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Cajal's Butterflies of the SoulScience and Art$

Javier DeFelipe

Print publication date: 2009

Print ISBN-13: 9780195392708

Published to Oxford Scholarship Online: January 2010

DOI: 10.1093/acprof:oso/9780195392708.001.0001

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Introductory Remarks

Introductory Remarks

(p.3) Introductory Remarks
Cajal's Butterflies of the Soul

Javier Defelipe

Oxford University Press

Abstract and Keywords

This introductory chapter begins with a brief discussion of the many contributions of Santiago Ramón y Cajal, who is considered the father of modern neuroscience. He published almost 300 articles and several books of great importance, such as the classics Textura del Sistema Nervioso del Hombre y de los Vertebrados (1899-1904) and Estudios Sobre la Degeneración y Regeneración del Sistema Nervioso (1913-1914). He also received numerous awards and distinctions, including some of the most prestigious awards of his time: the Moscow Award (1900); the Helmholtz Gold Medal (1905); and the Nobel Prize for Physiology or Medicine (1906). The chapter then goes on to discuss why scientists often referred to trees and forests in their descriptions of the brain and, in particular, of the cerebral cortex, and how these neuronal forests served as an unlimited source of artistic and poetic inspiration to many scientists.

Keywords:   Santiago Ramón y Cajal, neuroscientists, neurons, illustrations, microscopy

Santiago Ramón y Cajal (1852–1934) is considered the father of modern neuroscience for providing the first detailed analysis of the nervous system (DeFelipe, 2002a; Fig. F-1). Thus, we have honored his name in the title of this book, even though the figures contained in the main body of the text were composed by 95 different authors.

Cajal's studies and theories had a profound impact on the researchers of his era. He published almost 300 articles and several books of great importance, such as the classics Textura del Sistema Nervioso del Hombre y de los Vertebrados (Ramón y Cajal, 1899–1904) and Estudios Sobre la Degeneración y Regeneración del Sistema Nervioso (Ramón y Cajal, 1913–1914). He also received numerous awards and distinctions (Fig. F-1 right and F-2, left), including some of the most prestigious awards of his time: the Moscow Award (1900); the Helmholtz Gold Medal (1905); and the Nobel Prize for Physiology or Medicine (1906), which he shared with Camillo Golgi (1843–1926), the renowned Italian scientist who discovered the reazione nera (see “The Discovery of the Reazione Nera” in Section 2) and the organelle he defined as the “internal reticular apparatus” that was later called the Golgi apparatus (Bentivoglio, 1999). Over the years, Cajal has also received many tributes, such as the homage during the NASA Neurolab space flight mission in 1998 (Fig. F-2, right). The inclusion of “butterflies of the soul” in the title of this book refers to one of Cajal's favorite topics: the human neocortex and the most common neuron in the cerebral cortex, the pyramidal cell that he sometimes poetically named butterflies of the soul. In his book Recuerdos de Mi Vida, he wrote the following paragraph when he started studying the cerebral cortex:

I felt at that time the most lively curiosity—somehow romantic—for the enigmatic organization of the organ of the soul. Humans—I said to myself—reign over Nature through the architectural perfection of their brains [ … ]. To know the brain—we said to ourselves in our idealistic enthusiasm—is equivalent to discovering the material course of thought and will. [ … ] Like the entomologist hunting for brightly coloured butterflies, my attention was drawn to the flower garden of the grey matter, which contained cells with delicate and elegant forms, the mysterious butterflies of the soul, the beating of whose wings may some day (who knows?) clarify the secret of mental life. [ … ] Even from the aesthetic point of view, the nervous tissue contains the most charming attractions. In our parks are there any trees more elegant and luxurious than the Purkinje cells from the cerebellum or the psychic cell that is the famous cerebral pyramid?

