Dynamic Neurons

Dynamic Neurons Tanya Kelley Discoveries in the neurosciences made possible by technical advances in the late 19th century had great influence in the field of psychology. The idea that one can manipulate the very structure of the brain by what one experiences has its roots in the research that led to the discovery of the synapse. Scientists of the late 19th century diverged from hundreds of years of assumptions about the structure and function of the nervous system. Traditional views were bitterly guarded even as evidence against them mounted. In the end, strong observational research and exciting speculation about the nature of the nervous system laid the groundwork for work now being done in the fields of neuroplasticity and neurogenesis. The field of psychology was to be changed dramatically by the discovery of the dynamic nature of neurons. In a discussion of the synapse, and by extension the nervous system, one should begin with a tip of the hat to the early philosophers and physicians. Aristotle (384-322 B.C.), among a few other topics, wrote about the causes for human sensory and volitional capacities. Through a series of crude investigations, he came to believe that the voluntary movement of the limbs was initiated by the blood vessels. This false assumption was later corrected by Erasistratus (310-250 B.C.) when he traced the nerve supply from the muscles to the spinal cord. Galen (129-200 A.D.) popularized the views of Erasistratus, and thus began 2000 years of investigation into nerve function. Although there were many important contributions on the way, such as those of anatomist Andreas Vesalius (1512-1564), the research and writings of philosopher René Descartes (1596-1650) and physician Thomas Willis (1621-1675) set the stage for 19th century neuroscience. Before moving on to the revolutionary achievements and the bitter wrangling that characterize 19th century neuroscience, it will be useful to have a brief overview of the contributions of Descartes and Willis. Like so many natural scientists before him, Descartes was concerned with how the mind could activate the body. As did Galen, Descartes believed that animal spirits originating in the brain traveled through hollow nerves to animate the limbs. Descartes found a specific location for the origination of animal spirits in the pineal gland. Descartes had singled out the pineal gland as the seat of the soul for a number of idiosyncratic reasons, such as its central location and small size, but unbeknownst to him, the pineal gland has since been shown to have an unusual provenance. Before the Triassic era, vertebrates had a third, or median eye on top of the head. The pineal gland is the remnant of this third eye, and it is still linked to the visual system. See Rapport, Richard, Nerve Endings: The Discovery of the Synapse (New York: W.W. Norton and Company, Ltd., 2005), 175-176. Fine particles of animal spirits originated in the pineal gland, traveled through capillaries, were released into the ventricles, entered into the hollow nerve canals and finally to the muscles, and organs. Finger, Stanley. The Minds Behind the Brain. (Oxford: Oxford University Press, 2000), 75-76 Much of Descartes’ work in anatomy was inspired by the mechanical functions of the devices surrounding him. He used the workings of the automated fountains in the royal gardens to make analogies to the function of the nervous system. Similarly, you may have observed in the grottoes and fountains of our kings that the force that makes the water leap from its source is able of itself to move diverse machines and even to make them play certain instruments or pronounce certain words according to various arrangements of the tubes through which the water is conducted. And truly one may very well compare the nerves of the machine which I am describing to the tubes of the mechanism of these fountains, its muscles and tendons to diverse other engines and springs which serve to move these mechanisms, its animal spirits to the water which drives them, of which the heart is the source and the brain’s cavities the water main. Finger, quoting Descartes, 76. Descartes extrapolated from mechanical principles to explain the functions of the nervous system. Like Galen, Descartes interpreted bodily functions more in terms of theory than observation. That mechanistic nerve functions were common to all sentient beings presented a philosophical problem that occupied much of Descartes further efforts. To distinguish among sentient beings, Descartes concluded that the capacity for thought sets humans apart, thus giving to posterity his famous phrase, “cogito ergo sum.” Although he was a contemporary of Descartes, Thomas Willis took a decidedly more experimental approach to physiology. Willis can be credited with bringing rigorous first-hand investigation into the field. His research required extensive fodder from the gallows and slaughterhouses. From the hundreds of dissections he carried out while a Sedlian Professor of Natural Philosophy at Christ Church, Oxford, he gathered the drawings and notes for two monumental works. Cerebri anatome (1664) and De anima brutorum (1672) became known as the founding texts of modern brain and nerve science. In these texts Willis coined many new words having to do with the nervous system, such as lobe, hemisphere, corpus striatum and the word neurology itself. Because of the accuracy of his drawings and the relative objectivity of his descriptions of the brain and nervous system Willis is revered for having laid the foundations