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Home , Eduard Hitzig, History of neuroscience, Neuroethology, Neurophysiology, Neuroscience, Neuroscientist

Some Revolutions in

Charles Gross Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 Abstract

■ In the long history of the study of the , tics and strategies for studying it. These may be termed there have been a number of major developments that Revolutions in Neuroscience. This essay considers eight of involved radical and permanent changes in fundamental these, ranging from the 6th century BCE to the end of the beliefs and assumptions about the nervous system and in tac- 20th century. ■

THE PRE-SOCRATIC PHILOSOPHERS AND THE IDEA OF and Democritus. Many of them were interested in sensory processes as sources of knowledge. The pre-Socratic philosophers were responsible for the The first writer to advocate the as the site of very idea of formal science: the idea that the physical sensation and was the pre-Socratic Alcmaeon of and biological universe was governed by consistent and Croton, a Greek colony in what is now southern Italy. He universal laws that were amenable to understanding by is said to have written: . This was a revolutionary change from the previous prevailing view of the universe as a plaything The seat of sensations is in the brain. This contains of gods and ghosts acting in an arbitrary and capricious the governing faculty. All the are connected fashion. in some way with the brain; consequently, they The pre-Socratics lived in the 6th–4th century BCE in are incapable of action if the brain is disturbed or various Greek city-states. They called themselves “physio- shifts its position, for this stops up the passages logia,” which is best translated as “natural philosophers.” through which senses act. This power of the brain They conceived their inquiries as demanding rational to synthesize sensations makes it also the seat criticism and public debate and involving observation and of : the storing up of gives measurement (systematic experimentation especially in and , and when these are stabilized would be almost unknown for several centuries). you get knowledge (Theophrastus, 1917). The earliest pre-Socratics were Thales, Anaximander, and Anaximenes. All three came from the city of Miletus, Alcmaeon is reported to have been the first to use a Greek city-state in Ionia on the West shore of modern as a tool for intellectual inquiry. He dissected Turkey, and thus are often known as Milesians or Ionian the eye and described the optic and chiasm and philosophers. There are several likely reason why Miletus suggested that they brought light to the brain. He ob- was the “cradle of science.” It was a wealthy port city, served phosphenes after a blow to the head and inferred which brought together products and ideas from Greek, that the eye contained light and that this light was neces- Phoenician, and Egyptian sea traders and caravan mer- sary for vision, a view only disproved in the middle of the chants from as far as India and China. Power was moving 18th century. from the landed aristocracy to the merchant classes inter- Democritus is among the other pre-Socratic philoso- ʼ ested in new techniques and concepts. In this new city- phers who extended Alcmaeon s views on the functions state, there was open debate about the of society of the brain. He taught that everything in the universe is and the world. composed of atoms. The psyche (, ) is made up These early natural philosophers sought fundamental of the lightest, most spherical, and fastest-moving atoms. principles underlying the universe. For example, Thales Psychic atoms are found mostly in the brain. Slightly cruder thought that water was fundamental, whereas Anaximenes atoms are found in the , making it the center of emo- argued for air as the basic element and discussed the tion, and still cruder ones are in the liver, making it the ʼ various forms it might take. Among the other major pre- seat of lust. This trichotomy developed into s hier- Socratics were Heraclitus, Pythagoras, Empedocles, Zeno, archy of the parts of the soul, and through his treatise, “Timaeus” was very influential into the 18th century. The various pre-Socratic natural philosophers had a Princeton University variety of views on the nature of the universe, the body,

© 2012 Massachusetts Institute of Journal of 25:1, pp. 4–13 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00308 by guest on 28 September 2021 and the brain. What they held in common was the view the brain, a clear statement of Mullerʼs doctrine of spe- that these could be understood by the use of observation cific energies. Galenʼsdescriptionsofthegross and reason. This assumption was a revolutionary one, of the brain were very accurate, particularly with marks the beginning of formal science in the West, and respect to the ventricles and the cerebral circulation, is still the basis of modern science. which are both important in his physiological system. This account is based on Gross (1998); the usually presented his as if they were of of Freeman (1954); the accounts of Longrigg (1993), Lloyd the human, but in fact, except for the osteological ones, (1970), Sigerist (1961), Sarton (1959), and Farrington they were invariably of , which are usually the ox (1944); and the appreciations of Popper (1969) and in the case of brain anatomy, the Barbary “ape” (the Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 Schrodinger (1954). M. sylvana) for cranial nerve anatomy, and pigs Systematic rational inquiry into the