Ramón y Cajal, 1917

Throughout the nineteenth and early twentieth centuries, neuroscience is marked by two (p.4)

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Figure F-1. (Left) Santiago Ramón y Cajal (1852–1934). (Right) Cover of the magazine Blanco y Negro (1922) to illustrate the award of the Echegaray Medal to Cajal at the Academia de Ciencias Exactas, Físicas y Naturales (Madrid), in the presence of His Majesty the King of Spain Alfonso XIII (1886–1941).

milestones: the developments in light microscopy and anatomical methods, and the progress made in localizing particular brain functions. Nevertheless, many of the ideas regarding functional localization, and in particular those related to mental attributes, have now been proven wrong. However, these studies were fundamental not only for the development of our present ideas on the function and physiology of the brain. From a structural point of view, anatomists began to consider that it might be possible to explain functional specialization through structural specialization (Figs. F-3 and F-4).

The nervous system is made up of two main classes of specialized cells: neurons and neuroglia (or simply glial cells as I shall refer to them in the remaining text). The function of the brain, and of the nervous system in general, depends on the connections between neurons that are established through complex and specialized structures named synapses. These connections are organized into intricate networks or neuronal circuits, and they utilize electrochemical signals and neurotransmitters that are packed into small vesicles (synaptic vesicles) located in the presynaptic side of the synapse. In addition, close anatomical and functional coupling exists between neurons, glia, and blood vessels (see section, “The Beauty of the Nervous System: Neurons and Glia”).

As the reader will see, neurons and glia are arranged so that they constitute a true forest. Indeed, some types of neurons, like the pyramidal cells of the cerebral cortex (Fig. F-5a) and the Purkinje cells of the cerebellar cortex (Fig. F-5b)—the most (p.5)

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Figure F-2. (Left) Photograph showing a plaque and some medals that Cajal received in recognition of his studies. The images of the medals were kindly supplied by Pere Berbel (Instituto de Neurociencias, Alicante). (Right) Copy of one of the nine drawings of Cajal that traveled aboard the Space Shuttle Columbia as a tribute to him during NASA's Neurolab mission. The signatures are those of the crew members: Scott D. Altman, Jay C. Buckey, Richard M. Linnehan, Kathryn P. Hire, James A. Pawelczyk, Richard A. Searfoss, and Dafydd Rhys Williams. Neurolab was a NASA research mission to study how the nervous system responds in microgravity, a fundamental question for future long-duration space flights. Neurolab was born when the U.S. President declared the 1990s the Decade of the Brain, and NASA proposed the Neurolab mission as its contribution to this dictate. Other international space agencies also participated in the Neurolab mission. The seven-member crew were not only involved in various experiments with animals (rats, mice, fish, snails, and crickets) aboard the Space Shuttle Columbia, but they were also themselves subjected to a number of sophisticated biomedical studies. The Shuttle was launched on April 17, 1998 and landed on May 4, 1998 at the Kennedy Space Center in Cape Canaveral, Florida. The Shuttle reached an altitude of around 320 km above the planet's surface and traveled at a speed of approximately 7.5 km per second. Since the Shuttle orbited the earth every 92 minutes, during the 16-day spaceflight there were 16 sunsets and 16 sunrises every 24 hours. Accordingly, the Shuttle completed a total of 256 orbits around the earth.

characteristic neuronal type in the cerebellum—look like trees and due to their density and arrangement they constitute a thick forest (see the drawing in the center of Fig. F-3).

This is why Cajal and other scientists often referred to trees and forests in their descriptions of the brain and, in particular, of the cerebral cortex. Another beautiful example is the following comment from Cajal regarding cortical plasticity:

The cerebral cortex is similar to a garden filled with innumerable trees, the pyramidal cells, which can multiply their branches thanks to intelligent cultivation, send their roots deeper and producing more exquisite flowers and fruits every day.

Ramón y Cajal, 1894

These neuronal forests have served as an unlimited source of artistic and poetic inspiration to many scientists. Indeed, Figure F-6 is an artistic illustration showing a mysterious object, the brain, arising through the mist and emerging from the entangled branches of the trees that are condensed into an enchanted neuronal forest.


