Santiago Ramón y Cajal
Santiago Ramón y Cajal (May 1, 1852 – October 17, 1934) was a Spanish physician and scientist. He is considered the founder of modern neurobiology (Sotelo, 2003). His masterful use and modifications of the staining technique invented by Camillo Golgi, an Italian physician and scientist, allowed him to be the first to report with precision the fine anatomy of the nervous system. His work was central in the elaboration of the neuron doctrine: Cajal demonstrated that the nervous system was made up of individual cells (neurons, term coined by Waldeyer) connected to each other by small contact zones (synapses, term coined by Sherrington). The 3 distinct anatomical structures described by Deiters — the cell body, the axis cylinder (the axon) and the protoplasmic processes (dendritic arborizations) (Fig. 2) — were thus all part of an individual nerve cell.
Cajal's anatomical studies were always presented in a functional context (Llinás, 2003). One of his most insightful hypotheses was that neurons were functionally polarized, that is, electrical impulses propagate from dendrites to the cell body to the axon. He rightly saw neurons as information processing units that make connections and organize into dynamic networks to accomplish their various functions. The neuron doctrine constitutes the basis for our understanding of the organization of the nervous system, giving Cajal, its main architect, the stature of scientists such as Galileo, Newton and Darwin (Shepherd, 1991).
In addition, Cajal discovered dendritic spines, micron-size structures specialized in cell-to-cell communication. He also described axonal growth, a process central to the development of the nervous system, and proposed that axonal guidance was based on chemical gradients (chemotaxis). This guided his subsequent work on regeneration of nerve cells after injury. Finally, Cajal made contributions to research on color photography, hygiene and several diseases, including cancer and cholera.
Note: Like most Spanish family names, Ramón y Cajal is made up of the paternal surname (Ramón) followed by the maternal surname (Cajal). The proper use is thus Ramón y Cajal. However, this text uses Cajal, continuing the tradition initiated by Prof. Kölliker who introduced Cajal to the European neuroscience community. Cajal himself adopted this name, which served to avoid being confused with his brother Pedro, a scientist who became known as Pedro Ramón, or his son Jorge, who worked in his laboratory for several years and was known as Jorge Fañanás.
Santiago Ramón y Cajal was born in May 1852 in Petilla de Aragón, in northeastern Spain, where his father was the village surgeon. Shortly, the family moved to different villages of Aragón, where the father worked as a rural doctor: Larrés, Valpalmas, Luna, Ayerbe and, finally, the city of Zaragoza. When Cajal was 6 years old, his father, through sacrifice and determination, obtained a doctorate in medicine while supporting his family. As an adolescent, Cajal’s inclination was for the arts, especially drawing. His father, however, decided that his son would be a doctor, reasoning that he could always explore the arts on his leisure time after graduating. Some persuasion was necessary, and among other stratagems, the strong-minded and rebellious teenager was apprenticed to a barber and to a shoemaker. With a novel interest in the natural sciences, Cajal completed his preparatory year and entered the first year of medicine. His father, who had been appointed professor of dissection at the University of Zaragoza, trained him in the art of anatomy. His artistic skills finally proved useful in the eyes of his father through anatomical drawings. Cajal received his license in medicine in 1873 and shortly after was drafted into the army, where he soon joined the Army Medical Service. He served in Cuba during the second insurrection against Spanish rule and contracted malaria and dysentery during the expedition (1874-1875). Discharged for health reasons, Cajal returned to Spain. He started his academic career toward the end of 1875.
In 1879 Cajal married Silvería Fañanás García. They would have four daughters and three sons.
On his return from Cuba Cajal became an assistant in the School of Anatomy in the Faculty of Medicine at the University of Zaragoza (1875) while studying for his doctoral degree and the competitive examinations for professorships. Two years later he obtained a doctorate in medicine in Madrid. His first attempts at obtaining a professorship were unsuccessful, but he eventually succeeded in an examination and became director of the anatomical museum of the Faculty of Medicine in Zaragoza (1879). Finally, in 1883 he was appointed to the chair of anatomy at the Faculty of Medicine in Valencia. In 1887 Cajal was appointed professor of histology and pathological anatomy at Barcelona and in 1892 he was appointed to the same chair at Madrid. In 1900 he was appointed director of the National Institute of Hygiene and Serotherapy and in 1901 of the Biological Research Laboratory, ancestor of the Cajal Institute, founded in 1920. Cajal continued to work productively in Madrid until his death in 1934.
