The ascending monoamine pathways in the rat brain are demonstrated by the pile up of fluorescent material occurring in the axons after various types of lesions. The anatomy of the pathways is outlined in drawings of frontal sections of the brain and the origin and termination of several pathways is determined by studying the anterograde and retrograde degeneration occurring after well localised lesions. It is possible to separate the ascending NA pathways into a dorsal and a ventral bundle of axons. The dorsal bundle innervates the cortex and the hippocampus and the ventral bundle supplies NA nerve terminals to the medulla, the pons, the mesencephalon and the diencephalon. The dorsal bundle is found to originate in the locus coeruleus. Lesions of this nucleus abolish the nerve terminals in all cortical areas and in several other areas of the brain indicating a unique role for the locus coeruleus in influencing the activity of the entire brain. The 5-HT pathways have a distribution similar to the ventral NA pathyway. The course of the nigro-striatal and the meso-limbic DA pathways is presented in detail.

Stereotaxic mapping of the monoamine pathways in the rat brain.

Located between vessels of the choriocapillaris and light-sensitive outer segments of the photoreceptors, the retinal pigment epithelium (RPE) closely interacts with photoreceptors in the maintenance of visual function. Increasing knowledge of the multiple functions performed by the RPE improved the understanding of many diseases leading to blindness. This review summarizes the current knowledge of RPE functions and describes how failure of these functions causes loss of visual function. Mutations in genes that are expressed in the RPE can lead to photoreceptor degeneration. On the other hand, mutations in genes expressed in photoreceptors can lead to degenerations of the RPE. Thus both tissues can be regarded as a functional unit where both interacting partners depend on each other.

The Retinal Pigment Epithelium in Visual Function

Degeneration and regeneration of the nervous system

We quantified the spatial distribution of presumed ganglion cells and displaced amacrine cells in unstained whole mounts of six young normal human retinas whose photoreceptor distributions had previously been characterized. Cells with large somata compared to their nuclei were considered ganglion cells; cells with small somata relative to their nuclei were considered displaced amacrine cells. Within the central area, ganglion cell densities reach 32,000-38,000 cells/mm2 in a horizontally oriented elliptical ring 0.4-2.0 mm from the foveal center. In peripheral retina, densities in nasal retina exceed those at corresponding eccentricities in temporal retina by more than 300%; superior exceeds inferior by 60%. Displaced amacrine cells represented 3% of the total cells in central retina and nearly 80% in the far periphery. A twofold range in the total number of ganglion cells (0.7 to 1.5 million) was largely explained by a similar range in ganglion cell density in different eyes. Cone and ganglion cell number were not correlated, and the overall cone:ganglion cell ratio ranged from 2.9 to 7.5 in different eyes. Peripheral cones and ganglion cells have different topographies, thus suggesting meridianal differences in convergence onto individual ganglion cells. Low convergence of foveal cones onto individual ganglion cells is an important mechanism for preserving high resolution at later stages of neural processing. Our improved estimates for the density of central ganglion cells allowed us to ask whether there are enough ganglion cells for each cone at the foveal center to have a direct line to the brain. Our calculations indicate that 1) there are so many ganglion cells relative to cones that a ratio of only one ganglion cell per foveal cone would require fibers of Henle radiating toward rather than away from the foveal center; and 2) like the macaque, the human retina may have enough ganglion cells to transmit the information afforded by closely spaced foveal cones to both ON- and OFF-channels. Comparison of ganglion cell topography with the visual field representation in V1 reveals similarities consistent with the idea that cortical magnification is proportional to ganglion cell density throughout the visual field.

Topography of ganglion cells in human retina.

Muller glial cells span the entire thickness of the tissue, and ensheath all retinal neurons, in vertebrate retinae of all species. This morphological relationship is reflected by a multitude of functional interactions between neurons and Muller cells, including a 'metabolic symbiosis' and the processing of visual information. Muller cells are also responsible for the maintenance of the homeostasis of the retinal extracellular milieu (ions, water, neurotransmitter molecules, and pH). In vascularized retinae, Muller cells may also be involved in the control of angiogenesis, and the regulation of retinal blood flow. Virtually every disease of the retina is associated with a reactive Muller cell gliosis which, on the one hand, supports the survival of retinal neurons but, on the other hand, may accelerate the progress of neuronal degeneration: Muller cells protect neurons via a release of neurotrophic factors, the uptake and degradation of the excitotoxin, glutamate, and the secretion of the antioxidant, glutathione. However, gliotic Muller cells display a dysregulation of various neuron-supportive functions. This contributes to a disturbance of retinal glutamate metabolism and ion homeostasis, and causes the development of retinal edema and neuronal cell death. Moreover, there are diseases evoking a primary Muller cell insufficiency, such as hepatic retinopathy and certain forms of glaucoma. Any impairment of supportive functions of Muller cells, primary or secondary, must cause and/or aggravate a dysfunction and loss of neurons, by increasing the susceptibility of neurons to stressful stimuli in the diseased retina. On the contrary, Muller cells may be used in the future for novel therapeutic strategies to protect neurons against apoptosis (somatic gene therapy), or to differentiate retinal neurons from Muller/stem cells. Meanwhile, a proper understanding of the gliotic responses of Muller cells in the diseased retina, and of their protective vs. detrimental effects, is essential for the development of efficient therapeutic strategies that use and stimulate the neuron-supportive/protective-and prevent the destructive-mechanisms of gliosis.