for modern neuroscience, which has its beginnings in the late 19th century. Two major controversies characterize the study of the brain and the nerves in the 19th century. One concerns the shape of the nerve cell itself. For two thousand years it was assumed that the nervous system was formed by a sort of net of interconnecting hollow tubes. This view of the nervous system as a large syncytium came to be known as the reticular view. Late in the 19th century, as microscopes and specimen staining techniques improved, some scientists began to speculate and then to see that nerve cells were individual and discrete. This view came to be known as the neuronal view. The second controversy involves movement of signals through the nervous system. One camp defended the view that movement occurred electrically and the other camp maintained that it occurred chemically. Before delving into the intricacies of the controversies that characterize studies of the nervous system in the late 19th century, a brief summary of current thinking on neuron morphology and of movement of impulses through the nerves will be helpful. Today we speak of a neuron as a discrete unit. Light microscopes revealed axonal endings conforming to dendrites, but with the invention of the electron microscope in the 1940’s, the details of the meetings between axons and dendrites became visible in greater detail. Neuronal cell bodies and dendrites are covered with up to eighty thousand boutons, the bare, unmyelinated axonal endings that terminate in a synapse to the next cell. This terminus is separated from the next cell by a synaptic cleft. An impulse jumps over the cleft in one of two ways. Most clefts are jumped with the use of neurotransmitting chemicals, such as norepinephrine, serotonin, acetylcholine. However, other synapses have what is known as gap junction clefts. At gap junctions the impulse jumps the cleft electrically through minute protoplasmic viaducts or connexins. Despite the discovery of connexins at gap junctions, neurons are now considered to exist as discrete units instead of as a syncytium. Movement of an impulse through the nervous system is both chemical and electrical. By storing dissimilar metal ions across nerve membranes, a sort of battery is created. In a resting state, potassium ions on the inside of the nerve fiber or cell maintain the negative charge and the sodium ions outside maintain the positive charge. This is known as a nerve’s resting potential. When a nerve is active, depolarization takes place. This sets off a nerve impulse. This is known as a nerve’s action potential. Such an impulse takes less than a thousandth of a second. To pass the impulse along, a change in the permeability of the nerve fiber or cell occurs. Impulse conduction Ernesto Lugaro is credited for making the distinction between conduction and transmission as such: “One can distinguish two different processes in the propagation of nervous excitations: a process of conduction, which is essentially intraneuronal, and a process of interneuronal transmission.” My translation from Lugaro, Ernesto, “La fonction de la cellule nerveuse,” XVIe Congrés International de Médecine, 11e Session (Budapest, 1909, 5-57), 24. is the result of a successive and transient permeability of nerve membrane, which allows positive sodium ions on the outside to pass through to the inside and negative potassium ions on the inside to the outside. Such an exchange of ions is the source of the electrical current that accompanies the propagation of the nerve impulse. The potassium ions that have entered the cell or fiber immediately leave it again, thus restoring the nerve’s resting potential. Such an intrusion and extrusion of ions through the nerve membrane is passed along its length in sequence, thus conducting the nerve impulse and releasing an action potential and then immediately restoring polarization and bringing the nerve back to its resting potential. The nerve impulse can be defined as a self-propagating chain reaction. Since both electrical and chemical actions are at work, nerve function can be described as a physiochemical event. The electrical charge accompanies this physiochemical episode, but is secondary to it. Not the initial stimulus, but the nerve itself provides the immediate source of energy for conduction. For a more detailed explanation of nerve function see Clark, Edwin and L.S. Jacyna, Nineteenth Century Origins of Neuroscientific Concepts (Berkley: University of California Press, 1987), 157-211. With this brief sketch of current thinking on neuron morphology and the movement of impulses through the nervous system one may better understand the debates that took place in the 19th century on these topics. It is through the resolution of these two questions that scientists were able to speculate about neuroplasticity and neurogenesis and then conduct experiments to test their hypotheses. The study of the nervous system is particularly dependent on technical advances. The use of improved microscopes in the 1820’s led to a great many new observations. Before cell theory had become widely accepted, the anatomist Jan Purkyne (1787-1869) described a cell from the cerebellum at a scientific congress in Prague in 1837. He illustrated a cell with a nucleus and elongated fibers extending from it. These particularly large cerebellar cells are called Purkyne cells in his honor. As helpful as these improved microscopes were, it was the invention of techniques to make clear slide specimens that revolutionized the study of nerve cells. Hardening and