Elsevier

Brain Research Bulletin

Volume 70, Issues 4–6, 16 October 2006, Pages 391-405
Brain Research Bulletin

Neuron theory, the cornerstone of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramón y Cajal

https://doi.org/10.1016/j.brainresbull.2006.07.010Get rights and content

Abstract

Exactly 100 years ago, the Nobel Prize for Physiology and Medicine was awarded to Santiago Ramón y Cajal, “in recognition of his meritorious work on the structure of the nervous system”. Cajal's great contribution to the history of science is undoubtedly the postulate of neuron theory. The present work makes a historical analysis of the circumstances in which Cajal formulated his theory, considering the authors and works that influenced his postulate, the difficulties he encountered for its dissemination, and the way it finally became established. At the time when Cajal began his neurohistological studies, in 1887, Gerlach's reticular theory (a diffuse protoplasmic network of the grey matter of the nerve centres), also defended by Golgi, prevailed among the scientific community. In the first issue of the Revista Trimestral de Histología Normal y Patológica (May, 1888), Cajal presented the definitive evidence underpinning neuron theory, thanks to staining of the axon of the small, star-shaped cells of the molecular layer of the cerebellum of birds, whose collaterals end up surrounding the Purkinje cell bodies, in the form of baskets or nests. He thus demonstrated once and for all that the relationship between nerve cells was not one of continuity, but rather of contiguity. Neuron theory is one of the principal scientific conquests of the 20th century, and which has withstood, with scarcely any modifications, the passage of more than a 100 years, being reaffirmed by new technologies, as the electron microscopy. Today, no neuroscientific discipline could be understood without recourse to the concept of neuronal individuality and nervous transmission at a synaptic level, as basic units of the nervous system.

Introduction

The neuron doctrine constitutes the cornerstone on which, throughout the 20th century, all the neuroscientific disciplines were constructed. This year sees the centenary of the award of the Nobel Prize for Physiology and Medicine to Santiago Ramón y Cajal (1852–1934), the great ideologue and driving force behind this theory, for his meritorious work on the structure of the nervous system. One hundred years later, the majority of Cajal's postulates, laid out in his lecture to the Swedish Academy, continue to be of remarkable scientific currency, and have made Cajal the most cited classical scientist in history. It is in recognition and honour of this notable achievement that we examine in this work the circumstances in which the neuron doctrine came into being.

Neuron theory should be considered, from the historical perspective, as the final and definitive link in the development of cell theory, the doctrine that consolidated itself in the second half of the 19th century as a result of extensive progress in the anatomical disciplines, the coming of age of physiological knowledge, the definitive adoption of proper experimental methods, improvements in optical technology and advances in micrographic techniques. The first cell theory began to emerge in the 1830s, thanks to the work of researchers such as Samuel Thomas von Sömmerring (1755–1830), Karl Asmund Rudolphi (1771–1832), Johann Evangelista Purkinje (1787–1869), Ernst Heinrich Weber (1795–1878), Johannes Peter Müller (1801–1858), Friedrich Gustav Jackob Henle (1809–1885) or Gabriel Gustav Valentin (1810–1863), though it was the contributions of Matthias Jacob Schleiden (1804–1881) and of Theodor Schwann (1810–1882) that made possible the definitive formulation of cell theory [2]. Schwann produced one of the first descriptions of cell structure (Zellentheorie) in animal tissue (cytoblasteme, cell membrane, cell nucleus and nucleoli), in which he considered the cell as a structure made up of several superimposed layers. Schwann concludes his work with the proposal of a cell theory (Theorie der Zellen) focusing not such much on anatomical as on physiological aspects: “In general we should attribute autonomous life to cells” [61].

Rudolph Albert von Kölliker (1817–1905), in his Handbuch der Gewebelehre des Menschen, first published in 1852 [45], brought together and gave substance to all the disperse knowledge that could contribute to cell theory. For Kölliker, the cell would be made up of a container vesicle (cell membrane) and a content composed of a liquid surrounding different particles and a special round body (cell nucleus), which contained in turn, another liquid and another smaller corpuscle (nucleus corpuscle or nucleolus). Eleven years later, in the 4th German edition of his Handbuch, von Kölliker stated that cells “should be conceived as the essential formal units of the body”. However, and with no disrespect to all the other authors mentioned, it is fair to acknowledge Rudolf Ludwig Carl Virchow (1821–1902) as the great ideologue of the cellular theory. A disciple of Müller and Professor at Würzburg and Berlin, in 1855 he pronounced his famous sentence: “omnis cellula e cellula” [68], that is, cells can only multiply from themselves. For Virchow, life is essentially cellular activity, so that the life of organisms is the sum of the life of each of its cells.