https://www.springer.com/cda/content/document/productFlyer/productFlyer_978-1-4419-1671-6.pdf?SGWID=0-0-1297-173938007-0

Müller Cells in the Healthy and Diseased Retina

Interplexiform cells are a class of retinal neuron that extends processes widely in both plexiform layers. In goldfish they contain dopamine and readily take up certain biogenic amines. Two of these amines, 6-hydroxyopamine (6-HDA) and 5, 6-dihydroxytryptamine (5,6-DHT), induce fine structural changes in the neurons that accumulate them, allowing the processes of the cells to be recognized by electron microscopy. Typically, the synaptic vesicles within the processes show electron-dense cores. The terminal cytoplasm may also show increased density, as may the cellular and cytoplasmic membranes, presumably an indication of degenerative changes induced by the drugs. 5, 6-DHT gives more readily observable changes than 6-HDA but labels both dopaminergic and indoleamine-accumulating neurons. The terminals of the indoleamine-accumulating terminals were therefore removed by intraocular injections of 5, 7-dihydroxytryptamine (5, 7-DHT) prior to the labelling with 5, 6-DHT. This procedure allowed an analysis of the dopaminergic terminals without interference by the terminals of the indoleamine-accumulating cells. The dopaminergic neurons were found to make synapses of the conventional type. In the outer plexiform layer they contacted both external horizontal cells and bipolar cell dendrites, but not hotoreceptor terminals or intermediate (rod) horizontal cells. No synapses onto the dopaminergic processes were found in the outer plexiform layer despite an extensive search. In the inner plexiform layer the dopaminergic processes were observed to be both pre- and postsynaptic to amacrine cells and their processes. No synaptic contacts between dopaminergic processes and bipolar cell terminals or ganglion cell dendrites were seen. We conclude that the dopaminergic interplexiform cells provide a centri­fugal pathway for information flow in the retina from inner to outer plexiform layer.

The interplexiform cell system. I. Synapses of the dopaminergic neurons of the goldfish retina.

Fluorescence microscopy has revealed a new type of amine-containing retinal neuron, the interplexiform cell, that extends processes in both plexiform layers. After intravitreal injection of 5,6-dihydroxytryptamine in goldfish and Cebus monkey, the processes of these cells can be identified by electron microscopy. In goldfish, the processes are pre- and postsynaptic to amacrine cells in the inner plexiform layer and presynaptic to bipolar and horizontal cells in the outer plexiform layer. Interplexiform cells thus provide an intraretinal centrifugal pathway from inner to outer plexiform layers.

https://science.sciencemag.org/content/sci/188/4185/270.full.pdf

Synaptic organization of the amine-containing interplexiform cells of the goldfish and Cebus monkey retinas

Autoradiography of some suspected neurotransmitter substances: GABA glycine, glutamic acid, histamine, dopamine, and pl-dopa

Fluorophores induced from noradrenaline and dopamine in tissue sections by treatment with formaldehyde can be separated by their different behavior upon HCl treatment. The noradrenaline fluorophore converts to a fully aromatic isoquinoline while the dopamine fluorophore remains in the form of a nonquinoidal dihydroisoquinoline. The two fluorophores have readly distinguishable excitation spectra. The procedure has been tested both in model systems and in tissue sections. The microspectrofluorometer used is described.

Berndt Ehinger

Papers

The interplexiform cell system. I. Synapses of the dopaminergic neurons of the goldfish retina.

Synaptic organization of the amine-containing interplexiform cells of the goldfish and Cebus monkey retinas

Autoradiography of some suspected neurotransmitter substances: GABA glycine, glutamic acid, histamine, dopamine, and pl-dopa

A method for differentiating dopamine from noradrenaline in tissue sections by microspectrofluorometry

Neurotransmitter systems in the retina.