staining specimens with desiccants and dyes allowed individual cells to be distinguished from surrounding tissue. First nonmyelinated nerves were stained with carmine. Although this staining method allowed scientists to see general outlines more clearly, it did not preserve fine detail. Because the terminal details of axons and dendrites were not clear, histologists still believed that nerves fused together creating a great net or reticulum. This view harmonized with the ancient idea that the nerves were connected hollow tubes. Working at the University at Pavia, Italy in 1873, the anatomist Camillo Golgi (1843-1926) invented an improved method for staining nerve cells. Golgi’s method became known as “the black reaction” because his silver stain turned nerve cells black against a yellow background. Even with the invention of an improved staining technique the terminations of axons and dendrites still seemed to fade away. For this reason, Golgi and many others such as the leading histologist Albrecht von Kölliker (1817-1905), maintained the belief that, although they could not as yet be seen, connections among all nerves existed. Working independently the anatomist Wilhelm His (1863-1934) and neuroanatomist August Forel (1848-1931) suggested that transmission of nerve impulses was possible without a reticular system. This speculation was made because of evidence from nerves that visibly ended at the muscles or sensory organs. If nerves can send their signals to muscles and sensory organs without direct connection, why, asked His and Forel, must nerves all be fused together? Perhaps the “invisible connections” that stains could not yet reveal, really didn’t exist. The scientific community, however, was not willing to make such a break with tradition without better evidence from slides, so most held fast to the reticular theory. It wasn’t until the physician Santiago Ramón y Cajal (1852-1934), working in Spain in isolation from the larger scientific community, had greatly improved Golgi’s silver staining methods that the terminations of axons and dendrites could be seen clearly. Cajal delighted in showing his clear and detailed slides to his students at the University of Zaragoza. When his students were hesitant to go against inherited wisdom, Cajal said, “Instead of elaborating on accepted principles, let us simply point out that for the last hundred years the natural sciences have abandoned completely the Aristotelian principles of intuition, inspiration, and dogmatism.” Rapport, quoting Cajal, 29. Although his students eventually rejected reticular theory and became convinced that Cajal’s neuron theory was correct, it was more difficult to convince scientists working further east in Europe. Cajal made several efforts to publicize his discoveries, which were repeatedly thwarted. German, English and French were the languages that predominated in science journals. Since Cajal wrote in Spanish and published in a science journal that he himself started, his discoveries went unnoted. Cajal reached a wider audience when he had some of his work translated into French and joined the German Anatomical Society in order to present his findings at their meeting in Berlin in 1889. Even at the meeting in Berlin, where many illustrious scientists had set up display tables, Cajal’s demonstration initially met with indifference. Finally, Cajal insisted that the respected histologist Kölliker come look at his slides under the microscope. Although Kölliker was a life-long reticularist, upon seeing Cajal’s slides, he almost immediately became convinced that axons and dendrites were not fused, and converted to the neuronal theory. The support of Kölliker led to widespread acceptance of Cajal’s description of the neuron as a discrete unit. It also led to the enmity of the reticularist Camillo Golgi. Eventually Golgi and Cajal would share the Nobel Prize for their work in histology. Both men traveled to Stockholm to accept the prize. Cajal made overtures to settle the long-standing dispute, but Golgi used the opportunity of his acceptance speech to bitterly defend the now almost universally abandoned reticular theory. For a more detailed account see Rapport’s biography of Cajal and Finger, 206-216. The growing acceptance of the neuronal theory required a new explanation for the movement of impulses through the nervous system. Until the 19th century some form of animal electricity, ethereal fluid or vis nervosa were thought to be the animating forces flowing through the hollow net of nerves. The professors of physics Luigi Galvani (1737-1798) and Alessandro Volta (1745-1827) carried on a lively debate about the nature of animal and physical electricity. Their experiments and research on electric fish did much to further understanding of the function of the nerves. Now that it was generally accepted that dendrites and axons did not actually meet, the transmission of information over the cleft, or gap had to be accounted for. Along with Kölliker’s seal of approval, the work of the physiologist Charles Sherrington (1857-1952) did much to foster further investigation into Cajal’s neuronal theory and the means by which messages were relayed over the gaps. It was Sherrington who coined the term for the gap between dendrites and axons. At first he proposed the term syndesm, but a friend suggested synapse because of its Greek meaning clasp. The synapse was thought to be traversed by turns via electrical or chemical means. The idea of electric conduction through the nervous system had a long history, but as experiments on electrical conduction became more sophisticated, it became apparent that electricity could not explain nerve function entirely. The organic physicist Hermann Helmholtz (1821-1894) proved that the conduction of electricity along a wire was faster than nerve conduction. This led to speculation about other methods of conduction through the nerves. The physicist and mathematician Carlo Matteucci (1811-1868) established his reputation with research on the physical aspects of electricity. Matteucci’s experimental results left him to believe, after wavering back forth, that electrical conduction could not explain nerve function. He concluded: 1) The vital actions of the nerves produce no electrical currents. 