Santiago Ram�n Y Cajal, the retina and the neuron theory

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‘A small block of nervous tissue left from several days, hardening in Müller fluid alone or mixed with osmic acid. Because the histologist was distracted, or because of a scientist’s curiosity, it was immersed in a bath of silver nitrate. One sections the block, dehydrates the sections, clears them, and examines them. Surprising sight! Against a perfectly translucent, yellow background, appear, thinly dispersed, the black filaments, either smooth and delicate or spiny and thick; the black cell bodies, triangular, stellate, fusiform. They might be drawings done with India ink on transparent Japanese vellum. One is taken aback; the eye is accustomed to the inextricable tangles seen in sections stained with carmine or hematoxylin, where the mind strains in prodigies of criticism and interpretation, always in doubt. Here everything is simple, clear without confusion. Nothing more to interpret.

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... Golgi and Santiago Ramon y Cajal led to the re-evaluation and abandonment of the reticular theory for the neuron theory (Piccolino M 1989). The former was introduced before the 1880's indicating of a collective nervous impulse based on a holistic response of the nervous system. ...
... It is those that will generate the various cell types that will migrate to either the developing outer nuclear layer (ONL) such as photoreceptors ( comprising or retinal ganglion cells (RGC). The basic scheme of histogenesis has been revealed by studies performed by Ramon y Cajal (Piccolino M 1988;Piccolino M 1989) (Figure 1.7). (Gouras et al. 1991)] Embryonic retinal progenitors can be categorised based on their responsiveness to growth factors and tendency to generate neurons or glia . ...
... Lower vertebrates display the capacity to generate new retinal neurons in response to injury (Hollyfield JG 1971;Reh TA 1998) of the glial population in the retina (non-neural cell population) (Piccolino M 1989), while the rest are astrocytic populations found in the nerve fibre layer adjacent to the RGC layer making unspecialised vascular contacts (Ogden 1978). Although the primary role of Müller glia was thought to be for retaining retinal architecture and orientation scaffolding as well as circuitry, a recent study shows that in mammals (Ogden 1983), upon injury these cells re-enter the cell cycle and perhaps play a role in photoreceptor degeneration (Wan et al. 2008), similarly to posthatch chick and lower vertebrate retina. ...
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The mammalian central neural retina (CNR) lacks the capability to regenerate, a phenomenon retained by lower vertebrates. However, retinal stem cells have been isolated from the ciliary epithelium of the mammalian retina. Chx10 is a paired-like homeobox transcription factor gene expressed in the presumptive neural retina of the invaginating optic vesicle. The Chx10 gene is expressed in the proliferating retinal progenitor cell population throughout retinal development hence is one of the earliest characterised RPC-specific markers. Mutations in the Chx10 homeobox gene cause reduced proliferation of retinal progenitor cells during development, leading to microphthalmia. Recently, it was showed that in the ocular retardation mouse model lacking Chx10 (Chx10orJ/orJ), dividing cells persist in the adult CNR, suggesting the existence of a dormant stem/progenitor population. The neurosphere-forming assay is a tool which has allowed scientists to study the behaviour of neural stem/progenitor cells in vitro. Here, I show that cells deriving from the CNR of the adult microphthalmic retina are proliferative and give rise to neurospheres in vitro, a characteristic of neural stem cells. However, these adult-derived CNR progenitors differ from those of the wildtype CE, leading to de-pigmented, larger and more numerous neurospheres expressing Müller glial cell markers. My results suggest that lack of Chx10 leads to maintenance of a dormant neural progenitor population in the adult CNR possible deriving from the abnormal appearance of GFAPpos Müller glia in late embryonic stages of the Chx10orJ/orJ retina. Furthermore, Chx10 is not required for in vitro proliferation of these progenitors. One of the cardinal features of stem cells is their differentiation potential and multipotency. My experiments illustrate that Chx10orJ/orJ CNR-derived neurospheres are able to differentiate in a similar fashion to wildtype CE-derived neurospheres. Furthermore, when neurospheres lacking Chx10 are placed in conditions that promote differentiation, they significantly up-regulate the expression of photoreceptor genes in comparison to wildtype. Hitherto, the developmental origin of CE-derived neurosphere-forming retinal stem cell is unclear. The ciliary body, where the CE is located in adult mammals, includes cells of mesodermal, neural crest and neural ectodermal origin. Here, data collected from lineage tracing analysis and in vivo BrdU-tagging experiments suggest that neurospheres are formed from BrdUpos cells observed in vivo, and that these cells originate from the embryonic anterior forebrain. The comparative analysis of the microphthalmic CNR retinal progenitors and CE-derived progenitors provides valuable information on cell properties relevant for potential cell-based replacement therapies, as well for retinal regeneration potential in mammals.
