Evolution of the Concept of ‘Extracellular Matrix’ in the Brain

The question as to whether an extracellular matrix exists between cells in the adult brain has been debated since the end of the last century. In the early years, zones containing neuropil and glial processes were mistakenly believed to represent this substance. But Golgi's discovery of the “perineuronal net” paved the way for future study of the true extracellular matrix. In the 1950s, application of histochemical techniques established the existence of interstitial material between nerve cells. Unfortunately the similarity between the pericellular distribution of this material and Golgi's “pericellular nets” was overlooked. The detection of an extracellular volume fraction in the central nervous system furnished further indirect proof for the existence of an extracellular matrix in the brain. However, the repeated failure of electron microscopy to reveal a substantial space between cell processes undermined the acceptance of the concept of “extracellular matrix” in the central nervous system. Nowadays this concept has, however, been firmly established.     

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.     

The origin of the term plasticity in the neurosciences: Ernesto Lugaro and chemical synaptic transmission

The Italian psychiatrist Ernesto Lugaro can be regarded as responsible for introducing the term plasticity into the neurosciences as early as 1906. By this term he meant that throughout life the anatomo-functional relations between neurons can change in an adaptive fashion to enable psychic maturation, learning, and even functional recovery after brain damage. Lugaro's concept of plasticity was strongly inspired by a neural hypothesis of learning and memory put forward in 1893 by his teacher Eugenio Tanzi. Tanzi postulated that practice and experience promote neuronal growth and shorten the minute spatial gaps between functionally associated neurons, thus facilitating their interactions. In addition to discovering the cerebellar cells known by his name and advancing profound speculations about the functions of the glia, Lugaro lucidly foresaw the chemical nature of synaptic transmission in the central nervous system, and was the first to propose the usage of the terms "nervous conduction" and "nervous transmission" in their currently accepted meaning.     

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).     

Representation and identity - convergence of brain research and mind-brain philosophy

The localization or representation of mental abilities in the brain have always been considered as key questions for understanding the organization of the human nervous system. Particularly with the advent of modern electrophysiological and imaging techniques that provide maps of electromagnetic fields and metabolic processes on the living central nervous system, the representation theory is experiencing a scientific renaissance in neurology, but is only one theory, however, in the succession of a long philosophical tradition dealing with the possible identification of mental phenomena and brain processes. This dichotomy was formulated at the latest in the Cartesian dualism of res cogitans and res extensa of the mind-body problem. Nowadays philosophical discussion, on the contrary, is dominated by monistic concepts that attempt to explain the mental realm on an organic foundation in order not to succumb to the problem of a psychophysical dualism. Of these, the identity theory offers a philosophically plausible concept postulating that the identity of brain conditions and mental phenomena is based on organic foundations. In this theory, the efforts of brain research converge on the representations of mental phenomena in the human nervous system. In a comprehensive approach, both concepts could complement each other.     

Representation and identity ‐ convergence of brain research and mind‐brain philosophy

Abstract

The localization or representation of mental abilities in the brain have always been considered as key questions for understanding the organization of the human nervous system. Particularly with the advent of modern electrophysiological and imaging techniques that provide maps of electromagnetic fields and metabolic processes on the living central nervous system, the representation theory is experiencing a scientific renaissance in neurology, but is only one theory, however, in the succession of a long philosophical tradition dealing with the possible identification of mental phenomena and brain processes. This dichotomy was formulated at the latest in the Cartesian dualism of res cogitans and res extensa of the mind‐body problem. Nowadays philosophical discussion, on the contrary, is dominated by monistic concepts that attempt to explain the mental realm on an organic foundation in order not to succumb to the problem of a psychophysical dualism. Of these, the identity theory offers a philosophically plausible concept postulating that the identity of brain conditions and mental phenomena is based on organic foundations. In this theory, the efforts of brain research converge on the representations of mental phenomena in the human nervous system. In a comprehensive approach, both concepts could complement each other.     

From the mind to the brain: an unusual pathway

One of the most unrecognized aspects of Golgi's life was his deep interest in neuropsychiatry. From 1865 to 1868 he attended the Clinica per le Malattie Nervose e Mentali in Pavia directed by Cesare Lombroso, the founder of modern criminology. Golgi was involved in research on the etiology of psychiatric ailments. During this short period of time he produced significant theoretic advances in clinical psychiatry. However, very soon he started to criticize the conceptual approach as well as the nosological system proposed by his academic mentor. In July 1868 he left Lombroso's school in search for a more rational method of studying brain functions and diseases. In spite of his anatomical approach to the central nervous system, he always maintained curiosity in the phenomenology of functional and organic mental disorders. This predisposition is witnessed by his capability to relate clinical observations to neuropathological findings.     

