The workings of the brain have fascinated anatomists and philosophers for millennia. That the early Egyptians knew something about the coverings of the brain -- and that injury to the brain can have effects far from the site of the injury -- is evident from the papyrus bought by Edwin Smith ( 1822 – 1906 ) in Luxor in 1862 . But theological and social opposition to the dissection of cadavers hampered the advancement of knowledge of human anatomy until late into the Renaissance . Andreas Vesalius ( 1514 – 1564 ) included twenty-five illustrations of the human brain and its parts in De Humanis Corporis Fabrica which was completed in 1543 , but the book that was without equal for several centuries was Cerebri anatome published by Thomas Willis ( 1621 – 1675 ) in 1664 ; the illustrations were by Christopher Wren ( 1632– 1723 ) .

However , by the end of the eighteenth century knowledge of the microscopic anatomy ( histology ) of the brain and nerves still lagged far behind that of the macroscopic anatomy , mainly because the essential techniques needed for histology -- fixing , mounting , cutting of thin sections , staining and microscopy -- were still in their infancy . Antony van Leeuwenhoek ( 1632 – 1723 ) in 1719 examined the sliced surface of a peripheral nerve stained with saffron ( yellow ) with one of his magnifying glasses ( microscopes ) and saw what he thought were the minute canals for conveying the ‘animal spirits’ to and from the brain as had been postulated by Galen of Pergamon ( 130 – 200 ) , while Felice Fontana ( 1731 – 1805 ) who used ‘ ..... a lens that magnified five hundred times ..... ‘ concluded in 1781 : “The basic structure of a nerve is as follows : a nerve is formed of a large number of transparent , homogenous , uniform , and simple cylinders” [1].

The main problem with studying the brain , as Johann Reil ( 1759 – 1813 ) had pointed out in 1809 , was that the organ was too soft for it to be dissected properly . The limitations in the histological techniques which impaired the microscopic study of nervous tissue were overcome during the nineteenth century and by the end of the century the tissues could be fixed with minimal distortion of their in vivo architecture , serial thin sections could be cut with a microtome , stains , notably the silver stain , were available , and the simple compound microscope with its blurring spherical aberrations had made way for instruments supplied with achromatic and , after 1886 , apochromatic lenses [2].

These new technical advances now gave neuro-anatomists the chance to learn more about the finer structure of the central nervous systems of animals and humans , an opportunity grabbed with both hands by a remarkable Spaniard who was born on 1 May 1852 in a small town called Petilla de Aragon where his father was a minor surgeon . He was named Santiago Ramόn y Cajal , but chose to be known by his mother’s name , Cajal [3].

In an article published in 2015 , “From the neuron doctrine to neural networks “ , Rafael Yuste , Madrid-born ( 1963 ) Professor of Neuroscience at Columbia University , included a time-bar with information-tags denoting the historical evolution of the Neuron Doctrine between 1873 and 1973 on one page , and from 1977 to 2007 and beyond on the next page ; 1873 is followed by 1888 , 1891 and 1906. The inscriptions in these tags read :, “Invention of the Golgi method” , “Birth of the neuron doctrine” , “Endorsement of neuron doctrine by Waldeyer” , and “Description of receptive fields of neurons in the skin” , respectively [4].

“Invention of the Golgi method” . This refers to the stain for nervous tissue which Camillo Golgi ( 1843 – 1926 ) , Chief Physician of the Pio Luogo degli Incurabili near Milan , ‘invented’ in the kitchen-turned-into-laboratory of the hospital ; it was first mentioned in a letter to a friend on 16 February 1873 [5]. This stain , usually referred to as the “silver stain”, renders the nerve cells and its branches black and the background yellow .