nature of the universe for vivisection. (He did not like to vivisect monkeys arose in China at about the time as the pre-Socratics, but because, he said, of the expressions of their faces when the two traditions are rather different (Lloyd & Sivin, 2002; he did so.) It was only very recently when Galenʼsde- Lloyd, 1996) and had little interaction for many centuries. scriptions were evaluated in terms of the actual species dissected that their great accuracy was recognized (Rocca, GALEN AND THE EXPERIMENTAL 2003). ʼ INVESTIGATION OF THE NERVOUS SYSTEM However, Galen s truly revolutionary work was in car- rying out the first systematic experiments on the func- Galen of Pergamon (129–213 CE) was, by far, the most tions of the nervous system. Galen realized that the important physician, anatomist, and physiologist of clas- was an extension of the brain. In his brilliant sical antiquity. His ideas were so pervasive that Western and systematic experiments on sectioning the cord, he well into the 18th century largely saw the struc- compared the effects of hemi-transection and total tran- ture and of the body through his eyes. Today, section at different levels and noted that injuries inter- his voluminous writings provide a vivid account of the fered with sensory and motor function below the level controversies and achievements of the 600 years of clas- of the section, that hemisection affected only one side, sical biology and medicine. and that sagittal section did not produce paralysis. He Galen was the first to carry out systematic experiments accurately described the different roles of the spinal on the nervous system, thereby initiating a major revolu- nerves in . He even came very close to the tion in the study of the nervous system. Before Galen, Law of Spinal Roots: “The physicians do not even know there were only a few isolated examples of systematic that there is a special root at the origin of the nerves experiments such as in , those of Strato and Hero which are distributed to the entire hand and from which on vacuums and Ptolemy on optics. In biology and medi- sensation arises; [nor do they know] that there is another cine, observation and dissection were the only methods of root for the nerves moving the muscles” (Galen, 1962). investigation, unless one wants to consider trying out pos- Galen used piglets in his experiments on brain lesions. sible poisons on prisoners as a type of experimentation. He found that anterior had less deleterious Galen was born in Pergamon, which is now the Turkish effects than posterior. He viewed sensation as a central city of Bergama, and studied medicine there. His first process because he knew from his clinical observations three medical treaties were published while he was a medi- and experiments that sensation could be impaired cal student. (Although most of his writing was lost, the by brain injury even when the organs were intact. extant ones comprise 22 large volumes, more are discov- Because animals could survive lesions that penetrated to ered every few years and many are still untranslated into the ventricles, Galen thought that the soul was not located English). He then continued his medical studies in several there but rather in the cerebral substance. He taught that other medical centers including Alexandria, which was a all mental diseases were brain diseases. leading center of . He then returned to Galenʼs most famous experiment was the public dem- Pergamon as the physician to the gladiatorial school there onstration of the effects of cutting the recurrent laryngeal where he acquired considerable clinical experience. When nerve on squealing in a pig. Although the encephalocentric the “games” were closed, Galen moved to Rome where he view that the brain controlled sensation, movement, and rapidly rose in medical and social circles, eventually serving cognition remained strong in the Greco–Roman medical as physician to four Roman emperors starting with Marcus , the opposing cardiocentric view that the heart Aurelius. was the center of sensation and cognition was also active Galen made a number of major discoveries, particu- in Rome at this time, being advocated by the Stoic school larly on the anatomy and of the nervous sys- and its leader Chyrsippus (280–207 BCE). To refute their tem. He described in detail the course of nine, if not 10, view that the heart, not the brain, controlled cognition, of the (although he grouped them as seven Galen arranged this public demonstration and invited lead- pairs) as well as the sympathetic nerve trunks. He distin- ing Roman intellectuals on both sides of the question. guished sensory and motor nerves for the first time and Previously, Galen had carried out a series of anatomical thought that this distinction derived from their source in and physiological studies on the recurrent laryngeal nerve