Mesoglia & microglia--a historical review of the concept of mononuclear phagocytes within the central nervous system

More than a century and a half has elapsed since the first accounts of mesodermal phagocytic elements were proposed within the central nervous system. Over the intervening decades, body and substance were added to this concept through the advancement of histological techniques at the disposal of the researcher and the acute and keen-minded skills of the pathologist. Notable among these pioneering efforts were the contributions of W. Ford Robertson, Santiago Ramon y Cajal, Pio del Rio-Hortega and Wilder Penfield amongst an entire cavalcade of other noteworthy figures. The term 'mesoglia' and 'third element of the nervous system' was bestowed upon these cells towards the beginning of the twentieth century to account for their separate origins from neurons and macroglia. It was later amended by del Rio-Hortega in 1919, to 'microglia' in order to further discriminate between true mesodermal elements and oligodendrocytes, previously regarded as a component of 'mesoglia'. This particular contention sparked much controversy among del Rio-Hortega's peers and resulted in an escalation of fruitful research throughout Europe that eventually declined up to the outbreak of the Second World War. The post-war years were a period of the 'dark ages' that cast doubt on the very existence and nature of microglia, until the 'renaissance' of research was once again rejuvenated in the 1960s, by a new cohort of intrigued minds: Cammermeyer, Blinzinger, Kreutzberg and others who saw in the 'third element' the potential that is now commonly ascribed to microglia: the intrinsic immune effector cells of the CNS. It is now universally accepted that microglia are involved as the first line of rapid defence in any pathology of the nervous system, and as such, present a diagnostic tool for the neuropathologist. Although our knowledge of microglia stems from an extensive body of work conducted over the last two decades, much of the earlier work (pre-1960s) has remained somewhat obscure. This is partly accountable due to the limited availability of translated works, and additionally to the lack of a compendium of these articles. This paper will present a comprehensive overview of the pioneering research on mononuclear phagocytes within the central nervous system, which has direct bearing on our present-day understanding of the concept of microglia.     

The Origin of the Term Plasticity in the Neurosciences: Ernesto Lugaro and Chemical Synaptic Transmission

The Italian psychiatrist Ernesto Lugaro can be regarded as responsible for introducing the term plasticity into the neurosciences as early as 1906. By this term he meant that throughout life the anatomo-functional relations between neurons can change in an adaptive fashion to enable psychic maturation, learning, and even functional recovery after brain damage. Lugaro’s concept of plasticity was strongly inspired by a neural hypothesis of learning and memory put forward in 1893 by his teacher Eugenio Tanzi. Tanzi postulated that practice and experience promote neuronal growth and shorten the minute spatial gaps between functionally associated neurons, thus facilitating their interactions. In addition to discovering the cerebellar cells known by his name and advancing profound speculations about the functions of the glia, Lugaro lucidly foresaw the chemical nature of Synaptic transmission in the central nervous system, and was the first to propose the usage of the terms “nervous conduction” and “nervous transmission” in their currently accepted meaning.     

The neurophysiological aspects of Pavlov's theory of higher nervous activity: in honor of the 150th anniversary of Pavlov's birth

Whereas Ivan P. Pavlov (1849-1936) is well-known for his work on classical conditioning, his contribution to neuroscience, particularly his interest in the function of neural centers in the central nervous system, is not as widely known. During the last three decades of his life, Pavlov explored cortical processes by salivary reflex conditioning, a method he used to develop his theory of higher nervous activity. This theory outlined the function of the brain in higher organisms in their interaction with the changing environmental contingencies. As early as 1908, Pavlov outlined a neurophysiological theory as the physiological basis of his theory of higher nervous activity. He maintained that the neural processes of excitation and inhibition irradiate and concentrate among the cortical neural centers. Most of all, he emphasized the plasticity of the cortex in higher organisms' in the Darwinian struggle for existence.     

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.     

The Neurophysiological Aspects of Pavlov’s Theory of Higher Nervous Activity: In Honor of the 150th Anniversary of Pavlov’s Birth

Whereas Ivan P. Pavlov (1849-1936) is well-known for his work on classical conditioning, his contribution to neuroscience, particularly his interest in the function of neural centers in the central nervous system, is not as widely known. During the last three decades of his life, Pavlov explored cortical processes by salivary reflex conditioning, a method he used to develop his theory of higher nervous activity. This theory outlined the function of the brain in higher organisms in their interaction with the changing environmental contingencies. As early as 1908, Pavlov outlined a neurophysiological theory as the physiological basis of his theory of higher nervous activity. He maintained that the neural processes of excitation and inhibition irradiate and concentrate among the cortical neural centers. Most of all, he emphasized the plasticity of the cortex in higher organisms’ in the Darwinian struggle for existence.     