- "I [...] was led to a conciliatory or compromising solution, erroneous, as are almost all intermediate opinions in science." Cajal, Recollections, 1917; p276.
This quote reflects Cajal's perception of his early work (on inflammation) and the subsequent disregard for authority he was to display during his career. In the same spirit, he noted that "hypotheses come and go, but data remain" (Cajal, 1999; p86). To complete this introduction to Cajal's approach to science, let us mention his emphasis on "mastery of technique", which is "so important that [...] it may be stated that great discoveries are in the hands of the finest and most knowledgeable experts on one or more of the analytical methods" (Cajal, 1999; p65).
Anatomy before Cajal
The 19th century saw significant progress in optics and microscope technology, particularly the introduction of the achromatic microscope in the 1820s. This allowed a breakthrough in our understanding of the fine structure of living tissue. Theodor Schwann, after realizing the similarities between the animal cells he was studying and plant cells studied by his friend Matthias Schleiden, enunciated that
- "The elementary parts of all tissues are formed of cells in an analogous, though very diversified manner, so that it may be asserted, that there is one universal principle of development for the elementary parts of organisms, however different, and that this principle is the formation of cells." (Schwann, 1839)
Schwann, Schleiden and Virchow further developed these ideas into three principles: 1. All living things are composed of one or more cells. 2. Cells are the basic units of structure and function in living things. 3. New cells are produced from existing cells. The cell theory, as Schwann named it, became progressively accepted for all tissues except that of the nervous system, where technical limitations and the complexity of the tissue made anatomical characterization difficult. The prevalent view at the time was that the nervous system was organized in a reticular way, i.e., nerve fibers would form a diffuse, anatomically connected network (Fig. 4). Some authors (His, Forel, Nansen) argued that cell theory should apply to the nervous system as well, in light of some evidence in the neuromuscular junction and spinal cord, but their demonstration was far from definitive. The 3 distinct anatomical structures typically forming a neuron the cell body, the axis cylinder (the axon) and the protoplasmic processes (dendritic arborizations) — had been described by Deiters . However, Deiters mischaracterized thin axons (b, in Fig. 2) as emerging from dendrites and perhaps continued with myelinated fibres. This erroneous interpretation gave rise to the reticular theory according to Cajal (1899).
On the physiological level, it was known that electrical impulses travel along nerve fibers. The distinction between sensory and motor fibers was also relatively clear.
Cajal's early research
While he was preparing for the competitive examinations for professorships, Cajal had the opportunity to see microscopic preparations in the laboratory of Dr. Maestre de San Juan, in Madrid. Impressed, he decided to set up his own laboratory in the attic of his home in Zaragoza. His first efforts were directed towards the study of inflammation, muscle anatomy and microbiology (1880-1887; for details, see his publications during that period). Unlike other scientists of his era, Cajal’s scientific career did not start under the direction of a mentor. Rather, he became an accomplished histologist of his own making.
"La reazione nera" and the ontogenetic method
Although improved microscope technology had led to the first formulations of the cell theory, there was still no efficient coloration method for making the components of the nervous system clearly visible. This changed when Camillo Golgi discovered a histological method to impregnate tissue that was capable of staining the entire nerve cell (Golgi, 1873). Golgi's staining technique involves the immersion of nervous tissue in a solution of potassium dichromate for several days, followed by immersion in a silver nitrate solution for 1-2 days. The nerve cells and processes become filled with a fine opaque precipitate of silver chromate (the so-called black reaction, "reazione nera") that renders the neurons clearly visible against the transparent yellow/orange background ( Figure 5). This is made possible by the fact that only a small fraction of the neurons (1-5 %) are stained, a key feature of Golgi's coloration that is still not well understood over a century after its discovery (Pannese, 1999).
In 1887 Santiago Ramón y Cajal, then a young anatomist, visited a colleague in Madrid, the psychiatrist Luis Simarro, who showed him some preparations made with the Golgi method. Instantly seduced and impressed by the quality of the preparations, Cajal decided to use the method in his own laboratory. He quickly became aware of the "capriciousness" of the method, and so worked on improving its reliability. He observed that double impregnation gave better results, as did using different impregnation times for different tissues. He also noticed that the myelin sheath made neuronal processes impossible to stain, and thus he started to use preparations from younger animals, a practice known as the ontogenetic method that had been used before by Wilhelm His in developmental studies (His, 1886).
