Some Aspects of the History of the Law of Dynamic Polarization of the Neuron. From William James to Sherrington,from Cajal and Van Gehuchten to Golgi

William James was the first to suggest that propagation of impulses in the nervous system proceeds in one direction, from sensory to motor neurons, but not viceversa. His law of forward direction preceded the formulation of the law of dynamic polarization of van Gehuchten and Cajal, which assumed that nerve impulses are conducted cellulipetally along dendrites and cellulifugally along axons, based on different anatomo-functional properties of these neuronal components. Golgi did not accept the law of dynamic polarization because he believed that dendrites are involved in the nutrition of the neuron rather than in impulse propagation, and that impulses can travel in any direction in the axonal components of the diffuse nerve network. Sherrington in turn experimentally demonstrated that intraneuronic conduction is reversible, whereas, in accord with James's law, propagation of impulses along neuronal chains is irreversible, due to the valve-like action of synapses. The story of the law of dynamic polarization shows that neither Golgi nor Cajal paid much heed to Sherrington's findings and to neurophysiological studies in general, probably because they felt that histology alone could provide the key for understanding the general functioning of the nervous system. It is argued here that this attitude was detrimental to the progress of the neurosciences, because a multidisciplinary approach based on different techniques is inevitably called for in order to develop a plausible theory of the nervous system.     

The impossible interview with the man of the hidden biological structures. Interview by Paolo Mazzarello

This paper presents an "impossible interview" to Professor Camillo Golgi, placed in time in December 1906. The Italian Professor Golgi from Pavia has been awarded the Nobel Prize for Physiology or Medicine ex aequo with the Spanish anatomist Santiago Ramón y Cajal. Both scientists have obtained the award for their work on the anatomy of the nervous system. However, they have opposite views on the mechanisms underlying nervous functions. Golgi believes that the axons stained by his "black reaction" form a continuous anatomical or functional network along which nervous impulses propagate. Ramón y Cajal is the paladin of the neuron theory, a hypothesis questioned by Golgi in his Nobel lecture of Tuesday, December 11. After the ceremony, an independent journalist has interviewed Professor Golgi in the Grand Hotel in Stockholm. Excerpts about his education, his main scientific discoveries, and his personal life are here given (reconstructing the "impossible interview" on the basis of Golgi's original writings).     

The impossible interview with the man of the neuron doctrine. Interview by Edward G Jones

This paper follows the form of that by Mazzarello that precedes it (Mazzarello, 2006) and presents an imaginary interview with Santiago Ramón y Cajal in December 1906. A few days earlier Cajal had been awarded the Nobel Prize for Physiology or Medicine, an award that he shared equally with Professor Camillo Golgi. Golgi had been recognized for his work as a pioneer into investigations of the nervous system, primarily on account of his discovery of the "black reaction" of silver chromate impregnation of whole nerve cells and their processes. Cajal had been recognized for his implementation of that method and for laying with it the foundations of what was to become modern neuroanatomical science. Paradoxically, the two awardees had been led by their researches to diametrically opposed views of the organization of the nervous system. Golgi believed in a continuous network of axons that formed the basis of all the integrative properties of the nervous system, while Cajal had provided the information that led to the formulation of the neuron doctrine that saw the nervous system as being made up of chains of discontinuous cells joined by polarized functional contacts that we now call synapses. The paper takes the form of an interview with Professor Cajal in the Grand Hotel Stockholm. His responses to questions posed by the imaginary interviewer are all taken from Cajal's own writings.     

Colgi, Cajal and the Neuron Doctrine

Camillo Golgi and Santiago Ramon y Cajal shared the Nobel Prize in 1906 for their work on the histology of the nerve cell, but both held diametrically opposed views about the Neuron Doctrine which emphasizes the structural, functional and developmental singularity of the nerve cell. Golgi's reticularist views remained entrenched and his work on the nervous system did not venture greatly into new territories after its original flowering, which had greater impact than is now commonly credited. Cajal, by contrast, by the time he was awarded the Nobel Prize, was already breaking new ground with a new staining technique in the field of peripheral nerve regeneration, seeing the reconstruction of a severed nerve by sprouting from the proximal stump as another manifestation of the Neuron Doctrine. Paradoxically, identical studies were going on simultaneously in Golgi's laboratory in the hands of Aldo Perroncito, but the findings did not seem to influence Golgi's thinking on the Neuron Doctrine.     