“Birth of the neuron doctrine”. On 1 May 1888 Cajal , now Professor of Histology and Pathological Anatomy at Barcelona , published the first of a long line of articles detailing his studies of the micro-anatomy ( histology ) of the central nervous systems of animals and humans using his modification of the silver stain ; he had an apochromatic Zeiss microscope [6]. Cajal became the leader of the choir of scientists who said the suggestion put forward by Joseph Gerlach ( 1820 – 1896 ) of Erlangen in 1872 [7] that the nerve cells were all joined together to form a diffuse network ( the Reticular Theory ) was wrong . However , convincing the neuroscientific - world that this was so took several decades .

“Endorsement of neuron doctrine by Waldeyer” . One of the most important events in the history of the neuron was the article published by Wilhelm Waldeyer ( 1836 – 1921 ) , Professor of Anatomy at Berlin , in the Deutsche medizinische Wochenschrift of 10 December 1891 . After reviewing the newer researches on the histology of the central nervous system he concluded : “The nervous system is made up of innumerable nerve units ( neurons ) which are anatomically and genetically independent of each other . Each nerve unit consists of three parts : the nerve cell , the nerve fiber and the fiber aborizations ( terminal aborizations )” [8]. Not only did he coin the word “neuron” , which was almost immediately adopted by other neuroscientists , but he laid the foundation for the acceptance of the Neuron Doctrine , the central tenet of which is that the nervous system , like the rest of the body , is made up of a myriad of individual cells .

“Description of receptive fields of neurons in the skin”. An alternative inscription for the 1906 tag could be : “Nobel prize : Golgi and Cajal” . This would refer to the award of the Nobel Prize for Physiology or Medicine of 1906 to Camillo Golgi , Professor of General Pathology at Pavia , and Santiago Ramόn y Cajal , Professor of Histology and Pathological Anatomy at Madrid. The professors of Karolinska Institutet of Stockholm that year recognized Golgi for the development of the silver stain and Cajal for convincingly proving that in animal and human tissues the dendrites and axons of one neuron were in contact with but not in continuity with those of adjacent neurons [9].

If Yuste had pulled the time-bar back to 1800 he would probably have included 1837 , with an inscription in the tag : “Prague 23 September : Purkyně” .

On that Saturday , during the fourth session of the Congress of German Physicians and Naturalists held that year in Prague , Jan Evangelista Purkyně ( 1787 – 1869 ) , Professor of Physiology at Breslau since 1823 , gave a talk in which he shared his recent observations on the histology of the brain cells and nerve bundles .

That this was an important event is evident from the fact that mention of Purkyně’s talk is spread throughout articles and books dealing with the history of the neuron . A commemorative conference “Jan Evangelista Purkyně in Science and Culture” was held in Prague from 26 to 30 August 1987 . In “Purkyně’s Contribution to the Neuron Theory” two Bratislava – based authors discussed the discovery of the neuron and concluded : “Based on ..... it can be stated that it was Purkyně who was the first to describe clearly nerve cells and processes of nerve cells in the brain and spinal cord , as well as unambiguously confirm ..... that nerve tubes indeed have marrow” [10].

Purkyně was born on 18 December 1787 at Libochovice , Bohemia where his father Josef was an economic administrator to a big estate . After primary school he went to a gymnasium run by a Piarist Order which he joined as a novitiate In 1804 . While teaching at a school in eastern Bohemia he came across books about philosophy , and particularly Naturphilosophie , in a monastery library , a subject that was to remain a passion of his all his life. Purkyně continued his philosophical studies at Prague University in 1807 , but when his interests shifted towards science he switched to medicine and graduated Doctor of Medicine on 9 December 1818 having defended his thesis -- “Beiträge über das subjektiver Sehen und Hinsicht” -- in public nine days earlier .

After graduation Purkyně decided against medical practice and continued his teaching and research on visual phenomena and vertigo while observing the physiological effects of drugs -- he tried a crude extract of emetine on himself. At the same time he was taking part in the movement to revive the Czech language and culture in a part of the world dominated by the German language and culture . He wrote poetry in Czech and emphasized the need for a Czech scientific terminology ; with Jan Svatopluk Presl ( 1791 – 1849 ) he co-founded the scientific journal “Krok” ( step / take a step ) in 1821 .