At that moment, Cajal had the right tools — an improved Golgi staining technique and the ontogenetic method — to tackle one of the most important questions of his time, the structure of the nervous system. Results were to follow at an amazing pace, forcing Cajal to edit (and finance) his own journal, the Revista trimestral de Histología normal y patológica. In his own words, "1888, my greatest year arrived [...] my year of fortune [...]" (Cajal, 1917).
Nerve cells as independent entities
When he started conducting research, Cajal was, like most scientists of his time, a reticularist, believing that the nervous system was a continuous network of interconnected fibers (Iturbe et al., 2008). The major proponent of the reticular theory was the German anatomist Josef von Gerlach. Based on observations made with his gold chloride method, he argued that the processes of contiguous nerve cells fuse to create a meshed network (Gerlach, 1871). In 1888, Cajal started a systematic histological study of the nervous system, making several descriptions and discoveries that would lead him to challenge the widely accepted reticular theory. These important discoveries took place between 1888 and 1894 and were published in the Revista trimestral de Histología normal y patológica (López-Munoz et al., 2006).
- 1888: Cajal reported that axons terminate freely in the cerebellum and retina, concluding that communication between neurons was done by contiguity, not by continuity. He also discovered characteristic structures in dendrites, which he called dendritic spines because of their appearance (Fig. 6). Dendritic spines are sharp thorn-like structures that appear when brain cells are stained with Golgi's method. These were probably observed by other investigators and discarded as artifacts. However, Cajal noticed that spines were consistently present on dendrites but absent on the soma and on the origin of thick dendrites. Later, Cajal demonstrated that dendritic spines can also be stained using his modification of the Methylene Blue method. His technical skill also allowed him to differentiate types of spines according to their morphology (García-López et al, 2007).
- 1890: Cajal observed an amoeboid-like structure at the end of the axon of developing nerve cells. Seeing a dynamic pictures in the static images of fixed tissue, he reasoned that the end of the axon was mobile and involved in the growth and targeting necessary for the axon to connect with other neurons. He called this structure the axonal growth cone (de Castro et al., 2007).
- 1892: Cajal summarized his views on the conduction of electric impulses by nerve cells in his law of dynamic polarization, perhaps the most impressive hypothesis he proposed. Already in 1889, Cajal observed that the processes of nervous cells of the retina and olfactory bulb comparable to the dendrites are oriented towards the “external world” and they have evidently cellulipetal conduction of the nervous impulse; meanwhile the axon or the cellulifugal processes is oriented towards the nervous centers. Van Gehuchten criticized this Cajal’s view considering the spinal ganglia of mammals with a single axon giving rise to two axonal processes. Cajal argued that the peripheral process of spinal ganglion cells has dendritic character in spite of their myelin sheath. In view of his new findings and those of others, he adopted the “formula of dynamic polarization” in 1891: “The transmission of nervous movement occurs from protoplasmic branches [dendrites] and the soma to the nervous expansion [axonal process]”. According to Cajal, Van Gehuchten was one of the first to adhere to the new theory and defended it ardently in his works on the optic lobe and spinal ganglia (1892). However, the classification of processes into cellulipetal and cellulifugal and the obligatory conductive function of the soma proposed by Van Gehuchten are not applicable to all instances. Thus, Cajal adopted a new formula of dynamic polarization, in 1897, his theory of axipetal polarization: “The protoplasmic expansions [dendrites] and the cellular body have axipetal conduction (i.e., toward the axon); whereas the axon has dendrifugal and somatofugal conduction (i.e., it comes from the dendrites or the cellular body) (Fig. 7); (Cajal, 1899).
- 1894: Building on the hypothesis proposed by Eugenio Tanzi, which assumed that oft-used neural pathways would see their connections reinforced, Cajal speculated that learning requires the formation of new connections between neurons (Berlucchi & Buchtel, 2009). Mental exercise would modify the patterns of connections of cortical pyramidal cells, which he designated as psychic cells, through an enhanced development of their dendrites and axon collaterals. Indeed, to Cajal intelligence was to be found in the number and efficiency of the connections between pyramidal and non pyramidal (interneurons) cells in the cerebral cortex (Cajal, 1894).