Gross 5 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00308 by guest on 28 September 2021 in a variety of birds and mammals. He showed that cutting 3. Differences in traits among people and within individ- this nerve would eliminate vocalization. Because vocaliza- uals depend on differential of different tion was seen as reflecting the cognitive activity language, cortical areas. Galenʼs public demonstration that cutting a nerve originat- 4. Development of a cortical area is reflected in its size. ing in the brain would eliminate squealing in a pig was the 5. Size of a cortical area is correlated with the overlying first and most famous demonstration that the brain con- (“bumps”). trols cognition. It inspired Leonardo to produce a beautiful drawing of the human recurrent laryngeal nerve. Vesalius These otherwise reasonable hypotheses had one fatal gave it a prominent place in his great On the Fabric of the flaw: the nature of the evidence. Gall and Spurzheim re- Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 (without mentioning Galen) and repeated lied almost entirely on obtaining supportive or confirma- the demonstration in his own public lectures in Padua. tory evidence. They collected large numbers of of The edition of Galenʼs works included an people whose traits and abilities were known, examined engraving of him carrying out the experiment on a huge the heads of distinguished savants and inhabitants of pig in front of a very distinguished audience. mental hospitals and prisons, and studied portraits of This account is based on Gross (1998, 2009) wherein the high and low on various intellectual and affective di- reference to translations of Galenʼs works and various mensions. Throughout, they were seeking confirmation commentaries on Galen may be found. of their initial hypothesis usually deriving from a few cases. For example, the idea for a language organ in the frontal lobes came from Gallʼs experience of a class- GALL AND : LOCALIZATION OF mate who had a prodigious verbal memory and protrud- FUNCTION IN THE ing eyes (being pushed out by a well-developed , Gall thought). The idea for an organ of destructive- The revolutionary idea that different regions of the ness came from the skulls of a parricide and of a murderer cerebral cortex have different functions begins with Franz that were sent to him, from noticing its prominence in Joseph Gall (1748–1828) and phrenology. Before Gall, a fellow medical student who “was so fond of torturing the cerebral cortex was almost always dismissed as a animals that he became a surgeon,” and from examining mere covering or “rind,” which indeed is the the head of a meat-loving dog he owned. All their meth- of the Latin word “cortex.” It was usually drawn resem- ods were used to seek confirmations; contradictions were bling intestines following the description of the 2nd explained away. Gall and Spurzheimʼscorticallocalizations century Alexandrian anatomist . were of “higher” intellectual and personality traits. They Marcello Malpighi (1628–1694), the discoverer of capil- accepted the prevailing view that the highest sensory laries, was the first to examine the cortex under the micro- functions were in the thalamus and the highest motor scope. He saw it as a makeup of little glands or “globules,” functions, in the corpus striatum. and Leuwenhoek (1632–1723) and others followed suit. Phrenology met with considerable opposition from This was a common view in the 17th and 18th century per- political and religious authorities, particularly on the con- haps because it fits with the much earlier view of tinent, largely because it was viewed as implying mate- that the brain was a cooling organ and with the Hippo- rialism and determinism and denying the unity of the cratic theory that it was the source of phlegm. mind (and soul) and the existence of . On the The other common view was that the cortex was largely other hand, phrenology widely spread particularly in made up of blood vessels; as Frederik Rusch (1628–1731) the United States and Great Britain both as a medical put it, “The cortical substance of the is not doctrine and as a “pop” . It generated wide- glandular, as many anatomists have described it…but spread interest both among the general populace and highly vascular.” Albrech von Haller (1708–1777), who among such writers and savants as Honore de Balzac, dominated physiology in the 18th century, also held a vas- Charles Baudelaire, George Eliot, August Comte, Horace cular view of cortex. He found mechanical and chemical Mann, Alfred Russell Wallace, and George Henry Lewis. In stimulation to be without effect throughout the cortex fact, it rapidly became a popular fad and drawing room and declared it completely insensitive. amusement, particularly in Great Britain and the United Given this view of the insignificance and uniformity States. Phrenological societies and journals continued to of the cerebral cortex, the phrenological ideas of Gall flourish in both countries well into the 20th century. and his collaborator J. C. Spurzheim (1776–1832) were In spite of its absurdities and excesses, phrenology indeed revolutionary. became a major spur for the development of modern The central aim of phrenology was to correlate brain neuroscience in a variety of ways. Gallʼs mistaken assump- and function. It had five basic assumptions: tion of a correlation of skull and brain was 1. The brain was an elaborately wired machine for produc- soon recognized, at least in the scientific community. Phre- ing , thought, and . nology generated an interest in the brain and behavior. It 2. The cerebral cortex was a set of organs, each corre- directed to the cerebral cortex. It stimulated study sponding to an affective or intellectual function. of both damage and experimental lesions in