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Figure F-3. Left and right columns represent (from top to bottom and left to right): “Map of the mental faculties”; “Twelve mental functions and their products”; “Each faculty of the brain influences a region of the face”; and “The measurements of the mentologist.” Taken from Holmes W. Merton (Merton, H. W. Descriptive Mentality from the Head, Face and Hand. Philadelphia: MacKay, 1899). In the center is a drawing of the human cerebral cortex stained with the Golgi method and taken from Rudolf Albert von Kölliker (Kölliker, A. von. Handbuch der Gewebelehre des Menschen, 6th ed, vol II, first part. Nervensystem des Menschen und der Thiere. Leipzig: Engelmann, 1893). The ideas on the localization of brain functions inspired scientists to carry out comparative histology studies to investigate whether any structural peculiarities in the human cerebral cortex might explain specific human behaviors.

Pío del Río-Hortega (1882–1945; Fig. F-7), one of Cajal's outstanding disciples, wrote the following marvelous paragraph describing the relationships between neurons, glia, and blood vessels:

In the landscape of the brain there are endless irrigation canals—blood vessels— and on their banks the bush-like cells—glia—collaborate in nerve function.

Del Río-Hortega, 1933

It is interesting to note that trees have also served as artistic symbols to describe biblical texts, which on occasion mention cognitive alterations. In Figure F-8, King Nebuchadnezzar II of Babylon (sixth century BC) is shown with dementia and eating grass “like the beasts in the field”; his walking “on all fours” refers to the extreme bending of his trunk (camptocormia) due to his parkinsonism associated with Lewy body disease. As a main theme in the illustration, a tree is shown whose trunk represents the kingdom with its inhabitants, the birds in their branches (Martín-Araguz, 2006). Here, we can also imagine a charming bridge between literature, artistic drawings, and neuroscience (compare Figs. F-5b and F-8).

Another artistic example of these early scientists is again from Cajal himself. Indeed, he was a master of bringing together science and art not only through his drawings but also through his photography. In fact, he was a pioneer in the development of color photography (Ramón y Cajal, 1912; Fig. F-9).

In Figure F-10 we can see two interesting photographs taken by Cajal himself. On the left of the (p.7)

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Figure F-4. Drawings by Korbinian Brodmann (1868–1918) showing the lateral (left) and medial (right) aspects of the brain of a prosimian lemur, with stippling of the various cortical areas. Brodmann was one of the great German neurologists in an exciting period at the turn of the twentieth century when the neuronal theory was only just coming to the fore. He is best known for his “maps” of the cerebral cortex, which are still commonly used today, and especially that of the human cortex first published in 1908 in the Journal für Psychologie und Neurologie as well as that from the following year in his famous monograph Vergleichende Lokalisationslehre der Grosshirnride (translated by Laurence Garey as Localization in the Cerebral Cortex, third edition. New York: Springer Science Business Media, Inc., 2006). Brodmann's printed black-and-white maps are reasonably well known, but it is rare to find copies of his original hand-drawn color figures. Brodmann undertook a study of the prosimian brain for his “Habilitation” thesis, which was surprisingly rejected by the Berlin Medical Faculty, although this drawing became Figure 98 in his 1909 monograph. The text and drawing are provided by Laurence Garey, with thanks to Marc Nagel (http://www.korbinian-brodmann.de/).

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Figure F-5. Cajal's drawings from Golgi-stained preparations to illustrate the (a) pyramidal and (b) Purkinje cells in the human cerebral cortex and cerebellum, respectively. In (a), “a,” “c,” “d,” and “e” indicate axon, collaterals, long basal dendrites, and terminal [dendritic] tuft, respectively. In (b), “a,” “b,” “c,” and “d” indicate axon, recurrent collaterals, holes occupied by capillaries, and holes occupied by basket cells, respectively. These figures were reproduced in Textura del Sistema Nervioso del Hombre y de los Vertebrados (Cajal 1899–1904, figures 689 [left], and 10 and 365 [right]).