These discoveries came from the description of the fine anatomy of virtually every part of the nervous system and were organized by Cajal in his magnum opus, Textura del sistema nervioso del hombre y de los vertebrados (1899-1904).
The theory of the individuality of the nerve cell was first formulated in 1891 by Cajal, according to his recent discoveries. Shortly after, Waldeyer coined the word "neuron" to designate the individual nerve cells described by Cajal. Then, the term "neuron doctrine" was born. This theory constitutes the fundamental principle of neuroscience (Bullock et al., 2005). In current terminology, it can be formulated as follows:
1. The neuron is the structural and functional unit of the nervous system.
2. Neurons are individual cells, which are not anatomically continuous to other neurons.
3. The neuron has three parts: dendrites, soma (cell body) and axon. The axon has several terminal arborizations, which make close contact to dendrites or the soma of other neurons.
With its physiological corollary:
4. Conduction of nerve impulses is directional and follows the theory of axipetal polarization. According to Cajal, the polarization of the nerve impulse is due to the pre-established relations between the neurons and the initial position of the excitation; if the point of entry of the current varies, the excitation wave can go from the axon to the cell body or from an axonal branch to its main trunk; and the same can apply to dendrites.
In proving that the cell theory applied to the nervous system, Cajal made the definitive argument that the cell theory provided an accurate description of all tissues in every living thing, and thus helped alongside Schwann, Schleiden and Virchow to establish this pillar of modern biology. The neuron doctrine also had its own merits, especially regarding the physiological characterization of neurons as information processing units. It became complete after the introduction of the concept of synapse by Sherrington in 1897. Here one of the weaknesses of Cajal’s exclusive grounding in anatomical studies becomes apparent: despite his talent for inferring function from morphological data, Cajal could not envision the one-way property of synaptic transmission (Berlucchi, 1999).
The neuron doctrine today
The description in 1952 of the mechanisms underlying the generation and propagation of action potentials opened up new directions for research in functional neurobiology (Hodgkin & Huxley, 1952). In light of the considerable progress that has been made since then, some aspects of the neuron doctrine must be reevaluated (Bullock et al., 2005). For instance, although neurons are indeed anatomically discrete units, they are not always single functional units in the sense envisioned by Cajal. Some neurons are connected by gap junctions, a type of channel that provides the neurons with cytoplasmic continuity. These electrical synapses cause groups of neurons to be functionally coupled in a way reminiscent of the reticular theory.
The theory of axipetal polarization has exceptions as well. In many neurons, action potentials can travel backward from the axon and soma regions into the dendrites (Stuart et al., 1993), a possibility already considered by Cajal. Moreover, under certain conditions action potentials can be initiated in dendrites, remaining local or sometimes propagating into the soma to initiate single or multiple spikes of activity in the axon (Golding & Spruston, 1998).
Finally, current research points to a role for glia (non-neuronal cells) in information processing by the central nervous system, a feature that Cajal and his contemporaries began already to envision (García-Marín et al., 2007). Two-way communication between neurons and glial cells is actually essential for axonal conduction, synaptic transmission, and information processing (Fields & Stevens-Graham, 2002).
A neuron undergoes several stages during development (Fig. 8). At first, it has an ovoid shape and no projections. Then it develops thin extensions (axon and dendrites) that connect the neuron to other neurons over distances of up to a meter for the axon while following a precise connectivity pattern. Cajal wondered about the guidance mechanisms involved in axonal growth. Reasoning by analogy, he proposed in 1892 that axonal guidance could be similar to that observed for leukocytes, that is, based on gradients of chemoattractive substances guiding the growth cones toward their final targets. Cajal's brilliant hypothesis was mostly correct, as he didn't foresee the existence of chemorepellents or the fact that a same molecule could attract or repel a growth cone depending on the battery of receptors expressed by the neuron or its metabolic state (de Castro et al., 2007).
Degeneration and regeneration of the neurons and axons
Cajal's ideas on nerve regeneration after injury (Fig. 9) are closely related to his findings on how neurons grow and mature during development. He was aware that damage repair would be more difficult than during normal development, and that both growth and proper guidance were needed to effectively repair severed connections (Lobato, 2008).
Cajal also made some of the first references to the brain's plasticity. At the time, neuronal plasticity was thought to be limited to the peripheral nervous system. He extended the concept to the brain and spinal cord. Cajal's opinion on adult brain plasticity was ambiguous but can perhaps be summarized as follows: he considered regeneration after injury likely, but adult neurogenesis unlikely (Stahnisch & Nitsch, 2002).