6 Journal of Cognitive Neuroscience Volume 25, Number 1 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00308 by guest on 28 September 2021 animals. It inspired tracing pathways from sense organs with platinum wires with “galvanic stimulation”:briefpulses andtothemusclestoidentify“organs” of the cerebral cor- of monophasic direct current from a battery at the mini- tex. It spurred the anatomical subdivision of the cerebral mum current that evoked a sensation on their tongue. cortex (cytoarchitectonics, myeloarchitectonics) to find The usual response to this stimulation was a muscle organs of the brain. twitch or spasm (“Zückung”). Their central findings were When Broca reported a language area in the frontal that (a) the stimulation evoked contralateral movements; lobe in 1861, he claimed it as a double confirmation of (b) only stimulation of the anterior cortex elicited move- Gall: both in the specific location of a language area in ments; (c) the stimulation of specific parts of the cortex the frontal lobe and the more general idea of punctate consistently produced the activation of specific muscles; Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 localization of psychological function in the cerebral and (d) the excitable sites formed a repeatable, if rather cortex. sparse, map of movements of the body laid out on the The cytoarchitectonic, PET, fMRI, and other imaging cortical surface. They went on to show that lesion of maps of the cerebral cortex that are now ubiquitous in a particular site impaired the movements produced by , , and stimulation of that site. The loss of function was not com- textbooks bear more than a coincidental resemblance plete, suggesting to them that there were other motor to phrenological charts. They are the direct descendants centers that had not been impaired by the lesion. of the iconoclastic, ambitious, and heavily flawed program Fritsch and Hitzig had no hesitation in announcing the of phrenology to relate brain structure and behavior. general significance of their discovery: This account is based on Gross (1998, 2009) and the by the results of our own investigations, the premises references cited therein, especially Young (1970) and Gall for many conclusions about the basic properties of the and Spurzheim (1835). brain are changed not a little…some psychological functions, and perhaps all of them…need circumscribed centers of the cerebral cortex. (Fritsch FRITSCH AND HITZIG: THE DISCOVERY OF & Hitzig, 1870/1960) What led Fritsch and Hitzig (1870/1960) to electrically Modern neurophysiology began with Fritsch and Hitzigʼs stimulate the cortex of a dog? This was a period of great (1870/1960) discovery that stimulation of the motor cor- activity and interest over the new discoveries about elec- tex produces movement. Their discovery was a major tricity in both salons and laboratories: such intriguing revolution in neuroscience becauseitwasthefirstex- gadgets as electrostatic machines, the Leyden jar, and perimental evidence that the cortex was involved in the gold leaf electroscope (Gross, 2009). At this time, it movement, the first demonstration that the cortex was was realized that man-made electricity and lightning were electrically excitable, the first strong experimental evi- the same phenomenon as that found in the dence for functional localization in the cortex, and the (an animal whose shocking properties had been known first experimental evidence for somatotopic representa- since classical times). There were a number of attempts tion in the brain. to use electricity for therapeutic purposes (including that At the time of their 1870 experiment, Fritsch and Hitzig by the French revolutionary Marat and the American were young physicians associated with the Physiolog- savant and revolutionary Benjamin Franklin) and even ical Institute. Fritsch, before and after this collaboration, studies of electrical stimulation of various from was interested in studying hair and eye color in non- to dead human (Finger, 2000; Brazier, 1959, 1984). European societies with a view toward establishing the Although there were reports of effects of stimulation of superiority of the White race (Grundfest, 1963). Hitzig the spinal cord and brain stem, all attempts at eliciting continued research on motor cortex after his article with effects of stimulation of the cerebral cortex had been uni- Fritsch and, in addition, became a successful . versally ineffective. As Fritsch and Hitzig put it in the in- He came from a distinguished Jewish family; he was later troduction to their article: described by one of his biographers as “a stern and for- Even in other fields than in physiology, there can bidding character of incorrigible conceit and vanity com- hardly be a question about an opinion which seems plicated by Prussianism” (Finger, 2000; Kuntz, 1953). to be so unanimous, which seems to so completely In their now classical experiment, Fritsch and Hitzig settled as that of the excitability of the cerebral strapped their dogs down on Frau Hitzigʼs dressing table, hemisphere. (Fritsch & Hitzig, 1870/1960, p. 75) as there were no animal facilities at the institute (Kuntz, 1953). In their early experiments, they used no anesthe- One impetus to their experiment was the paradox that sia or analgesic, although ether surgical anesthesia had some CNS were excitable and yet the cortex been introduced in 1846 and morphine analgesia in 1803 did not seem to be. Another was their own previous ob- (Magner, 1992). Later, they did use “morphine narcosis.” servations. Hitzig had tried electrical stimulation of the They began by removing the cranium and cutting the dura, for therapeutic purposes and had noticed the dog showing “vivid .” They stimulated the cortex that it caused eye movements (Hitzig, 1870). He then