... The structure of the retina and main types of its cells are rather similar to each other in all vertebrates, which was verified in the classical studies of Ramon y Cajal [5]. From the anatomical aspect, the retina looks like a thin envelope. ...
... Thus, in the retina of vertebrates, a direct pathway for the signals caused by light consists of photoreceptors connected synaptically with bipolar cells that, in turn, are connected with ganglion cells. Each rod and each cone are connected with several bipolar cells, while each bipolar unit is connected with several ganglion cells [1,2,5,7,[26][27][28][29][30][31][32][33][34][35][36]. ...
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Examination of the functioning of the visual analyzer is an urgent task in modern neurophysiology. The peripheral receptor part of this analyzer, the retina, provides perception of light signals, their transformation into nerve impulses, and transfer of impulsation to the brain. Retinal rods responsible for perception of black-and-white images and cones responsible for color light perception are connected, via bipolar neurons, to ganglion retinal cells. Horizontal and amacrine cells are inhibitory neurons responsible for horizontal interaction within the retina. Processing of visual information in the retina is, to a significant extent, based on interaction of the receptive fields of its sensitive elements, the stimulation of which causes a response of the output neuron, the ganglion cell. This review considers modern concepts of functioning of the visual system of mammals at the retinal level and summarizes the data on cell elements of the retina, their connections, blood supply, and innervation, as well as on pathways for visual signal propagation in the retina.
... 6 In the human retina, there are not only Müller cells but also astroglia and microglia, which were all discovered there by Santiago Ramón y Cajal in 1892. 7 Müller cells are regarded as the main type of retinal glial cells, which within retinal neurons orginate from a single progenitor cell. 8 Actually, at fi rst stage, primary neurons that include cone cells, horizontal cells and ganglion cells are developed and secondly Müller cells and rod photoreceptors, bipolar cells and amacrine cells are generated from apical neuroepithelium adhering to pigment epithelium. ...
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This paper presents a review on retinal gliosis illustrated by series of three cases of patients (a 39-year-old man and a 35-year-old woman with massive retinal gliosis (MRG) and a 51-year-old man with truly focal nodular gliosis of retina) with intraocular tumor-like masses and loss of vision, who recently suffered from painful inflammation of eyeball and who classically had a history of remote ocular trauma, onset of blindness early in lifetime or gradual but progressive loss of sight. The diagnosis of this pathological entity is given for the lesions that are composed of GFAP strongly positive, elongated, fusiform cells consistent with fibrillary astrocytes. As illustrated in cases from our pathological practice, PAS gave positive patchy disseminated reaction in form of cellular densely purplish granules in minority of cells representing glycogen storing. This feature could be consistent with PAS-positive Müller cells that also constitute retinal gliosis as one of cellular components of normal retina that is induced to reactive proliferation. Thus, the paper presents histological background and differential diagnosis of the entity.
