulating the electrical conduction between the bipolar cells and ganglion cells, preventing lateral potentiation.[5][6]
  • Inner Nuclear Layer – the layer composed of the cell bodies of bipolar cells, horizontal cells, and amacrine cells. Bipolar cells function as channels that transmit and encode various synaptic inputs from photoreceptor cells onto ganglion cells.[7] Horizontal cells provide feedback modulation onto rod and cone cells.[8]
  • Outer Plexiform Layer – the region where projections from photoreceptor cells synapse with the dendrites of the cells residing in the inner nuclear layer. 
  • Outer Nuclear Layer – the layer containing the cell bodies of both rods and cones. 
  • External Limiting Membrane – the region that is composed of gap-junctions between photoreceptor cells and Muller cells; it separates the cell bodies of the rods and cones from their inner segments and outer segments.
  • Photoreceptor Layer – the region consisting of the inner segments and outer segments of rods and cones. The outer photoreceptor segments consist of membrane-bound discs that contain the light-sensitive pigments such as rhodopsin that are necessary for phototransduction. The inner segments house the abundance of mitochondria needed to meet the high metabolic demands of the photoreceptor cells.[9]
  • Retinal Pigment Epithelium – the outermost retinal layer that spans a width of a single cell located between the neural retina and the Bruch membrane, adjacent to the highly-vascularized choroid layer. The retinal pigment epithelium (RPE) contributes to the blood-retinal barrier in conjunction with the endothelium of the retinal vessels and has many functions including ion and water transport and secretion of growth factors and cytokines.[10] The RPE cells intermingle with the outer segments of the rods and cones. This proximity allows for the recycling of all-trans-retinal back into 11-cis-retinal and its delivery back to the cones and rods to be used again for phototransduction.[11] RPE cells are crucial in the support and maintenance of both photoreceptor cells and the underlying capillary endothelium.

Macula

The macula, also called the macula lutea for its yellowish pigmented appearance, makes up the most sensitive area of the retina, offering the highest visual acuity. It is found temporally from the optic disc upon fundoscopic examination. Lutein and zeaxanthin are carotenoids that make up the macular pigments and produce the yellow coloring.

These macular pigments are known to have anti-inflammatory and blue-light filtering properties.[12] Dietary supplementation of lutein and zeaxanthin has been shown to increase pigment density and is associated with reduced risk of diabetic retinopathy in adults and retinopathy of prematurity in infants born pre-term.[13] In the center of the macula is an avascular depression called the fovea, which contains a high concentration of cones. 

The macula further subdivides into the following sequentially-smaller concentric zones that characteristically show decreasing rod density and fewer layers of cells covering the photoreceptor cells:

  • Perifovea
  • Parafovea
  • Fovea
  • Foveal avascular zone
  • Foveola
  • Umbo

Embryology

The retina arises from the diencephalon of the embryo as the optic vesicle during the first month and forms an invagination called the optic sulcus.[14] This process of invagination results in the formation of the neural layers and the pigmented layer of the retina. During this time, mesenchymal tissue will surround the optic vesicle, which will eventually develop into the uvea.[15] The neural retina originates from the inner layer, and the pigmented retina originates from the peripheral layer. Axons from the ganglion cells travel through the optic stalk that bridges the optic cup to the embryo and eventually form the optic nerve.[3] Ventrally, another invagination called the optic fissure engulfs a temporary blood vessel called the hyaloid artery which ultimately develops into the central retinal artery.

Blood Supply and Lymphatics

Blood vessels and the choroid vascularizes the retina. The choroid supplies the outer layers of the retina while branches of significant blood vessels supply the inner retinal layers. Descriptions of the individual vessels that contribute to the vascularization of the retina appear below.

Central Retinal Artery – the major vessel that supplies the inner layers of the retina; it travels inside of the optic nerve sheath and similarly penetrates the eye at the optic disc. The central retinal artery divides into superior and inferior arcades that will form the blood-retina barrier.[16] It originates as a major branch of the ophthalmic artery.

Central Retinal Vein – the main drainage pathway of the retina and travels alongside the central retinal artery within the sheath of the optic nerve.

Long Posterior Ciliary Arteries – these two vessels branch from the ophthalmic artery and pierce the sclera on the posterior of the eye near the entry zone of the optic nerve. The long posterior ciliary arteries supply the choroid in the medial and lateral horizontal planes and, eventually, the anterior structures of the eye.

Short Posterior Ciliary Arteries – these vessels arise as a few branches from the ophthalmic artery and subsequently branch into 10 to 20 smaller vessels that penetrate the posterior sclera in a ring around the optic nerve.  These branched vessels anastomose to form the circle of Zinn that encircles and supplies the area of the optic cup at the level of the choroid. Perpendicular terminal arterioles from the short posterior ciliary arteries also supply the Bruch membrane and the outer retina.[16]

Choroid – the second major layer, or tunic, of the eye that vascularizes the outer layers of the retina.[15] The Bruch membrane sits between the retinal pigment epithelial layer and the choriocapillaris, forming the basement membrane of the choroid. The choriocapillaris, also known as the capillary lamina of the choroid, is the thickest behind the fovea (10 micrometers) and thins out towards the periphery (7 micrometers).[15]

The retina does not contain lymphatic vessels.[17]


Source:
UC Berkeley
Media Contacts:
Robert Sanders – UC Berkeley
Image Source:
The image is credited to Franklin Caval-Holme, UC Berkeley.

Original Research: Open access
“Gap Junction Coupling Shapes the Encoding of Light in the Developing Retina”. Franklin Caval-Holme, Marla B. Feller.
Current Biology doi:10.1016/j.cub.2019.10.025.

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