The enormous technical advances in the field of cytohistology during the second half of the 19th century provided scientists with more and more precise knowledge about the true structure of cells. It suffices to mention, by way of illustration, the comprehensive progress in the construction of microscopes (Leitz), the development of immersion lenses in 1850 (Amici), the introduction of the microscope condenser system in 1873 (Zeiss and Abbe) and the apochromatic lens in 1887 (Abbe), the introduction and refinement of the microtome in 1886 (Minot), techniques of paraffin embedding in 1869 (Klebs) and celloidin embedding in 1879 (Duval), techniques for fixing sections in chromic acid in 1850 (Corti), or in chromic-acetic mixtures in 1854 (Remak), the new colouring methods, such as Gerlach's carmine (1847), Schultze's osmic acid (1865), Perkin and Ehrlich's aniline derivatives (1854–1870), and Böhmer's hematoxylin (1865), von Recklinghausen's metallic impregnations (1863) and the subsequent discovery of silver bichromate by Golgi (1883) or silver nitrate by Cajal (1903), the microphotographic methods developed by Gerlach (1863) and Koch (1877), and so on. Thus, cell theory became definitively consolidated in the 1890s, precisely the same decade that saw the birth of the neuron doctrine, thanks largely to the work of Cajal.

In the words of the great science historian Pedro Laín Entralgo (1908-2001), “the work of Cajal thus constitutes the definitive vindication of cell theory, making Schleiden, Schwann, Virchow and Cajal the four principal figures in the history of the theory” [48]. A similar view was expressed by one of Cajal's disciples, the Uruguayan Clemente Estable (1894–1976), for whom his mentor was “the final illustrious architect of cell theory, the most transcendent of all the biological theories” [29]. In the present work we undertake a historical analysis of the circumstances in which Cajal formulated the neuron doctrine, considering the authors and works that influenced his postulate, the difficulties involved in its dissemination within science, and how it finally became established. Table 1 shows some of the major milestones in the development of neuron theory.

Section snippets

The pre-Cajalian period: first approaches to knowledge of the microscopic anatomy of the nervous system

Although some authors, such as Antoni van Leeuwenhoek (1632–1723), had already, in the early 18th century, carried out some microscopic observations (Fig. 1A), the first descriptions of nerve cells are attributed, almost simultaneously, in the period 1833–1837, to Christian Gottfried Ehrenberg (1795–1876), who analyzed the nervous system of the leech [28], and to Purkinje, Professor at the Universities of Breslau and Prague, who described, in the mammalian cerebellum, some large cells (Fig. 1C)

The formulation of the “neuron doctrine” (1888–1889)

In early January of 1884, Cajal (Fig. 4), having won the corresponding competitive exam, moved to Valencia to take up his post as Professor of Anatomy at the city's University. His time in Valencia (1884–1887) coincided with a period of great development of medical scientific activity there [49]. It is while Cajal was in Valencia that he first came into contact with the intimate texture of the nervous system, “that masterwork of life” [21]. His future success in this field would be due, as he

The culmination of neuron theory: introduction to the concept of synapse

The mid-19th century also saw the emergence of arguments on the way neurons enter into contact with one another or with other structures. Kühne, using histological methods of fixation and staining, described, in the 1870s, the way the nerve endings terminate on a formation of the muscular membrane (subsequently the motor end-plate), labelling the whole structure “the neuromuscular junction”. For Kühne, this neuromuscular junction constituted, from the physiological perspective, a form of

Epilogue: the historical relevance of neuron theory

Cajal's great achievements in defence of neuron theory throughout 45 years of work are compiled in the so-called “scientific testament of Cajal”, in a work first published in 1933 in the journal Archivos de Neurobiología, entitled Neuronismo o reticularismo. Las pruebas objetivas de la unidad anatómica de las células nerviosas [22], and also published, posthumously (1935), in German, with the title Neuronenlehre, in the Handbuch der Neurologie, by Oswald Bumke (1877–1950) and Otfrid Foerster

References (70)

  • M.R. Bennett

    The early history of the synapse: from Plato to Sherrington

    Brain Res. Bull.

    (1999)
  • K. Akert et al.

    Cofounder of the neuron doctrine (1848–1931)

    Brain Pathol.

    (1993)
  • A. Albarracín

    La teoría celular. Historia de un paradigma

    (1983)
  • S.V. Apathy

    Das Leitende Element der Nervensystems und seine topographischen Beziehungen zu den Zellen

    Mitth. Zool. Stat. Neapel.

    (1897)
  • A. Bethe

    Allgemeine Anatomie und Physiologie des Nervensystems

    (1903)
  • S.R. Cajal

    Estructura de los centros nerviosos de las aves

    Rev. Trim. Histol. Norm. Patol.

    (1888)
  • S.R. Cajal

    Sobre las fibras nerviosas de la capa molecular del cerebelo

    Rev. Trim. Histol. Norm. Patol.

    (1888)
  • S.R. Cajal

    Conexión general de los elementos nerviosos

    Med. Práct.

    (1889)
  • S.R. Cajal

    Sur le morphologie et les conexions des éléments de la retine des oiseaux

    Anat. Anzeiger.

    (1889)
  • S.R. Cajal

    Sur l’origene et la direction des prolongations nerveuses de la couche moléculaire du cervelet

    Int. Monatschr. Anat. Physiol.

    (1889)
  • S.R. Cajal

    El nuevo concepto de la histología de los centros nerviosos

    Rev. Cienc. Med.