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Figure F-6. Artistic composition showing a brain in the center that seems to be generated by the condensation of neurons (see text for further details).

figure Cajal is looking through a microscope, while on the right his daughter Paula is posing in a colorful dress with a basket of flowers. My interpretation of this photograph is that Cajal wants to tell us that science and art can coexist. The picture on the right seems to me as if Paula were like an angel or a muse of scientific inspiration.

Cajal also inspired poets like Juan Ramón Jiménez (1881–1958; Nobel Prize for Literature in 1956; Fig. F-11), who in his book Españoles de Tres Mundos wrote:

I saw him once in a tram, a long afternoon that rained full and blind, putting on his reading glasses through his silver hair, forgotten, leaning against the glass window, and that was how he remained, staring leisurely, abandoned and melancholic, into the horizon.

Ramón-Jiménez, 1942

In line with this poetic prose is the picture taken by Cajal himself in 1915 showing some trams in the Puerta del Sol, Madrid (Fig. F-11, right).

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Figure F-7. Picture of Pío del Río-Hortega (1882–1945, right) when he received the honorary degree Doctor Honoris Causa from the University of Oxford. (Left) Charles Sherrington (1857–1952). This picture was dedicated to Severo Ochoa (1905–1993) and his wife Carmen García Cobián. Sherrington and Ochoa were awarded the Nobel Prize in Physiology or Medicine in 1932 and 1959, respectively.


In the nervous system there are billions of neurons and even more glia (at least 10 times more). As the reader will see under the section “A Sketch History of the Microscopic Anatomy of the Nervous System,” the discovery of the neuron has a long, fascinating history in which many researchers have participated up to the present day. Of course, glial cells are fundamental elements of the nervous system, and the history of these cells is tightly linked to that of the neuron. However, in the present book we shall only deal with these cells in a superficial manner. In general, neurons consist of (p.9)

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Figure F-8. This figure was taken from a Beato, a manuscript with miniatures from the tenth to thirteenth century, which contains comments by the Abbot Beato de Liébana (eighth century) on the Apocalypse and additions of various exegetic texts like the Commentary on the Book of Daniel of Saint Jerome. This miniature belongs to the Mozarabic Beato of San Miguel de Escalada (León, Spain), the work of the monk Maius in the tenth century. The tree is cut at its base showing the risk for the kingdom caused by the disease of King Nebuchadnezzar II (Martín-Araguz, 2006). King Nebuchadnezzar II, also called Nebuchadnezzar the Great, is mainly known for the conquest of Judah and Jerusalem, and for the construction of the Hanging Gardens of Babylon.

a cell body or soma (usually 10–20 μm in diameter) that gives rise to several processes, of which only one forms the axon (0.5–2.0 μm thick) while the remainder form dendrites (1–5 μm thick). Neurons adopt a considerable variety of shapes and sizes, as well as many patterns of dendritic and axonal arborization (Fig. F-12). Glial cells are characterized by their relatively small soma (5–10 μm of diameter), which emit several thin (0.5–1.0 μm) and short processes that branch locally. There are two major classes of glia: macroglia (astrocytes and oligodendrocytes) and microglia. The astrocytes are subdivided into protoplasmic and fibrous, while oligodendrocytes are subdivided into interfascicular and perineuronal satellites (Fig. F-13).

As for axons, they adopt one of two general designs: (1) axons that only branch near the cell body from which they originate, such that neurons with this kind of axon are named interneurons or short-axon cells (Fig. F-12, right); (2) axons that leave the region where the cell body of origin is located, and these cells are known as projection neurons (Fig. F-12, left). In this case, the axon can travel over enormous lengths, which can often be in the order of several millimeters or even meters (for example, pyramidal cells projecting to the spinal cord in large mammals like the giraffe). Furthermore, the axon of projection neurons frequently gives rise to collaterals along its trajectory and, in turn, these collaterals can give rise to local axonal arbors that may be located near to or a distance from the cell body of origin (Fig. F-12, left). As an example of the richness of dendritic and axonal arborization and of the complexity of the organization of the nervous system, it has been estimated that there are approximately 3 km and 400 m of axonal and dendritic length, respectively, and an average density of 90,000 neurons per mm3 in the mouse cerebral cortex (Schüz and Palm, 1989). Furthermore, the brain is one of the organs of the body with the highest metabolic demands, and thus, there is a very dense network of blood vessels in association with the neurons and glia.