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Neural inhibition plays a key role in determining the specific computational tasks of different brain circuitries. This functional "braking" activity is provided by inhibitory interneurons that use different neurochemicals for signaling. One of these substances, somatostatin, is found in several neural networks, raising questions about the significance of its widespread occurrence and usage. Here, we address this issue by analyzing the somatostatinergic system in two regions of the central nervous system: the retina and the hippocampus. By comparing the available information on these structures, we identify common motifs in the action of somatostatin that may explain its involvement in such diverse circuitries. The emerging concept is that somatostatin-based signaling, through conserved molecular and cellular mechanisms, allows neural networks to operate correctly.
With the main objective being the description of biologically inspired computer vision, this chapter mixes results that come from psychophysics with results stemming from biology. It focuses on the processes carried out at the retinal stage and then introduces some pathways between retinal biology and physiology, which are useful for computer vision and which result from psychophysical experiments and computational modeling. The chapter provides a short description of the anatomy and physiology of the retina. It further summarizes different types of retinal models. The chapter presents a panorama of these models and discusses their performance and usefulness both to explain vision and to explain their use in computer vision. It also provides some examples of the utilization of models of vision in the context of digital color camera processing. The chapter concludes with a discussion on tone mapping and dynamic local tone mapping operators.
Advances in understanding the initial stages of the visual process have been made over the centuries. This heritage will be reviewed with respect to the passage of light through the eye, as well as its gross anatomy and microscopic structure. The links between image formation in the camera and the eye were integrated with the anatomy of the eye in the seventeenth century. They drew attention to the problem of accommodation and to corrections for errors of refraction. Investigations of the structure of the retina were to await the invention of achromatic microscopes in the early nineteenth century. An armory of devices for examining vision and the eye were to follow later in the century. These transformed the study of vision from an observational to an experimental discipline.
December 2006 marked 100 years since the Nobel Prize in Physiology or Medicine was awarded jointly to 2 pioneers in the cellular anatomy of the central nervous system (CNS), Camillo Golgi and Santiago Ramon y Cajal. Golgi developed the silver impregnation method for studying nerve cells, a technique that clearly showed entire cells with their arborizing dendrites and axons for the first time. Ramon y Cajal seized on the method for a series of groundbreaking studies that provided convincing support for what came to be known as the neuron theory, in opposition to the reigning model of the time, the reticular theory. The retina was one of Ramon y Cajal's favorite tissues for study. Although he was perplexed by the horizontal and amacrine cells, he was remarkably prescient in his analysis of retinal and CNS cellular anatomy. Few scientists have cast such a long shadow in their field, but Ramon y Cajal did not establish the neuron theory single-handedly, and the real tale is much more complicated.
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Previous studies have shown that dopamine, bicuculline, or d-amphetamine reduce the electrical and dye-coupling between the axon terminals of the horizontal cells of the turtle retina (see Piccolino et al., 1984). In the present study we observed similar effects following the application of veratridine. The actions of all these drugs were prevented by dopamine antagonists acting on D1 receptors such as flupenthixol and SCH 23390. However, in contrast to dopamine, the actions of d-amphetamine, bicuculline, and veratridine were attenuated or abolished by pharmacological agents (such as 6-OH-dopamine, alpha-methyl-p-tyrosine, or reserpine) known to reduce the release of dopamine from dopaminergic neurons. Moreover, the actions of veratridine and bicuculline were prevented by tetrodotoxin, indicating that one or more neurons in the dopamine pathway are spike-generating. We conclude that d-amphetamine, bicuculline, and veratridine reduce electrical coupling between the axon terminals of the turtle horizontal cells by promoting the release of endogenous dopamine from the dopaminergic amacrine cells previously identified (Witkovsky et al., 1984). Electron-microscopic observations revealed that 6-OH-dopamine selectively attacked this population of amacrine cells. No degenerating terminals were found adjacent to the horizontal cell axon terminals. On this basis, we postulate that dopamine reaches the horizontal cell by diffusion through the extracellular space.