As a physician and scientist, Cajal's first focus was infectious diseases. Indeed, before he turned his attention to the structure and function of the nervous system, Cajal published studies on tuberculosis, rabies, leprosy, syphilis, cholera and cancer.
Cajal's cancer studies have not received much attention in the literature, perhaps in part because they were published in local journals in Spanish. For instance, he seemed aware of the existence of stem cells and their role in tumors. He was also convinced that tumors were not independent entities, but relied instead on signals and nourishment from the connective tissue, a property of tumors that is well-known today (Martínez et al., 2005).
Cajal was also a teacher. He taught anatomy, histology and pathological anatomy at the Universities of Valencia, Barcelona and Madrid. While his research focus was neuroscience, the lack of up-to-date pathology books written in Spanish prompted him to write an anatomopathology textbook entitled Manual de anatomía patológica general y de bacteriología patológica, of which over 10 editions were published.
Cajal’s considerable achievements were rewarded by learned societies, academies, and governments from all over Europe and the Americas.
Election to learned societies and academies: Cajal was elected member of the Royal Academy of Exact, Physical and Natural Sciences of Madrid (1895); of the Royal Academy of Medicine of Madrid (1897); of the Spanish Society of Natural History (1897); associate member of the Academy of Medicine, Paris (1906); member of the Royal Academy of Medicine & Surgery of Madrid (1907); fellow of the Royal Society (1909); foreign member of the Swedish Academy of Sciences (1916); member extraordinary of the Royal Academy of Sciences of the Netherlands (1920). In addition, Cajal was honorary or foreign corresponding member to over 60 learned societies and academies of Europe and the Americas.
Honorary degrees: Doctorate of Medicine from the Universities of Cambridge (1894), Würzburg (1896), Louvain (1909), Mexico (1922) and Guatemala (1925). Doctorate of Laws from Clark University (Worcester, U.S.A., 1899). Honorary doctorates were also granted to Cajal by the Universities of Bordeaux (1922), Paris (1924) and Strasbourg (1925).
Prizes: Among the prizes won by Cajal are the following: a medal presented by the International Congress of Hygiene (1892); the Fauvelle Prize of 1500 francs of the Society of Biology of Paris (1896); the Rubio Prize of 1000 pesetas for the publication of the book Elementos de histología normal y de técnica micrográfica (1897); the Moscow Prize of 5000 francs rewarding medical works which, published during the latter three years, have rendered the greatest services to science and humanity was awarded to Cajal by the International Congress of Medicine in Paris (1900).
In 1894, Cajal was invited to give the prestigious Croonian Lecture by the Royal Society of London.
The Royal Academy of Sciences of Berlin awarded him the Helmholtz Gold Medal in 1905.
Finally, in 1906, Cajal shared the Nobel Prize in Physiology or Medicine with Camillo Golgi. The 1906 prize was the first to be jointly awarded to two individuals. Another notable fact was the fundamental disagreement between both recipients, resulting in Nobel lectures presenting mutually exclusive theories. While the neuron doctrine was widely accepted at the time, and the reason why Cajal was awarded the prize, Golgi was still unconvinced and favored the reticular theory (Jones, 1999). Indeed, even though the prize was awarded to him mainly for other discoveries, Golgi's lecture was entitled The neuron doctrine: theory and facts. This was frustrating to Cajal, who gave his lecture on the following day. Although convincing evidence had been available since 1888, the controversy was to continue for decades, until definitive evidence was obtained using electron microscopy (Palade & Palay, 1954). That Golgi kept rejecting the neuron doctrine while at the same time contributing the technique that allowed its emergence and the results that Cajal built on fascinates neuroscientists to this day (Jones, 2010).