The exchange of information between neurons mainly takes place through two types of highly specialized structures: chemical synapses (the majority) and electrical synapses. The space between the cell bodies of the neurons, glia, and blood vessels—the neuropil—is occupied by a very dense network of axonal, dendritic, and glial processes. In the neuropil there is a high density of synapses, and, for example, there are approximately 1000 × 106 synapses per mm3 of neuropil in the human temporal cortex. Indeed, the neuropil represents between 90% and 98% of the volume of the cerebral cortex (Alonso-Nanclares et al., 2008). Thus, the main problem when analyzing the (p.10)

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Figure F-9. (Left) Cover of Cajal's book Fotografía de los Colores, 1912. (Right) Cajal's photograph, a still life in color with flowers, fruit, and bottles (trichrome procedure on paper, 1907). Taken from María de los Ángeles Ramón y Cajal Junquera: Cajal, Artista, in Paisajes Neuronales. Homenaje a Santiago Ramón y Cajal (Madrid: CSIC, 2007).

nervous system is its extreme complexity, particularly in higher vertebrates (Fig. F-14).

Thus, throughout the history of neuroscience, scientists have sought to develop appropriate methods to analyze different aspects of the structure and function of the nervous system. Some of these methods were discovered at random, whereas others were designed to resolve a given problem. Nevertheless, the development of science not only depends on the methods available but also on the ways they are exploited. Thus, there are examples of methods that were available to scientists but that were not fully exploited until an individual made an important discovery or an astute interpretation that generated new concepts. This was the case of the Golgi method, which remained unexploited for many years before Cajal entered the scene to change the course of the history of neuroscience (DeFelipe, 2002a, 2006; Jones, 2006; also see heading under Section 2 in this volume, “Cajal's First Study with the Golgi Method: Dendrites and Axons End Freely”).


At the beginning of the nineteenth century and for several decades afterward, microphotography was not a well-established technique to study histology. Certainly, several types of microphotography accessories were available for light microscopy at that time, some of which were very sophisticated (Fig. F-15), but good techniques of microphotography had not yet been developed. Thus, obtaining high-quality microscopy images, particularly high-power microphotographs, was a difficult task. Moreover, the structure of the nervous system is very complex and the selective staining methods used, such as the Golgi method, do not define all (p.11)

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Figure F-10. Photographs taken by Cajal of himself and his daughter Paula. From the private collection of Silvia Cañadas, daughter of Paula Ramón y Cajal, and as also reproduced in the doctoral thesis of José María Martínez Murillo (2004).

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Figure F-11. (Left) Photograph of the poet Juan Ramón Jiménez (1881–1958). (Right) Photograph taken by Cajal of the Puerta del Sol, Madrid.

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Figure F-12. Schematic drawings showing a typical pyramidal cell (left) and two interneurons (right: upper part, “common type,” lower part, “chandelier cell”) from the neocortex. The dendrites are shown in red.

the elements labeled in a given region in the same preparation or in the same focal plane. Therefore, the illustration of a given structure—with its possible connections—through microphotography was a difficult and often inefficient task. For these reasons, many of the drawings of the time were complex compositions, and the organization of a given region of the nervous system was shown synthetically. This is perhaps the most crucial aspect of these scientific drawings because it meant coupling artistic aptitudes with the interpretation of the microscopic images. In other words, the scientist had to discern between an artifact and a real element, and highlight the key features of the structure in an exact copy of the image obtained through the microscope. Thus, the illustration of histological findings through drawings inevitably led to some skepticism (DeFelipe and Jones, 1992).