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Vertebrate photoreceptors generate electrical signals across their cell membrane when they absorb light. Recent studies show, moreover, that the membrane potential of an individual photoreceptor may be also modified by illumination of its neighbors. Two types of lateral interactions have been described: a direct interaction mediated by electrical synapses between adjacent photoreceptors, and a recurrent interaction mediated by a feedback circuit involving horizontal cells. In the first mechanism, photoreceptors summate their responses over short retinal distances. In the feedback circuit photoreceptors may develop light responses of opposite polarity to those induced by direct illumination. In general, these ‘antagonistic’ responses are best elicited by large area retinal illumination. As a consequence of these photoreceptor interactions rather complex processing of visual information, in both spatial and chromatic domains, occurs at the first stage of the retinal network.
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Hubel & Wiesel proposed in 1962 a hierarchical structure for the cat visual system. A particular property, they argued, is established at one level, sharpened at successively higher levels, and generalized to a larger region of visual field. Their idea developed from studies of single units at the third through sixth levels (ganglion cells to complex cells in area 17). The studies reviewed here strongly support their concept as applied to the first through third levels (receptors to ganglion cells). In regard to simple and complex cortical cells, the hierarchical model has been strongly criticized (Stone et al 1979). However, if area 17 is anything like the retina, it probably contains many discrete cell types connected in specific ways. These probably do not form a single simple-to-complex hierarchy but many parallel hierarchies to further abstract and generalize the 'qualitative contexts' relayed there from the many types of retinal ganglion cells. Anatomical and physiological evidence grows that a single sublayer of area 17 does have many discrete types (Davis & Sterling 1979, Solnick et al 1983, Hamos et al 1983), and new 'contexts' apparently are created in the domains of orientation (Hubel & Wiesel 1962) and spatial frequencey (Movshon et al 1978). What is needed to identify the continuation of the retinal hierarchies into area 17 is more detailed knowledge of the cortical cell types and their circuitry (Gilbert 1983, this volume). Strong concepts have emerged to guide research on microcircuitry of the cat retina. It is now believed that cell types are discrete and number roughly 60. Each type is believed to have a particular transmitter, set of connections, and mosaic distribution. As knowledge of circuitry becomes very detailed, hypotheses regarding function emerge. These hypotheses are quite specific and testable; whether they are correct seems less important than that they can be read directly from the circuitry. Powerful technologies to extend our knowledge of circuitry in cat retina exist and are still developing. We may expect, in addition to the approaches already noted, to have monoclonal antibodies specific for particular cell types (Sterling & Lampson 1983). Further, since neural activity is strongly reflected in oxidative metabolism and this can be recognized at the electron microscope level (Wong-Riley et al 1978), it may be possible to determine directly by electron microscopy which pathways are active under particular conditions. Where concepts and methods are strong, one may expect progress to be rapid.
The photoreceptor cells are transducers which absorb incident photons and transmit a proportional signal to other cells. More complex retinal functions such as the discrimination of colors and the detection of contrast and movement are accomplished by networks of many cells. This chapter is a critical historical review of attempts to establish the spatial relationships of the structural, functional, and chemical units in the retina which correspond to such networks.