Santiago Ramón y Cajal died in Madrid on October 17, 1934. He left all his scientific belongings to be conserved in the institute he founded in Madrid. The institute started as the Laboratorio de Investigaciones Biológicas, founded in 1900 on the occasion of the Moscow Prize to Cajal. In 1920, on the recommendation of the Minister of Education and Culture, the King Alfonso XIII signed a Royal Decree (February 20th) by which an Institute for Biological Research was to be created that should bear the name "Cajal Institute", with Cajal being its director. Construction of the building began in 1922, but after a series of setbacks and many problems, it was completed and inaugurated in 1932 (Instituto Cajal, Madrid). The institute - the largest neuroscience research center in Spain - hosts the collection of his works and other items, including thousands of scientific drawings and illustrations, histological preparations, books, publications, letters, photographs and microscopes in what is known today as the Cajal Legacy. With these belongings was inaugurated in 1945 in the Institute a Museum that accompanied the Cajal Institute in all its movements, with the exception of the current headquarters, where there is a small exhibition in the library, emulating the working place of Cajal. The rest of the Legacy is preserved, waiting for a new opening of the Museum in a close future. The house where he was born in Petilla de Aragón (Navarra) is also a museum with some Cajal original publications as well as some drawings reproductions, photographs and objects from that period.
However, his most significant and far-reaching legacy is the monumental sum of his published works, with a special mention for his magnum opus, Textura del sistema nervioso del hombre y de los vertebrados, that has been compared in importance to Darwin's On the origin of species. Cajal's impact on the scientific community of Spain was considerable and is still felt in the 21st century. Many scholarly reviews are written on some aspect of Cajal's work and life by Spanish neuroscientists, of whom many have a scientific genealogy tracing back to Cajal and his pupils (Andres-Barquin, 2002).
There is a Santiago Ramón y Cajal monument, work done by the sculptor Victorio Macho, that was inaugurated in 1926 in Retiro Park, Madrid (Fig. 10). In 1977, the Ramón y Cajal University Hospital was founded in Madrid. In 2007, the Universidad Politécnica de Madrid and Instituto Cajal became involved in the Blue Brain project with an initiative called Cajal Blue Brain that comprises several research groups and laboratories.
The Spanish government launched in 2001 its Ramón y Cajal program to attract back Spanish expatriate scientists with 5-year contracts and a path to tenure in Spanish research institutions (Pain, 2006). In the first 5 years the program has been running, about 2500 young researchers have moved to Spain to accept Ramón y Cajal fellowships.
The Cajal Club (founded 1947) is an international organization of neuroscientists whose goals are "to 1) revere Cajal, 2) provide an opportunity for neuroscientists with special interests in the structure and function of the nervous system to confraternize, and 3) contribute to the welfare of neuroanatomy and neuroanatomists".
Cajal-Retzius cells are neurons of the embryonic cortical marginal zone that were first described in rodents by Cajal (1890) and in humans by Retzius (1893), being the most relevant anatomical data that they have more than one axon. At present, we know that they are involved in the layering of the cerebral cortex and perhaps in the establishment of early neural circuits in the developing brain (Meyer et al., 1999).
Interstitial nucleus of Cajal: Located in the midbrain reticular formation, this nucleus is involved in eye movement control.
Petilla Interneuron Nomenclature Group (2008) proposes a standardized nomenclature of interneuron properties. This proposal arose out of a meeting devoted to this topic in Cajal's native town, Petilla de Aragón (Navarra, Spain), and is rooted in the collective work that has been performed in many laboratories (PinG consists of 39 prominent neuroscientists).
The asteroid 117413 Ramonycajal, discovered by Juan Lacruz in 2005, was named in his honor by the Minor Planet Center, the institution responsible for the designation of minor bodies in the solar system. Cajal is a small lunar impact crater on the northern part of the Mare Tranquilitatis.
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- Berlucchi G. (1999). 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. Journal of the History of the Neurosciences, 8(2): 191–201.
- Berlucchi G., Buchtel H.A. (2009). Neuronal plasticity: historical roots and evolution of meaning . Experimental Brain Research, 192(3): 307-319.
- Bullock T.H., Bennett M.V.L., Johnston D., Josephson R., Marder E., Fields R.D. (2005). The neuron doctrine, redux. Science, 310(5749): 791-793.
- Cajal S.R. (1894). The Croonian lecture: la fine structure des centres nerveux. Proceedings of the Royal Society of London, 55: 444-468.