    (1892)
  • S.R. Cajal

    Les Nouvelles ideés sur la structure du système nerveux chez l‘Homme et chez les vertebrates

    (1894)
  • S.R. Cajal

    The Croonian lecture: La fine structure des centres nerveux

    Proc. R. Soc. Lond.

    (1894)
  • S.R. Cajal

    Consideraciones críticas sobre la teoría de Bethe, acerca de la estructura y conexiones de las células nerviosas

    Trab. Lab. Invest. Biol.

    (1903)
  • S.R. Cajal

    Das Neurofibrillennetz der Retina

    Int. Monatschr. Anat. Physiol.

    (1904)
  • S.R. Cajal

    Textura del Sistema Nervioso del Hombre y de los Vertebrados

    (1904)
  • S.R. Cajal

    Génesis de las fibras nerviosas del embrión y observaciones contrarias a la teoría catenaria

    Trab. Lab. Invest. Biol.

    (1906)
  • S.R. Cajal, Nobel Lecture. The Structure and Connexions of Neurons. December 12, 1906. URL:...
  • S.R. Cajal

    Los fenómenos precoces de la regeneración neuronal en el cerebelo

    Trab. Lab. Invest. Biol.

    (1911)
  • S.R. Cajal

    Estudios sobre la degeneración y regeneración del sistema nervioso, vol. 1. Degeneración y regeneración de los nervios

    (1913)
  • S.R. Cajal

    Recuerdos de mi vida

    Historia de mi labor científica

    (1923)
  • S.R. Cajal

    ¿Neuronismo o reticularismo? Las pruebas objetivas de unidad anatómica de las células nerviosas

    Arch. Neurobiol.

    (1933)
  • S.R. Cajal

    ¿Neuronismo o reticularismo?

    (1952)
  • E. Clarke et al.

    The Human Brain and Spinal Cord. A Historical Study by Writting from Antiquity to the Twentieth Century

    (1968)
  • O. Deiters

    Untersuchungen über Gehirn und Rückenmarke des Menschen und der Säugethiere

    (1865)
  • E.D.P. De Robertis et al.

    Some features of the submicroscopic morphology of the synapses in frog and earthworm

    J. Biophys. Biochem. Cytol.

    (1955)
  • A.S. Dogiel

    Uber die nervösen Elemente in der Retina des Menschen

    Arch. Mikrosk. Anat.

    (1891)
  • C.G. Ehrenberg

    Beobachtungeiner auffallenden bisher unerkannten Strukfurdes Seelenorgans bei Menschen und Thieren

    (1836)
  • C. Estable

    Don Santiago Ramón y Cajal

    Bol. Centro Coop. Cient. UNESCO

    (1952)
  • S. Finger

    Origins of Neuroscience. A History of Explorations into Brain Function

    (1994)
  • H. Fodstad

    The neuron theory

    Stereotact. Funct. Neurosurg.

    (2001)
  • A.H. Forel

    Einige hirnanatomische Betrachtungen und Ergebnisse

    Arch. Psychiatr. Nervenkrank.

    (1887)
  • A.H. Forel

    Ueber das Verhältniss der experimentellen Atrophie und Degenerationsmethode zur Anatomie und Histologie des Centralnervensystems

    (1891)
  • A.H. Forel

    Der Hypnotismus; seine psycho-physiologische, medicinische, Strafechtliche Bedeutung

    (1891)
  • M. Foster

    A Textbook of Phisiology. Part three: The Central Nervous System

    (1897)
  • Cited by (106)

    • Gene–environment interactions underlying the etiology of neural tube defects

      2023, Current Topics in Developmental Biology
      Citation Excerpt :

      They confirmed that BaP-induced NTDs were associated with hypermethylation of specific CpG sites within both the promoter and body region of Pax3 (Lin et al., 2019). Ramon y Cajal established the cornerstones of modern neuroscience by providing the morphological evidence of free termination at the extremities of neuronal cells, late in the 19th century, when methodologies for neuro-histological studies were emerging for the first time (López-Muñoz, Boya, & Alamo, 2006). No other organs in the human body are as intricate and with such a high level of cellular diversity, connectivity, and morphology as the brain and the spinal cord.

    • Searching for a paradigm shift in the research on the epilepsies and associated neuropsychiatric comorbidities. From ancient historical knowledge to the challenge of contemporary systems complexity and emergent functions

      2021, Epilepsy and Behavior
      Citation Excerpt :

      Moreover, most of this happened well before any definition of what is known today as Neuroscience would appear. In fact, the latter definition was born after the works of the famous Spaniard neuroanatomist and histologist Santiago Ramon y Cajal, with the conception of his neuronal theory, in opposition to the continuous reticular theory of Golgi [47,48]. Obviously, that with recent developments in basic science and clinical settings [49], both in the fields of microscopy, histology, cell and molecular biology, as well as spectacular imaging capturing and processing, allied to computational and network analysis, the precision to define structural and functional neuroanatomical territories, got exponential growth.

    • Molecular basis of diseases of the nervous system

      2020, Essential Concepts in Molecular Pathology
    • Synaptogenesis in the adult CNS-olfactory system

      2020, Synapse Development and Maturation: Comprehensive Developmental Neuroscience
    View all citing articles on Scopus
    View full text