Golgi,Cajal and the Neuron Doctrine

Camillo Golgi and Santiago Ramón y Cajal shared the Nobel Prize in 1906 for their work on the histology of the nerve cell, but both held diametrically opposed views about the Neuron Doctrine which emphasizes the structural, functional and developmental singularity of the nerve cell. Golgi's reticularist views remained entrenched and his work on the nervous system did not venture greatly into new territories after its original flowering, which had greater impact than is now commonly credited. Cajal, by contrast, by the time he was awarded the Nobel Prize, was already breaking new ground with a new staining technique in the field of peripheral nerve regeneration, seeing the reconstruction of a severed nerve by sprouting from the proximal stump as another manifestation of the Neuron Doctrine. Paradoxically, identical studies were going on simultaneously in Golgi's laboratory in the hands of Aldo Perroncito, but the findings did not seem to influence Golgi's thinking on the Neuron Doctrine.     

The Perineuronal Net: A Weapon for a Challenge

Theories and data do not always fit and sometimes are sources of conflicts among scientists. This is the case of a morphological structure, the perineuronal net, which was denied on the basis of an ideological conflict between two giants of neurosciences: Camillo Golgi and Santiago Ramón y Cajal. The perineuronal net is a reticular structure enveloping many neurons. Originally reported by Golgi in 1893 and 1898 and confirmed by several authors before the turn of the century, the perineuronal net was used by Golgi to support the reticular theory of the organization of the nervous system. Ramón y Cajal, the paladin of the neuronal theory who had also observed this anatomical structure, denied its existence suggesting that it was a fixation artifact. After Cajal's statements, only a few Italian scientists continued to work in this field, and after the 1930s the perineuronal net was forgotten. Only the recent advances in histochemical and immunocytochemical technology confirmed the existence of this structure opening new fields in functional neuroanatomy and neuropathology.     

The perineuronal net: a weapon for a challenge

Theories and data do not always fit and sometimes are sources of conflicts among scientists. This is the case of a morphological structure, the perineuronal net, which was denied on the basis of an ideological conflict between two giants of neurosciences: Camillo Golgi and Santiago Ramon y Cajal. The perineuronal net is a reticular structure enveloping many neurons. Orginally reported by Golgi in 1893 and 1898 and confirmed by several authors before the turn of the century, the perineuronal net was used by Golgi to support the reticular theory of the organization of the nervous system. Ramon y Cajal, the paladin of the neuronal theory who had also observed this anatomical structure, denied its existence suggesting that it was a fixation artifact. After Cajal's statements, only a few Italian scientists continued to work in this field, and after the 1930s the perineuronal net was forgotten. Only the recent advances in histochemical and immunocytochemical technology confirmed the existence of this structure opening new fields in functional neuroanatomy and neuropathology.     

Cajal's brief experimentation with hypnotic suggestion

Spanish histologist Santiago Ramón y Cajal, one of the most notable figures in Neuroscience, and winner, along with Camillo Golgi, of the 1906 Nobel Prize in Physiology or Medicine for his discoveries on the structure of the nervous system, did not escape experimenting with some of the psychiatric techniques available at the time, mainly hypnotic suggestion, albeit briefly. While a physician in his thirties, Cajal published a short article under the title, "Pains of labour considerably attenuated by hypnotic suggestion" in Gaceta Médica Catalana. That study may be Cajal's only documented case in the field of experimental psychology. We here provide an English translation of the original Spanish text, placing it historically within Cajal's involvement with some of the key scientific and philosophical issues at the time.     