- Cajal S.R. (1899). Textura del sistema nervioso del hombre y de los vertebrados. Imprenta y Librería de Nicolás Moya, Madrid. Volume I, page 20. Present Spanish edition: Histología del sistema nervioso del hombre y de los vertebrados. Imprenta Nacional del Boletín Oficial del Estado.Volume I, page 22, 2007. ISBN 978-84-340-1723-8
- Cajal S.R. (1899). Textura del sistema nervioso del hombre y de los vertebrados. Imprenta y Librería de Nicolás Moya, Madrid. Volume I, pages 80-95, 106-110. Present Spanish edition: Histología del sistema nervioso del hombre y de los vertebrados. Imprenta Nacional del Boletín Oficial del Estado.Volume I, pages 99-121, 2007. ISBN 978-84-340-1723-8
- Cajal S.R. (1999). Advice for a young investigator. MIT Press. Translation by Neely Swanson and Larry W. Swanson of Reglas y consejos sobre investigación cientifica: los tónicos de la voluntad (1897). ISBN 978-02-626-8150-6
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- Jones E.G. (2010). Cajal's debt to Golgi. Brain Research Reviews, In Press, Corrected Proof, Available online 18 April 2010
- Llinás R.R. (2003). The contribution of Santiago Ramón y Cajal to functional neuroscience. Nature Reviews Neuroscience, 4(1): 77-80.
- Lobato R.D. (2008). Historical vignette of Cajal’s work "Degeneration and regeneration of the nervous system" with a reflection of the author. Neurocirugía, 19: 456-468.
- López-Muñoz F., Boya J., Alamo C. (2006). Neuron theory, the cornerstone of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramon y Cajal. Brain Research Bulletin, 70: 391-405.
- Martínez A., Marín V.G., Junquera S.R., Martínez-Murillo R., Freire M. (2005). The contributions of Santiago Ramón y Cajal to cancer research - 100 years on. Nature Reviews Cancer, 5: 904-909.
- Meyer G., Goffinet A.M., Fairen A. (1999). What is a Cajal–Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex. Cerebral Cortex, 9(8): 765-775.
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- Pain E. (2006). The angst of Ramón y Cajal researchers. Science Career magazine, July 14 issue.
- Sanders K., Ward S. (2006). Interstitial cells of Cajal: a new perspective on smooth muscle function. Journal of Physiology, 576(3): 721–726.
- Schwann T. (1839). Microscopic investigations on the accordance in the structure and growth of plants and animals. Berlin. (English translation by the Sydenham Society, 1847)
- Sotelo C. (2003). Viewing the brain through the master hand of Ramón y Cajal. Nature Reviews Neuroscience, 4(1): 71-77.
- Stahnisch F.W., Nitsch R. (2002). Santiago Ramón y Cajal's concept of neuronal plasticity: the ambiguity lives on. Trends in Neurosciences, 25(11): 589-591
- Stuart G.J., Dodt H.U., Sakmann B. (1993). Patch-clamp recordings from the soma and dendrites of neurons in brain slices using infrared video microscopy. Pflügers Archiv 423: 511-518.
- Palade G.E., Palay S.L. (1954). Electron microscope observations of interneuronal and neuromuscular synapses. Anatomical Record, 118: 335–336.
- Pannese E. (1999). The Golgi stain: invention, diffusion and impact on neurosciences. Journal of the History of the Neurosciences, 8(2): 132–140.
- The Petilla Interneuron Nomenclature Group (2008). Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nature Neuroscience, 9(7): 557-568.
- Waldeyer W. (1891). Über einige neuere Forschungen im Gebiete der Anatomie des centralen Nervensystems. Deutsch Med Wochenschr, 17, 1213–1218, 1244–1246; 1267–1269; 1331–1332; 1352–1356.
The first two books are major references for the present article, and are listed here only because they constitute the natural reading list for anyone interested.
- Cajal S.R. (1989). Recollections of my life. MIT Press. Translation by E. Horne Craigie with Juan Cano of Recuerdos de mi vida. (1901-1917). ISBN 978-02-626-8060-8
- Shepherd G.M. (1991). Foundations of the neuron doctrine. Oxford University Press. ISBN 978-01-950-6491-9
- Jones E.G. (2006). The impossible interview with the man of the neuron doctrine. Journal of the History of the Neurosciences, 15(4): 326-340. [This article takes the form of an interview with Santiago Ramón y Cajal a few days after he was awarded the Nobel Prize. His responses to questions posed by the imaginary interviewer are all taken from Cajal's own writings.]
- Cajal Institute (Madrid) Largest neuroscience research center in Spain. Hosts the Cajal Legacy.
- Nobelprize.org: Cajal's Nobel lecture: the structure and connexions of neurons.
- Nobelprize.org: about the shared Nobel prize between Cajal and Golgi.