After three unhappy years during which he had unsuccessfully applied for professorships at Prague , ( Buda ) Pest , Graz and Ljubljana , Purkyně was appointed Professor of Physiology and Pathology at Breslau University by King Friedrich Wilhelm 111 ( 1770 - 1840 ) in January 1823 on the advice of his Minister of Culture , Karl vom Stein zum Altenstein ( 1770 - 1840 ) . The minister had overruled objections by members of the faculty and had accepted the recommendations of prominent Berlin professors who were acquainted with Purkyně’s work. One of these was the Stockholm – born anatomist and physiologist Karl Asmund Rudolphi ( 1771 – 1832 ) -- his future father- in- law -- who advised him to think about doing microscopic research .

Purkyně took up the post in Breslau , at the time a thriving city with a Stock Exchange and the largest wool market in Europe , soon after his appointment . He got a cold reception . The Curator ( Administrator ) of the university Friedrich Wilhelm Neumann ( 1763 – 1835 ) and the professor of anatomy Adolph Wilhelm Otto ( 1786 – 1845 ) were amongst those who thought he did not qualify for the post and opposed him at every turn . In his biography of Purkyně the Czech-born American Henry John ( 1885 – 1971 ) recalls what happened : “He had been asked to provide space for Purkyně’s laboratories in the old Anatomy Institute . The room that Professor Otto assigned him and in which demonstrations took place , had formerly been the legal post-mortem room and was also used for surgical exercises on cadavers . ..... But even this room , quite small , was not left to Purkyně’s work alone . It had to be shared with others . Soon he had to make his demonstrations in his own house and this continued for years . His scientific work also had to be done there and that is where the students worked on their dissertation investigations”. Purkyně gave his first physiology lecture on 15 March 1832 . The students liked his lectures and more enrolled to study medicine , including the son of the Rector of the university [11].

His star pupil was the son of a Breslau jeweller : “ The work of Gabriel Gustav Valentin ( 1810 – 83 ) falls into a different category from that of Purkyně’s other pupils , not only because of its much greater scope , but also because Valentin , although setting out as a pupil of Purkyně’s , attained a position of some independence while he was still in Breslau and should be classified as a collaborator rather than as a pupil , as he appears in most textbooks “ [12]. Valentin stunned the neuro-scientific world in 1836 when he published Über den Verlauf und die letzten Ende der Nerven in Acta Leopoldina . The manuscript , which was delivered to the editor on 9 February 1836 , consisted of 199 pages of text and eight plates with 86 images [13]. It was image 54 on plate V11 that caught the eye of other scientists because it was “The first clear image of a nerve cell ( called a globule , Kugeln , by Valentin ) , probably a Purkyně cell , from the cerebellum “ [14]. In his drawing Valentin had picked out four components of the cell -- the granular parenchyma , the nucleus , the nucleolus and the axonal cone – and described their features . Albert Koelliker ( 1817 – 1905 ) , Professor of Anatomy at Würzburg for many years and doyen of late nineteenth century histologists , in 1850 called it “Epochmachende Abhandlung , erste Beschreibung der Nervenelemente” [15].

But alas , by all accounts the personalities of Purkyně and Valentin were at odds : “In 1835 there was a precipitate deterioration in the relationship between the two men . The immediate cause of it remains unknown , but whatever it might have been , it seems probable that part of the problem was that Valentin had difficulty in Breslau in establishing his own scientific persona , a difficulty often encountered by the pupils or collaborators of eminent men” [16]. Valentin did , however , acknowledge his debt to his teacher and his long article of 1836 included phrases such as Purkyně gefünden , Purkyně zuerst beobachung , Purkyně zuerst gesehen hat, and wie Purkinje mir zuerst gezegt hat occur throughout . Because he was a Jew , Valentin accepted the Chair of Physiology and Pathology at Bern where the anti-Jewish bias did not exist and started there on 16 June 1836 ; he stayed until his resignation 45 years later.