Making the brain plastic: early neuroanatomical staining techniques and the pursuit of structural plasticity, 1910-1970

The concept of neuronal plasticity is widely used, but seldom defined in the neurosciences. It can signify many different occurrences, such as structural alterations of axons and dendrites (Cotman & Nadler, 1978), behavioural adaptations (Rosenzweig & Bennett, 1996), or physiological changes in synapse formation (Martin et al., 2000) at different stages of health and disease. Although there is such a wealth of research from many disciplines, the neuroanatomical aspects of plasticity are the focus of this paper. It seeks to illuminate the evolution of different concepts of plasticity concerning the structure and circuitry of the central nervous system (CNS). Early modern morphological research on de- and regeneration phenomena in the 19th- and early 20th-century is well documented. These studies, however, almost exclusively concentrated on the peripheral nervous system (PNS). It was one of the major contributions of Santiago Ramón y Cajal (1852-1934), that he applied the concept of regenerative capacities to the CNS. But the term plasticity seemed to have disappeared for about two decades after his death. The ensuing comeback of the expression may be attributed, at least in part, to new neuroanatomical staining and tracing methods. The pursuit of these techniques will serve as a guidepost through varying approaches in different times: It was the 1950s which seemed to spawn the time for new departures in structural investigations of neuronal plasticity.     

Cajal's Brief Experimentation with Hypnotic Suggestion

Spanish histologist Santiago Ramón y Cajal, one of the most notable figures in Neuroscience, and winner, along with Camillo Golgi, of the 1906 Nobel Prize in Physiology or Medicine for his discoveries on the structure of the nervous system, did not escape experimenting with some of the psychiatric techniques available at the time, mainly hypnotic suggestion, albeit briefly. While a physician in his thirties, Cajal published a short article under the title, “Pains of labour considerably attenuated by hypnotic suggestion” in Gaceta Médica Catalana. That study may be Cajal's only documented case in the field of experimental psychology. We here provide an English translation of the original Spanish text, placing it historically within Cajal's involvement with some of the key scientific and philosophical issues at the time.     

Luis Simarro Lacabra [1851–1921]: From Golgi to Cajal Through Simarro,via Ranvier

Knowledge of cerebral structure and function in its modern form can be traced to the neurone doctrine based largely on the work of Santiago Ramón y Cajal [1852–1934] and his lifelong exploitation of the Golgi method. Cajal openly acknowledged his debt to the neuropsychiatrist Luis Simarro Lacabra [1851–1921] who introduced him to the method in 1887, and recalled that the sight of the silver-impregnated nerve cells was the turning point which led him to abandon general anatomy and concentrate on neurohistology. Simarro, who dissipated his free time in trying to improve not only the scientific but also the political world around him, was able to produce exciting Golgi preparations of the cerebral cortex after he returned from voluntary exile in Paris from 1880 to 1885. Certainly it was there that he learned the methods of experimental histology from Louis-Antoine Ranvier [1835–1922] whose laboratory exercises, in the guise of lectures, he attended assiduously.     

Making the Brain Plastic: Early Neuroanatomical Staining Techniques and the Pursuit of Structural Plasticity, 1910–1970

The concept of neuronal plasticity is widely used, but seldom defined in the neurosciences. It can signify many different occurrences, such as structural alterations of axons and dendrites (Cotman & Nadler, 1978), behavioural adaptations (Rosenzweig & Bennett, 1996), or physiological changes in synapse formation (Martin et al., 2000) at different stages of health and disease. Although there is such a wealth of research from many disciplines, the neuroanatomical aspects of plasticity are the focus of this paper. It seeks to illuminate the evolution of different concepts of plasticity concerning the structure and circuitry of the central nervous system (CNS). Early modern morphological research on de- and regeneration phenomena in the 19th- and early 20th-century is well documented. These studies, however, almost exclusively concentrated on the peripheral nervous system (PNS). It was one of the major contributions of Santiago Ramón y Cajal (1852–1934), that he applied the concept of regenerative capacities to the CNS. But the term plasticity seemed to have disappeared for about two decades after his death. The ensuing comeback of the expression may be attributed, at least in part, to new neuroanatomical staining and tracing methods. The pursuit of these techniques will serve as a guidepost through varying approaches in different times: It was the 1950s which seemed to spawn the time for new departures in structural investigations of neuronal plasticity.     