Reviews Das leitende element des nervensystems und seine topographischen beziehungen zu den zellen , by Stefan Apáthy (1897). This comprehensive monograph details the important results of research in neural histology carried on by Professor Apáthy in the years preceding 1896. It is to be followed by a second part 'as soon as his other scientific duties will allow.' It is a well-written work of 254 pages, and is embellished by ten elaborate plates composed of eighty-nine most interesting drawings, some of them in colors. The investigation was made chiefly upon the neural systems of the leech and earthworm and the mussel, snail and crayfish among invertebrates, and upon the vertebrate newt, frog, Lophius , rabbit and ox. The sections for the microscope were stained by several different methods, most valuable of which, he considers, were his own Gold-chloride-and-formic-acid and his Methylin-blue methods. Many pages of the work are devoted to the elaborate details of his various staining processes, and form an important portion of the monograph. Perhaps the thesis of the work most interesting to psychologists involves the division of labor between the ganglion-cell and the nerve-cell. Altogether this work is a report of elaborate and most careful and patient research in a direction much in need of such thoroughly scientific treatment as Professor Apáthy has given the world in this monograph. It is by such labors that we shall sooner or later learn, if at all, the physiological processes concomitant to psychical action. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Contient: "Expériences sur les fonctions du système nerveux, par le professeur Rolando", p. 273-302
Retinas of ordinary and black moor varieties of goldfish (Carassius auratus) were prepared by the Golgi method, mounted flat or sectioned vertically, and studied in the light microscope. Three types of horizontal cells whose dendrites contact only cones, and one type whose dendrites contact only rods, were observed. The cone horizontal cells (Cajal's "external horizontal cells") all have slender axons which descend gradually to the inner nuclear layer and terminate there in long, fusiform expansions (Cajal's "internal horizontal cells"). The thin and thick portions of the axons, as well as the perikarya of the horizontal cells, bear small numbers of straight, horizontally-directed, knobby filamentous appendages which may be sites of synaptic contact. The cone horizontal cell axons in goldfish, unlike those in higher vertebrates, do not terminate in contact with synaptic endings of photoreceptor cells, but in proximity to cells and processes deep in the inner nuclear layer. Axons have not yet been demonstrated on rod horizontal cells in goldfish.
1. Intracellular recordings have been made of the responses to light of single cones in the retina of the turtle. The shape of the hyperpolarizing response to a flash depends on the pattern of retinal illumination as well as the stimulus intensity.2. Although changes in the stimulus pattern can produce changes in the effective stimulus intensity, the responses to certain patterns cannot be matched by any adjustment of stimulus intensity.3. The initial portion of responses to large or small stimulating spots is proportional to light intensity; this allows comparison of responses when the amount of light on a cone is kept constant but the light on surrounding cones is changed. For equal light intensity on the cone, the response to a spot 2 or 4 mu in radius is smaller than that to a spot 70 mu in radius.4. Responses to spots 70 and 600 mu in radius coincide over their rising phases and peaks without any adjustment of stimulus intensity. The responses to the larger spot, however, contain a delayed depolarization not present with the smaller spot.5. During steady illumination of a cone with a small central spot, the response to transient illumination superimposed on the same area is greatly reduced. Illumination of cones in the near surround, however, produces a hyperpolarizing response, and illumination of cones in the more distant surround generates a delayed depolarization.6. The results described above suggested that synaptic signals might impinge on cones. This possibility was tested by electrically polarizing one retinal cell while recording from another.7. Currents passed through a cone within 40 mu of another cone can change the membrane potential of the latter. Not all cones within this distance show the interaction, however, and it has never been detected at distances greater than 50 mu.8. Hyperpolarization of a horizontal cell with applied current can produce a depolarization of a cone in the vicinity. During this depolarization, the response of the cone to a flash is reduced in size and altered in shape.9. It is concluded that the response of a cone to light may be modified by synaptic mechanisms which are activated by peripheral illumination.
The axon terminals of the H1 horizontal cells of the turtle retina are electrically coupled by extensive gap junctions. Dopamine (10 nM to 10 microM) induces a narrowing of the receptive field profile of the H1 horizontal cell axon terminals, increases the coupling resistance between them, and decreases the diffusion of the dye Lucifer Yellow in the network formed by the coupled axon terminals. These actions of dopamine involve the activation of D1 receptors located on the membrane of the H1 horizontal cell axon terminals proper. Increases of the intracellular cyclic AMP concentration induced by either stimulating the adenylate cyclase activity with forskolin or inhibiting the phosphodiesterase activity with isobutylmethylxanthine, theophylline, aminophylline, or compound RO 20-1724 elicit effects similar to those of dopamine on the receptive field profile of the H1 horizontal cell axon terminals, on their coupling resistance, and on the diffusion of Lucifer Yellow in the axon terminal network. It is concluded that dopamine decreases the permeability of the gap junctions between the axon terminals of the H1 horizontal cells of the turtle retina and that this action probably involves cyclic AMP as a second messenger.
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