Purkyně took part in two sessions during the Congress of German Physicians and Naturalists held in Prague during September 1837 , the much heralded talk on the 23rd when he discussed the histology of the brain cells and nerve bundles , and another talk during the first session on the 19th when he told the delegates about the structure and secretion of the glands in the stomach -- like watered-down hydrochloric acid ; he briefly mentioned the microscopic appearances of some of the other internal organs . The report of Purkyně’s two talks in Bericht über die Versammlung deutscher Naturforscher und Aerzte in Prag im September 1837 , which was published the next year , was accompanied by a plate of twenty-one illustrations which are all about the nervous system except for the first nine which deal with the stomach [17].

Medical historians have passed on what Purkyně had said and illustrated on the 23rd September , most recently in Discovering the Structure of Nerve Tissue : Part 2 : Gabriel Valentin , Robert Remak , and Jan Evangelista Purkyně which was posted online on 3 February 2015 [18]. In The Neuron ( 1967 ) the nerve cell bodies from substantia nigra are described as having “ ..... multiple processes which exhibit the most adventurous forms .....” ; also depicted are the large cells of the cerebellum which became known as Purkyně cells [19]. The plate and translations of Purkyně’s explanatory notes are reproduced in John ( 1959 ) [20]. Two extensive excerpts from the transcript of the meeting ( in translation ) are included in The Human Brain and Spinal Cord ( 1968 ) [21], while in Foundations of the Neuron Doctrine ( 1991 ) some of the drawings are combined with a short quotation from the talk [22].

At the dawn of the twentieth century the evidence in favour of the Neuron Doctrine kept flowing in , but echoes of the Reticular Theory could still be heard . Ironically , one of the scientists who was not convinced was Golgi . He started his Nobel Prize lecture on 11 December 1906 by saying : “It may be strange that , since I have always been opposed to the neuron theory – although acknowledging that its starting point is to be found in my own work – I have chosen this question of the neuron as the subject of my lecture , and that it comes at a time when this doctrine is generally recognized to be going out of favour” [23] -- how wrong he was ! Ultimately the score was settled in favour of the Neuron Doctrine when electron microscopy during the 1950s proved beyond doubt that there was a “synapse” – the word for the gap coined by Charles Sherrington ( 1857 – 1952 ) in 1897 -- between the dendrites and axon of one neuron and those of adjoining neurons [24].

By then another date of note in the annals of the history of the neuron had come and gone -- 24 June 1891. On that day Cajal at a session of the Congreso medico valenciano presented his “Theory of forward polarization : The transmission of the nervous impulse is always from the dendritic branches and the cell body to the axon or functional process” (his italics ) [25]. This theory was similar to the “Law of forward motion” put forward in 1880 by the American physiologist-philosopher William James ( 1842 – 1910 ) to explain the transmission of the stimulus from the sensory root to the motor root. This in turn was an elaboration of the “Law of Bell and Magendie” ( Charles Bell , 1774 – 1842 , and Franςois Magendie , 1783 – 1855 ) that stated that the nerves in the dorsal roots of the spinal cord carry only sensory information from the periphery to the spinal cord whereas the nerves in the ventral roots carry only motor signals from the spinal cord to the muscles ( Bell’s work was published in 1811 and Magendie’s in 1822 ) .

The stage was now set to answer the question : how does the message from the terminal endings of the axon of one neuron cross the synapse to get to the dendrites of adjoining neurons ? It had been suspected for a long time that this was a combined electrical and chemical event , and so it turned out to be . Transmission within the synapse is a chemical event and dependent on receptors responsive to either acetylcholine , adrenalin or nor-adrenalin . Conduction of the impulse through the nerve cell and along the axon occurred when sodium and potassium channels in the cell membrane opened to permit positively charged sodium and potassium ions from outside the cell to enter the cell . This exchange changes the more negatively charged inside of the cell and produces an action potential ; at the level of the axon terminations calcium ions play this role. Much of this work , which was recognized by the award of nine Nobel Prizes in Physiology or Medicine between 1921 and 1970 , was associated with the development of electron microscopy and glass micro-electrodes which could be inserted directly into cells of the central nervous system .