Gross 7 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00308 by guest on 28 September 2021 tried rabbits and also elicited movements. Fritsch, while physiological, genetic, and metabolic bases of its func- working as a battlefield surgeon, had apparently noticed tions, may be viewed as the single most important revolu- that the contralateral limbs twitched while dressing an tion in the entire . The open head wound (Walker, 1998). doctrine was built on the work of several generations of Soon after the Fritsch and Hitzig (1870/1960) article . However, the work of two men were crucial appeared, the young Scotch physician David Ferrier set in its final acceptance, Camilio Golgi (1843–1926) and out to follow up the Germansʼ work on motor cortex Santiago Ramón y Cajal (1852–1934). Ironically, although (Viets, 1938). Ferrier had been heavily influenced by John Golgi provided the technique that allowed Cajal to accrue Hughlings Jackson and realized that they had confirmed convincing evidence for the , he bitterly Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 Jacksonʼs ideas. In a variety of species including , opposed this doctrine until the end of his . Ferrier replicated their basic findings that stimulation of Matthias Schleiden (1804–1881) suggested in 1838 the cortex can produce specific movements and that that all tissues are made up of cells, and Theodor there is a topographic “motor map” in the cerebral cortex Schwann (1810–1882) extended this to animal (Taylor & Gross, 2003; Ferrier, 1873, 1874–1875, 1875). the next year. However, the nervous system resisted in- Although not noticed at the time, there were actually terpretation in terms of theory for about another considerable differences in the methods, results, and 50 years. This was because, with the stains and micro- interpretation of Fritsch and HitzigʼsandFerrierʼsex- scopes available, independent -contained cells were periments on motor cortex (Taylor & Gross, 2003). The not discernible in the nervous tissue. Rather, the nervous former used brief, direct current pulses and obtained system often looked like an anastomosing network or localized muscle twitches, whereas Ferrier used much “reticulum.” Some neuroanatomists did hold the neuron longer duration biphasic stimulation that tended to pro- doctrine, the extension of to the nervous sys- duce complex integrated movements rather than muscle tem; whereas others supported the “reticular doctrine,” twitches. the idea that the nervous system was a network of inter- Both Fritsch and HitzigʼsandFerrierʼsarticleson connecting fibers. motor cortex were initially greeted with considerable The resolution of this question came, eventually, from and equal skepticism. Their results went against the gen- the discovery by Golgi in 1873 of a new silver stain that erally accepted views that the striatum was the highest stained a small proportion cells but did so in their entirety. motor center and that the cortex was inexcitable. The Using this stain Golgi (a) confirmed Otto Deitersʼs (1834– critics usually interpreted the results of Fritsch and Hitzig 1863) earlier observation of a single (“axis cylinder”) and of Ferrier as artifactual due to “spread of current” to coming from each nerve cell, (b) found that the striatum, then considered the highest motor center. (“protoplasmic prolongations”) ended freely, (c) discov- To overcome these criticisms, Horsley, Sherrington, and ered axon collaterals and thought that they merged with others began meticulous “punctate” mapping of cortex the axon collaterals of other nerve cells to form a diffuse using the minimum current to elicit the smallest dis- reticulum, and (d) classified nerve cells by their processes. cernable movement (e.g., Brown & Sherrington, 1915; Golgi believed that the functions of dendrites, and not Horsley & Schafer, 1888; Beevor, 1887). This resulted the conducting of messages, was nutritive. He had a holis- in both an acceptance of the reality of a motor cortex tic view of brain function and thought that the reticulum, and a stress on motor cortex controlling individual mus- made up of anastomosing axon collaterals, was the basic cles, that is, in a Fritsch and Hitzig view rather than a mechanism of brain function. This, he thought, accounted Ferrier one. for such phenomena as recovery from brain damage. His The extent to which motor cortex controls muscles, as holism led him to disbelieve the localization results of opposed to complex movements, continues to remain as Fritsch and Hitzig and Ferrier. an issue in the study of motor cortex, with most contem- Fourteen years later, Ramón y Cajal first came across porary investigators leaning toward a Ferrier-like view of the Golgi silver stain and was flabbergasted: complex movements rather than a Fritsch-and-Hitzig- type view of the punctate control of individual or small Against a clear background stood black threadlets, groups of muscles by a circumscribedregionofcortex some slender and smooth, some thick and (e.g., Graziano, Taylor, & Moore, 2002; Graziano, Taylor, thorny…. All was sharp as a sketch with Chinese Moore, & Cooke, 2002; Kakei, Hoffman, & Strick, 1999; ink on transparent Japanese paper. And to think Georgopoulos, Schwartz, & Kettner, 1986). that that was the same tissue which stained with carmine…left the eye in a tangled thicket where sight may stare and grope forever fruitlessly, baffled NEURON DOCTRINE: GOLGI AND in its effort to unravel confusion and lost forever RAMÓN Y CAJAL in a twilit doubt. Here on the contrary, all was clear and plain as a diagram. A look was enough. The neuron doctrine, the idea that the nervous system is Dumbfounded, I could not take my eye from the made up of discrete nerve cells that are the anatomical, (translated by Sherrington, 1935).