Readers interested in the various methods to reproduce microscopy images and the material used to produce these drawings can consult the work of Cajal itself. His book entitled Manual de Histología Normal y de Técnica Micrográfica (Handbook of Normal Histology and Micrography Techniques) is of particular interest, which was first published in 1889 (Ramón y Cajal, 1889a) and then re-edited over the years with additional and corrected content (e.g., Ramón y Cajal, 1893, 1914). An English version of this work was published with the help of his disciple Jorge Francisco Tello (1880–1958), considered to be Cajal's first disciple (Ramón y Cajal and Tello, 1933; see DeFelipe and Jones, 1992). In general, the (p.13)

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Figure F-13. Drawings to illustrate various types of glia in the central nervous system. (A) Protoplasmic astrocyte from the gray matter. (B) Fibrous astrocyte from the white matter. (C) Microglia. (D) Oligodendrocyte in the white matter (interfascicular form; taken from del Río Hortega, 1920). The discovery of glial cells is often attributed to Virchow, who in 1846 observed a nonneuronal connective or interstitial substance in the brain and spinal cord in which the elements of the nervous system were embedded (Virchow, 1846; quoted in Somjen, 1988). He referred to this using the term Nervenkitt (nerve-glue), later translated as “neuroglia” or simply “glia.” However, these cells were mostly studied by Cajal and del Río-Hortega, using both the Golgi method and a variety of metallic impregnation techniques that they had developed, particularly Cajal's gold chloride sublimate method. One of Cajal's most important articles on neuroglia was published in 1913 (Ramón y Cajal, 1913), in which he described the detailed morphology of astrocytes and their relationship with neurons and blood vessels (see Fig. F-33). Furthermore, in this article Cajal described a tercer elemento (third element) that was different from neurons and astrocytes, and that he often described as “dwarf adendritic corpuscles.” Some years later, two different types of these corpuscles were identified by del Río-Hortega in a detailed study using silver carbonate methods (del Río-Hortega, 1920, 1928): microglia and oligodendrocytes.

freehand drawings were made directly or with the aid of a camera lucida on different kinds of paper or cardboard, and using various types of pencils, pens, watercolor dyes, India ink, and other common drawing devices, either separately or in a variety of combinations. The camera lucida is a plotting device attached to the microscope that allows the observer to outline the optical microscope image that is projected upon a (p.14)
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Figure F-14. Drawing made by Bonne (1906) showing the main types of cortical neurons and unmyelinated axons (right) based on the studies of Cajal. Numbers 1–12 stand for projection neurons, and 13–35 for short-axon cells.

drawing table (Fig. F-16). Thus, with this device the observer can visualize the paper, the pencil, and the histological preparation at the same time, allowing an accurate drawing of the objects to be produced.

However, I would caution the reader that the use of the camera lucida does not mean that the drawing was always an accurate observation, since it depended on the interpretation of the observer. Indeed, the scientist's drawings of the histological preparations only illustrated those elements thought to be important for what they wanted to describe. As such, these illustrations were not necessarily free of technical errors. Finally, unless otherwise specified, most of the images in the present work are digitalized reproductions from the figures that appear in the publications or, in some cases, of the original drawings. Many of these figures have been retouched and restored in order to remove stains, wrinkles, or other artifacts (Fig. F-17) using Adobe Photoshop CS3 software (Adobe Systems Inc., San Jose, CA).


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Figure F-15. Zeiss model for microphotography published by Cajal in his book Manual de histología normal y de técnica micrográfica (1914).

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Figure F-16. Reichert microscope with Abbe camara lucida published by Cajal in his book Manual de histología normal y de técnica micrográfica (1914).

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Figure F-17. Illustration to show an example of the restoration of the images used in the present book. (Left) Original image. (Right) After restoration. Taken from Fragnito, Le Fibrille e la Sostanza Fibrillogena Nelle Cellule Ganglionari dei Vertebrati (1907).