MESOGLIA & MICROGLIA – A Historical Review of the Concept of Mononuclear Phagocytes Within the Central Nervous System

More than a century and a half has elapsed since the first accounts of mesodermal phagocytic elements were proposed within the central nervous system. Over the intervening decades, body and substance were added to this concept through the advancement of histological techniques at the disposal of the researcher and the acute and keen-minded skills of the pathologist. Notable among these pioneering efforts were the contributions of W. Ford Robertson, Santiago Ramon y Cajal, Pio del Rio-Hortega and Wilder Penfield amongst an entire cavalcade of other noteworthy figures. The term ‘mesoglia’ and ‘third element of the nervous system’ was bestowed upon these cells towards the beginning of the twentieth century to account for their separate origins from neurons and macroglia. It was later amended by del Rio-Hortega in 1919, to ‘microglia’ in order to further discriminate between true mesodermal elements and oligodendrocytes, previously regarded as a component of ‘mesoglia’. This particular contention sparked much controversy among del Rio-Hortega’s peers and resulted in an escalation of fruitful research throughout Europe that eventually declined up to the outbreak of the Second World War. The post-war years were a period of the ‘dark ages’ that cast doubt on the very existence and nature of microglia, until the ‘renaissance’ of research was once again rejuvenated in the 1960s, by a new cohort of intrigued minds: Cammermeyer, Blinzinger, Kreutzberg and others who saw in the ‘third element’ the potential that is now commonly ascribed to microglia: the intrinsic immune effector cells of the CNS. It is now universally accepted that microglia are involved as the first line of rapid defence in any pathology of the nervous system, and as such, present a diagnostic tool for the neuropathologist. Although our knowledge of microglia stems from an extensive body of work conducted over the last two decades, much of the earlier work (pre-1960s) has remained somewhat obscure. This is partly accountable due to the limited availability of translated works, and additionally to the lack of a compendium of these articles. This paper will present a comprehensive overview of the pioneering research on mononuclear phagocytes within the central nervous system, which has direct bearing on our present-day understanding of the concept of microglia.     

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.     

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.     

Narrating consciousness: language, media and embodiment

Although there has long been a division in studies of consciousness between a focus on neuronal processes or conversely an emphasis on the ruminations of a conscious self, the long-standing split between mechanism and meaning within the brain was mirrored by a split without, between information as a technical term and the meanings that messages are commonly thought to convey. How to heal this breach has posed formidable problems to researchers. Working through the history of cybernetics, one of the historical sites where Claude Shannon's information theory quickly became received doctrine, we argue that the cybernetic program as it developed through second-order cybernetics and autopoietic theory remains incomplete. In this article, we return to fundamental questions about pattern and noise, context and meaning, to forge connections between consciousness, narrative and media. The thrust of our project is to reintroduce context and narrative as crucial factors in the processes of meaning-making. The project proceeds along two fronts: advancing a theoretical framework within which context plays its property central role; and demonstrating the importance of context by analyzing two fictions, Stanislaw Lem's "His Master's Voice" and Joseph McElroy's "Plus," in which context has been deformed by being wrenched away from normal human environments, with radical consequences for processes of meaning-making.     

Alienation, authenticity and the self

While many commentators have held that the concept "alienation" is of crucial importance when attempting to understand human existence, others have held that it is an inherently empty concept that we should abandon. In this article, I refute the latters' charge by showing that each conception of "alienation" is underpinned by a normative ontological conception of the preferable, or authentic, self and show that the concept "alienation" has ethical, existential and socio-political uses. From this I conclude that, when properly understood, the concept "alienation" can provide us with vital insights into human existence.     

Origins of molecular neurobiology: the role of the physicists

The revolution in the foundations of physics at the beginning of the twentieth century suggested to several of its most prominent workers that biology was ripe for something similar. In consequence, a number of physicists moved into biology. They were highly influential in initiating a molecular biology in the 1950s. Two decades later it seemed to several of these migrants, and those they had influenced, that the major problems in molecular biology had been solved, and that it was time to move on to what seemed to them the final problem: the nervous system, consciousness, and the age-old mind-body problem. This paper reviews this "double migration" and shows how the hopes of the first generation of physicist-biologists were both realized and dashed. No new physical principles were discovered at work in the foundations of biology or neuroscience. On the other hand, the mind-set of those trained in physics proved immensely valuable in analyzing fundamental issues in both biology and neuroscience. It has been argued that the outcome of the molecular biology of the 1950s was a change in the concept of the gene from that of "a mysterious entity into that of a real molecular object" (Watson, 1965, p.6); the gates and channels which play such crucial roles in the functioning of nervous systems have been transformed in a similar way. Studies on highly simplified systems have also opened the prospect of finding the neural correlatives of numerous behaviors and neuropathologies. This increasing understanding at the molecular level is invaluable not only in devising rational therapies but also, by defining the material substrate of consciousness, in bringing the mind-body problem into sharper focus.