8 Journal of Cognitive Neuroscience Volume 25, Number 1 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00308 by guest on 28 September 2021 Cajal immediately began making the often-capricious modulated by the discovery of a very small number of Golgi method more reliable, particularly by working with gap junctions in which the cell membranes of adjacent younger animals with less because myelin is resis- are immediately contiguous even under the tant to silver . He soon confirmed Golgiʼs findings and synaptic transmission is elec- on single from each cell, on freely ending den- trical. The Law of Dynamic Polarization is still a property drites, and on the existence of axon collaterals. However, of neural circuits, although the existence of axon-less neu- unlike Golgi, Cajal concluded that axon collaterals did rons, dendro-dendritic, and axon-axonal has not anastomose but ended freely: neurons were separate complicated the picture. As Gordon Shepherd points independent units. Although were not able out, although the neuron is still the functional unit of Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 to actually see the gap between neurons, Cajal inferred the nervous system, it is useful to think of subcellular units (“intuited” might be a better term) its existence on sev- such as dendritic trees, microcircuits, and synapses as eral grounds. One was by using immature or even fetal well as supra cellular ones such as local circuits and inter- animals where he observed axons growing out of cell regional systems (Shepherd, 1991). bodies before approaching other neurons or muscles. This account is based on Shepherd (1991) as well as Another was that, when cutting a nerve fiber, it would Raviola and Mazzarello (2011), Jones (2010), and De Carlos degenerate but only up to the border with the next cell. and Borrell (2007). Cajalʼs of Golgiʼs silver staining methods spread rapidly among the neuroanatomists of Europe, and they used it to confirm Cajalʼssupportfortheneuron CHEMICAL TRANSMISSION theory: both axon collaterals and ended freely; Charles Sherrington (1857–1952) named the gap be- there was no evidence for an anastomosing network. tween neurons implied by the neuron doctrine as the Beyond confirming the idea of the neuron as an inde- “.” By this time, it was realized that conduction pendent unit, Cajal went ontomakefurtherdevelop- down the axon was electrical, so it was often assumed ments of the neuron theory. The first was the “Law of that conduction across the synapse was electrical too. Dynamic Polarization,” the idea that trans- There had also been some suggestions of a chemical mission was from the dendrites to the cell body and out mediator particularly at the neuromuscular junction. For along the axon. This had been put forward earlier by the example, in the 1840s, Claude Bernard (1813–1878) William James (1880) and the physiologist showed that curare (from a poison arrowhead obtained Charles Sherrington (1906) but had little impact on the from Brazil) caused muscle paralysis and did so with- anatomical community (both cited in Shepherd, 1991). out affecting either nerve conduction nor muscle re- Cajal then used this “law” to work out several neural cir- sponse but appeared to act on the junction between cuits that began with sensory receptors in the or in nerve and muscle. In 1878, Emil du Bois-Reymond the olfactory bulb. A further development was the demon- (1818–1896) suggested that muscle could be activated by stration of the reality of dendritic spines, which had earlier “” of a “powerful stimulatory substance” from been thought of by Golgi as staining artifacts. the nerve endings. In 1906, the Nobel Prize was shared by Golgi and Cajal The first clear suggestion of chemical transmission in “recognition of their work on the anatomy of the came from Thomas Elliott (1877–1961), a student of John nervous system,” which had made them “the principal Langley (1852–1925). Langley had been the first to dis- representative and standard bearers of the modern sci- tinguish the sympathetic and parasympathetic divisions ence of .” Golgiʼs Nobel address was a vigorous of the . Elliott showed that defense of the reticular theory, beginning with the claim (from the adrenal glands) reproduced the ef- that the neuron theory “is generally recognized as going fects of sympathetic nerve stimulation and suggested that out of favor” and going on to attack the idea of the neu- adrenaline might then be the chemical that stimulation ron as an anatomical, physiological, and developmental liberated when the nerve impulse arrives at the periphery unitaswellasCajalʼs law of dynamic polarization. In (Elliott, 1905). In 1914, Henry Dale discovered that acetyl- general, he ignored the previous 30 years of work by choline mimics the action of the parasympathetic system Cajal and much of the neuroanatomical community. Fi- and that adrenaline mimics the action of the sympathetic nally, he defended his ideas of a nerve network to explain system, but he did not yet realize that both chemicals are the holistic aspects of brain function. Many of his holistic produced by nerves. arguments anticipate contemporary nerve network theo- The chemical transmission revolution developed over ries. Cajalʼs Nobel address answered Golgi and reviewed the first 50 years of the 20th century, but the single most in detail his evidence supporting the neuron theory and important experiment was that of in 1921. It the law of dynamic polarization. was a very simple experiment, and Loewi claimed it came Over 100 years later, the neuron doctrine still stands to him in a . Here is his description of it: as the bedrock of neuroscience. Its fundamental tenet of discontinuity between neurons was finally confirmed The of two were isolated [in a bath by the electron microscope in the 1950s, only to be soon of Ringers], the first with its nerves attached, the

Gross 9 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00308 by guest on 28 September 2021 second without…. The of the first and a Nobel laureate, but then in 1935, a newly arrived heart was stimulated for a few minutes. Then the Jewish refugee from Germany noted: Ringer solution that had been in the first heart To my great astonishment [at the meeting of the during the stimulation of the vagus was transferred Physiological Society] I witnessed what seemed to the second heart. It slowed and its beats to be almost a stand-up fight between J. C. Eccles diminished just as if the vagus had been stimulated. and H. H. Dale, with the chairman E. D. Adrian Similarly when the accelerator nerve was stimulated acting as a most uncomfortable and reluctant referee. and the Ringer from this period transferred, the