Camillo Golgi's scientific biography

Born in Corteno, a tiny village in the province of Brescia, Camillo Golgi studied at the University of Pavia where he graduated in medicine in 1865 under the guidance of the psychiatrist Cesare Lombroso who sparked his vocation to study the brain. Golgi then began to learn histological techniques under the direction of the pathologist Giulio Bizzozero. In 1872 he moved to Abbiategrasso as chief of a hospital for chronic diseases. In a rudimentary laboratory he developed the silver-bichromate staining technique, the 'black reaction', which was a breakthrough for nervous tissue structure research. While in Abbiategrasso Golgi demonstrated the branching of the axons, and observed striatal and cortical lesions in a case of chorea. He returned to Pavia as Professor of Histology and General Pathology, and made a series of important discoveries that still bear his name: the Golgi tendon organ, the Golgi-Mazzoni corpuscles, another Golgi method to stain nerve cells based on the use of potassium dichromate and mercuric chloride, the canaliculi of the parietal cells of the gastric glands (Muller-Golgi tubules), the Golgi-Rezzonico myelin's annular apparatus (or Golgi-Rezzonico horny funnels), the cycle of malarian parasites (Golgi cycle), the relationship between recurrent malarian fever bouts and the multiplication of the Plasmodium in the blood (Golgi law), the relationship between the vascular pole of the Malpighian glomerulus and the distal tubule, the Golgi's pericellular nets and finally, and most importantly, the cytoplasmic 'internal reticular apparatus' (Golgi apparatus). In 1906 Golgi was awarded the Nobel prize for Medicine or Physiology. He died in Pavia on 21 January 1921.     

Camillo Golgi's Scientific Biography

Born in Corteno, a tiny village in the province of Brescia, Camillo Golgi studied at the University of Pavia where he graduated in medicine in 1865 under the guidance of the psychiatrist Cesare Lombroso who sparked his vocation to study the brain. Golgi then began to learn histological techniques under the direction of the pathologist Giulio Bizzozero. In 1872 he moved to Abbiategrasso as chief of a hospital for chronic diseases. In a rudimentary laboratory he developed the silver-bichromate staining technique, the ‘black reaction’, which was a breakthrough for nervous tissue structure research. While in Abbiategrasso Golgi demonstrated the branching of the axons, and observed striatal and cortical lesions in a case of chorea. He returned to Pavia as Professor of Histology and General Pathology, and made a series of important discoveries that still bear his name: the Golgi tendon organ, the Golgi-Mazzoni corpuscles, another Golgi method to stain nerve cells based on the use of potassium dichromate and mercuric chloride, the canaliculi of the parietal cells of the gastric glands (Müller-Golgi tubules), the Golgi-Rezzonico myelin's annular apparatus (or Golgi-Rezzonico horny funnels), the cycle of malarian parasites (Golgi cycle), the relationship between recurrent malarian fever bouts and the multiplication of the Plasmodium in the blood (Golgi law), the relationship between the vascular pole of the Malpighian glomerulus and the distal tubule, the Golgi's pericellular nets and finally, and most importantly, the cytoplasmic ‘internal reticular apparatus’ (Golgi apparatus). In 1906 Golgi was awarded the Nobel prize for Medicine or Physiology. He died in Pavia on 21 January 1921.     