To the great delight of the present Norwegian neuroscience community the Nobel Prize for Physiology or Medicine for 2014 was awarded to husband and wife team Edward and Britt-May Moser ( born 1962 and 1963 respectively ) who shared the prize with US-British citizen John O’Keefe ( born 1939 ) “for their discoveries of cells that constitute a positioning system in the brain” [26]. This comes 127 years after fellow Norwegian and renowned Polar explorer Fridtjof Nansen ( 1861 - 1930 ) in his doctoral thesis of 1887 was the first scientist to question the veracity of the Reticular Theory because he could not find any joined nerve cells in the many slides he had made of the central nervous systems of sea creatures he had found in the fjords around Bergen which he had coloured with the silver stain and examined with the best available Zeiss microscopes [27].

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• 1921 Charles Sherrington ( 1857 – 1952 )
• 1936 Otto Loewi ( 1873 – 1961 ); Henry Dale ( 1875 – 1968 )
• 1963 John Eccles ( 1903 – 1997 ); Alan Hodgkin ( 1914 – 1998 ); Andrew Huxley ( 1917 – 2012 )
• 1970 Bernard Katz ( 1911 – 2003 ); Ulf von Euler ( 1905 – 1983 ); Julius Axelrod (1917 – 2004 )

Under the banner “The New Century of the Brain -- Revolutionary tools will reveal how thoughts and emotions arise” of Scientific American of March 2014 , Yuste and Florida-born ( 1954 ) Harvard University Professor of Genetics George Church wrote : “Despite a century of sustained research , brain scientists remain ignorant of the workings of the three- pound organ that is the seat of all conscious human activity” [28].

They explain that for neuroscientists to understand how the brain recognizes , for example a face , they need technologies that will enable them to monitor and alter the electrical activity of thousands or even millions of neurons . In pursuit of this need the Obama Administration agreed to fund the $100 million BRAIN Initiative ( Brain Research through Advancing Innovative Neurotechnologies Initiative ) aimed at developing instruments that can record signals from multiple brain cells and preferably from whole areas of the brain , while the European Union had committed $ 1.6 billion to develop a computer simulation of the entire brain -- “The Century of the Brain is now upon us” , they declared .

These initiatives would have brought smiles to the faces of Hans Berger ( 1873 – 1941 ) and William Grey Walter ( 1910-1977 ) who between them first invented -- in 1928 -- and later -- from 1936 onwards -- further developed the electroencephalogram ( EEG ) which is today an indispensable part of medical practice .

After years of lobbying the university powers that be the Institute of Physiology , the first of its kind anywhere in the world , opened its doors on 8 November 1839. Sadly , and mainly due to financial constraints , the institute was housed in an adapted brick shed with a damp ground floor and dark rooms , and not the purpose-built building Purkyně had planned .

Purkyně stayed at Breslau until the Easter of 1850 when he returned to Prague as Professor of Physiology ; he was 63 years old . There he established another Institute of Physiology while continuing to be a major contributor to the revival of the Czech language and culture .

Jan Evangelista Purkyně died at noon on 28 July 1869 at the age of 81 from the consequences of bladder stones . He was buried three days later : “Yesterday Prague gave striking proof that she is totally conscious of the passing of a great man who lived here and worked for his people . Purkyně’s funeral was a magnificent tribute but a sad occasion . Nearly all of Prague took part . Sad faces showed how touched everyone was at the loss of a great man who can never be replaced” [29].

I am a long-retired gastro-enterologist and am not associated with any academic institution ; I paid for all the costs incurred myself. My wife Mary helped with the editing and corrected the spelling and punctuation mistakes .

The essay was recommended for publication by Associate Professor Alexandr Chvátal of the Department of Molecular Neurophysiology of the Czech Academy of Sciences in Prague , and Dr Juan De Carlos of the Cajal Institute in Madrid .