Eccles had presented a paper in which he disputed Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 second heart speeded up and its beats increased the role of as a transmitter in the (Loewi, 1960). sympathetic ganglion.… When [he] had given his talk, he was counterattacked in succession by On the basis of this experiment, Loewi reported that Brown, Feldberg, and Dale… [However] it did not stimulation of the vagus produced “” that take me long to discover that this form of banter slows the frogʼs heart (later identified as acetylcholine) led to no resentment between the contenders, and that stimulation of the accelerator nerve produces it was in fact a prelude to much fruitful discussion “acceleranstoff,” which speeds the heart (and was over the years and indeed to growing mutual later identified as adrenaline). It took over 10 years admiration between Dale and Eccles (Katz, 1996). for Loewiʼs results to be generally accepted in part be- cause getting positive results depended on the species Alexander Forbes, Professor of Physiology at Harvard of frog used, the season, the water temperature, and and one of the founders of modern neurophysiology other variables. commented on the debate in a 1939 review: In 1936, Loewi and Dale shared the Nobel Prize for their discovery of . Even after the prize So goes the controversy. Dale, in discussing it, was given to Loewi and Dale, there was still a great deal remarked that it was unreasonable to suppose of skepticism about the significance and generality of that nature would provide for the liberation in their results. Although it was conceded that adrenalin the ganglion of acetylcholine, the most powerful might be a transmitter at some visceral organs, most known stimulant of ganglion cells, for the sole neurophysiologists rejected acetylcholine as a possible purpose of fooling physiologists. To this, Monnier transmitter at skeletal muscles. One reason was that they replied that it was likewise unreasonable to thought that chemical transmission was much too slow suppose action potentials would be delivered at for their measurements of action at the neuromuscular the synapses with voltages apparently adequate junction. Another problem was that available estimates for exciting the ganglion cells merely to fool of the width of the synaptic cleft made chemical trans- physiologists (Forbes, 1939). mission across it seem very unlikely, if not impossible. To explain newly discovered phenomenon such as exci- The possibility of chemical transmission at central syn- tation at some sites and inhibition at others, Eccles de- apses was generally thought even more impossible veloped more and more arcane theories to account for for similar . It was certainly not possible to detect such phenomena in terms of electrical transmission at the transmission at central synapses at this time. Positive synapse, such as the “Golgi-cell hypothesis.” The develop- evidence for chemical transmission usually involved col- ment of intracellular recording electrodes in 1951 made lecting perfusates or applying drugs and was often dis- it possible to directly test these ideas on central synapses. missed as “pharmacological” (i.e., artifactual) and not Eccles and his colleagues did so on a small spinal cord “physiological.” cell, the Renshaw cell, later that year and falsified (he was Valenstein (2005) has pointed out a social–ideological a big Popper fan at this point) his hypothesis reporting: background of this reluctance to accept chemical trans- “ ” mission. In this battle of the soups and sparks, most of The potential charge observed is directly opposite the sparks advocating electrical transmission were neuro- to that predicted by the Golgi-cell hypothesis, which physiologists using high-tech electronic and quantitative is thereby falsified…. The experimental observations methods and looked down on the soups advocating chem- on synaptic excitatory and inhibitory action require ical transmission, who were usually pharmacologists using for their explanation two specific transmitter what the sparks consider crude methods. Furthermore, substances. (Brock, Cooms, & Eccles, 1952) even then pharmacologists were associated with the odium theologicum of drug companies in the of The “war of the soups and sparks” was over: The chief neurophysiologists (actually, Dale did work for Wellcome spark had capitulated. There are now hundreds of chemi- for most of his career). cals that are known to act as transmitters at synapses. J. C. Eccles was the leading “spark.” The intensity of Almost as soon as the dust had settled and chemical trans- the soup versus spark debate often surprised outsiders mission was enthroned, electrical synapses were found to the English academic scene. , later Sir by Furshpan and Potter (1957). Although very small in

10 Journal of Cognitive Neuroscience Volume 25, Number 1 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00308 by guest on 28 September 2021 number, they are widespread in both invertebrates and by now, universally held tenet of neuroscience. Altman vertebrates. was denied tenure at MIT, presumably on the authority This account is largely based on Shepherd (2010) and of , one of the leading anatomists of the Valenstein (2005). day, who was one of three tenured members of his de- partment at this time. Altman then moved to Purdue Uni- versity where he eventually turned to more conventional IN ADULT MAMMALS developmental questions, perhaps because of the lack of recognition of his work on adult neurogenesis (Altman, Virtually from the beginning of the neuron doctrine, a basic 2011; Gross, 2009). Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 corollary was that no neurons are added to the brain after Fifteen years after Altmanʼs first report of adult neuro- infancy in mammals. In Ramón y Cajalʼs (1913/1928) words: genesis, direct support for his claim came from a series of electron microscopic studies by Michael Kaplan and his In the adult centers the nerve paths are something co-authors. They showed that thymidine labeled cells fixed, ended and immutable. Everything may die, in the olfactory bulb, dentate gyrus, and neocortex of nothing may be regenerated. adult rats had the ultrastructural characteristics of neu- Because the elaborate architecture of the adult mamma- rons, such as dendrites and synapses, supporting the lian brain did not change even under the most powerful earlier claims of Altman. In spite of his evidence for adult microscopes, the idea that neurons were being continually neurogenesis, Kaplanʼs work had little impact at the time added to the brain was quite inconceivable. Further (Kaplan, 2001). Again, as in Altmanʼs case, publication support for this view was the total lack of evidence that in prestigious and rigorously reviewed journals by an damaged neurons were ever replaced in the CNSs of unknown figure was not sufficient to make any significant adults. This dogma of “no new neurons in the adult mam- dent in the central dogma of “No New Neurons.” malian brain” remained dominant until the adult neuro- A primary reason for the submergence of Altman and genesis revolution in the 1990s. There are few, if any, Kaplanʼs evidence for adult neurogenesis was probably a views of the brain in modern times that have persisted study by , professor at Yale Medical School so long with so little challenge. and, arguably, the leading student of brain devel- In the first half of the last century, there were a few dis- opment. He carried out a [3H]-thymidine study of adult sents from the dogma, but their accounts were invariably rhesus monkeys in which he examined “all major struc- ignored. Presumably, this was because of the weight of tures and subdivisions of the brain including association authority opposed to the idea and the inadequacy of the cortex, and olfactory bulb” and found “not available methods both for detecting cell division and for a single heavily labeled cell with the morphological char- distinguishing from small neurons (Gross, 2000, 2009). acteristics of a neuron in any brain of any adult animal.” A major advance in the study of neurogenesis came in He concluded that “all neurons of the rhesus monkey the late 1950s with the introduction of tritiated thymidine brain are generated during prenatal and early postnatal autoradiography. Thymidine is incorporated into the DNA life.” (Rakic, 1985) of dividing cells, and therefore, the cells that have just di- In a subsequent article with Eckenhoff, the results were vided can be labeled and their time and place of birth can again negative, and they claimed that the supposed lack be determined by autoradiography. Almost immediately, of adult neurogenesis in primates made good sense be- Joseph Altman at MIT began publishing a series of articles cause “a stable population of neurons may be a biological in which he reported thymidine autoradiographic evidence necessity in an whose survival relies on learned for new neurons in the olfactory bulb, the dentate gyrus of behavior acquired over a long period of time” (Eckenhoff the hippocampus, and the neocortex in the adult rat, the & Rakic, 1988). In other words, they suggested that the guinea pig, and the cat. He suggested that the new neurons absence of adult neurogenesis in primates was crucial for played a crucial role in and memory. Although their advanced cognition. published in prestigious journals such as Science and At about this time, and his co- Nature, his findings were ignored or dismissed for over workers showed that neurons were added to the adult two decades (Altman, 2011; Gross, 2009). avian . They did so by (a) demonstrating the One reason why Altmanʼs work was so ignored was new cells with tritiated thymidine labeling, (b) producing probably because the available techniques may not have ultrastructural evidence that the new cells were in fact been totally unambiguous for an objective demonstration neurons, and finally, (c) showing that the putative neurons that the adult generated cells were neurons rather than responded to sound with action potentials (Nottebohm, glia. Rather, the distinction rested on having a so-called 1996). This work was readily accepted probably in part “expert eye” to tell neurons from glia, and experts knew because Nottebohm was already an established figure, that adult neurogenesis was impossible. Another reason because it was a very elegant work, and because, after may have been because Altman was a self-taught junior all, it was just birds. In spite of this overwhelming evidence faculty member working on his own in a Psychology of neurogenesis in parts of the adult bird brain that were Departmentandpurportingtooverturnacentraland, known to be homologous to primate cerebral cortex and

Gross 11 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00308 by guest on 28 September 2021 primate hippocampus, Nottebohmʼs studies tended to be in the early 20th century, and perhaps, Hubel and Wieselʼs viewed as irrelevant to the primate or even the mamma- use of single neuron recording to reveal the hierarchical lian brain. Rather, the evidence for avian neurogenesis was processing of visual information. What revolutions are viewed as an exotic specialization related to the necessity underway now (? neurocomputation? neuro- for flying creatures to have light brains and to their sea- ?) remain to be seen. sonal cycles of singing. It was viewed as quite irrelevant to the human condition. Rakicʼs view of no new neurons Reprint requests should be sent to Charles Gross, Department was not particularly unique and was standard in the of Psychology and Neuroscience Institute, Princeton University, developmental neuroanatomy texts of the time. 18 East Shore Dr., Princeton, NJ 08540, or via e-mail: cggross@ Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/4/1778565/jocn_a_00308.pdf by MIT Libraries user on 17 May 2021 princeton.edu. In the 1990s, there were two developments that led to the revolutionary end of the “no new neurons” dogma (Gross, 2000). The first was the introduction of the syn- REFERENCES thetic thymidine analogue bromodeoxyuridine (BrdU). Like thymidine, BrdU is taken up by cells during the Altman, J. (2011). The discovery of adult neurogenesis. S-phase of the cell cycle and is a marker of proliferating http://neurondevelopment.org/Laboratory-History. cells or their progeny. One advantage of BrdU is that it Beevor, C. E. (1887). 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