The Legacy of Camillo Golgi for Modern Concepts of Brain Organization

The experimental advance made by Camillo Golgi's ‘black reaction’ has been universally recognized as the start of the modern revolution in the study of the nervous system. By contrast, his concepts of nervous organization, particularly his support for the idea of a ‘nervous reticulum’, have been universally rejected. The premise of the present paper is that the ideas of a biologist of this stature deserve re-examination. Golgi's arguments for considering the holistic function of the brain seem to come from his experience as a physician, and presage the views of the gestaltists and, more recently, the conceptual underpinnings of artificial neural networks. His interest in the possible nutritional roles of neuronal dendrites can be seen to anticipate current investigations, at the cellular level, of the metabolic basis of brain imaging. These and other currents in Golgi's thought deserve further study.     

The legacy of Camillo Golgi for modern concepts of brain organization

The experimental advance made by Camillo Golgi's 'black reaction' has been universally recognized as the start of the modern revolution in the study of the nervous system. By contrast, his concepts of nervous organization, particularly his support for the idea of a 'nervous reticulum', have been universally rejected. The premise of the present paper is that ideas of a biologist of this stature deserve re-examination. Golgi's arguments for considering the holistic function of the brain seem to come from his experience as a physician, and presage the views of the gestaltists and, more recently, the conceptual underpinnings of artificial neural networks. His interest in the possible nutritional roles of neuronal dendrites can be seen to anticipate current investigations, at the cellular level, of the metabolic basis of brain imaging. These and other currents in Golgi's thought deserve further study.     

Gustaf Retzius and Camillo Golgi

Gustaf Retzius (1842-1919), the Swedish anatomist and anthropologist, and Camillo Golgi were contemporaries. They met on several occasions and came in closer contact when Golgi, together with Ramon y Cajal, was awarded the Nobel Prize in Physiology or Medicine in Stockholm in 1906. Retzius came from an illustrious family. His father was professor of anatomy at Karolinska Institutet and Gustaf himself made a fast career. At 35, he was appointed to a professorship in histology, especially created for him at Karolinska Institutet, and later he became professor of anatomy in the same institution. Retzius was exceedingly productive, and published more than 300 scientific papers, most of which dealt with the nervous system and sensory organs. The majority of these were included in his magnificent volumes Biologische Untersuchungen, Neue Folge (Biological Investigation, New Series), which appeared from 1890 to 1921, and in Das Gehororgan der Wirbelthiere ("The Acoustic Organ of Vertebrates", 1881 and 1884), which may be his internationally better know contribution. Much of his work, especially on invertebrates, was based on Ehrlich's methylene blue method, but he also used the Golgi method early on. Particularly his studies of the innervation of the sensory organs became of great importance for the support of the neuron doctrine. His standing internationally was reflected in his membership in many of the most prominent academies abroad, as well as in invitations to him to give a "Croonian Lecture" in 1908 and "The Huxley Lecture" in 1909.     

Book Review

Gustaf Retzius (1842–1919), the Swedish anatomist and anthropologist, and Camillo Golgi were contemporaries. They met on several occasions and came in closer contact when Golgi, together with Ramón y Cajal, was awarded the Nobel Prize in Physiology or Medicine in Stockholm in 1906. Retzius came from an illustrious family. His father was professor of anatomy at Karolinska Institutet and Gustaf himself made a fast career. At 35, he was appointed to a professorship in histology, especially created for him at Karolinska Institutet, and later he became professor of anatomy in the same institution. Retzius was exceedingly productive, and published more than 300 scientific papers, most of which dealt with the nervous system and sensory organs. The majority of these were included in his magnificent volumes Biologische Untersuchungen, Neue Folge (Biological Investigations, New Series), which appeared from 1890 to 1921, and in Das Gehörorgan der Wirbelthiere (“The Acoustic Organ of Vertebrates”, 1881 and 1884), which may be his internationally better known contribution. Much of his work, especially on invertebrates, was based on Ehrlich's methylene blue method, but he also used the Golgi method early on. Particularly his studies of the innervation of the sensory organs became of great importance for the support of the neuron doctrine. His standing internationally was reflected in his membership in many of the most prominent academies abroad, as well as in invitations to him to give a “Croonian Lecture” in 1908 and “The Huxley Lecture” in 1909.