2) That the electrical force is quite different from nerve action. 3)…we are as ignorant of the nature of the nervous principle as we are of light and electricity. Matteucci as quoted in Clark and Jacyna, 205. Some scientists speculated about the role of chemicals in nerve function. The physiologist Emil Du Bois-Reymond (1818-1896) wrote that chemical conduction might account for movement of signals through the nervous system: Of known natural processes that might pass on excitation, only two are, in my opinion, worth talking about. Either there exists at the boundary of the contractile substance a stimulative secretion in the form of a thin layer of ammonia, lactic acid, or some other powerful stimulatory substance. Finger quoting Du Bois-Reymond, 260. Du Bois Reymonds’s conjecture about chemical conduction was to languish for several decades before it was taken up again in the early 20th century and proven to have explanatory power. The opinions of Helmholtz, Matteucci and Du Bois-Reymond serve to represent the general state of inconclusiveness about nerve function at the end of the 19th century. Concurrent to the studies of conduction of impulses through the nervous system, studies into nerve development in embryos were also taking place. Cajal was intrigued by how peripheral nerves always grew to connect to their corresponding sites in the brain, spinal cord, sensory preceptors and muscles. He used neuroblasts of chicks for many of his slides because such embryonic nerve cells were simpler in form. By studying embryonic nerve cells, Cajal speculated that, although nerve growth starts under mechanical influence by following the path of least resistance, axons then continue their growth through chemical affinity to specific receptor neurons. “He explained this neuronal deportment by the theory of neurotropism, an idea predicting a chemical beckoning that invariably lured axons to their proper destinations.” Rapport, 144. Cajal’s findings inspired a flood of interest and research into nerve development. In the early 20th century, research into nerve development, and the findings of chemical guidance, would contribute to ideas about the chemical factors involved in impulse conduction through the nervous system. Experiments with nicotine and curare also played an important role in discovering chemical factors in conduction. The biologist Ross Harrison (1870-1959) researched the idea that nerve growth was guided by chemical gradients. In his tissue culture studies Harrison confirmed that neurons grow club-shaped pseudopods or growth cones in response to chemical stimuli. It was thought at that time that nerve cells only generate until infancy. The findings from tissue culture studies involving adult neurons indicated that neurogenesis might continue throughout a person’s lifetime. This notion that the growth and proliferation of neural connections could continue into adulthood was a powerful one. Not only could nerve damage potentially be restored, scientists began to speculate about the cultivation of closer synaptic connections to improve intelligence and memory. In a lecture given in 1894 to the Royal Society in London, Cajal put forth his hypothesis that growth of glial cells might increase from learning new things, bringing axon and dendrite closer together, thus enhancing neuronal communication. These observations…have suggested to us an hypothesis which will enable us to understand intelligence acquired by good mental training, the inheritance of intelligence and even the creation of artificial ability. Mental training cannot better the organization of the brain by adding the number of cells; we know that the nervous elements have lost the property of multiplication past embryonic life; but it is possible to imagine that mental exercise facilitates a greater development of the protoplasmic apparatus and of the nervous collaterals. But the pre-existing connections could also be reinforced by the information of new collaterals and protoplasmic expansions. Cajal, Santiago Cajal y, “The Croonian Lecture: La fine structure des centres nerveau” Proceeding of the Royal Society of London, Series B, 55 (1894): 444-467. Cajal also speculated that neural connections could proliferate by learning a new skill, for instance, paying a musical instrument. Later Cajal regretted these speculations; he prided himself on sticking to the facts. Yet in the mid 20th century his ideas about the effects of a stimulating environment and of learning new skills on synaptic speed and strength proved to be true. Many psychologists of the early 20th century began to look for biological explanations for human behavior. The possibility that neurons were dynamic instead of fixed in nature gave rise to new ways of viewing brain function. In 1948 psychologist Donald Hebb (1904-1985) and biologist Jerzy Konorski (1903-1973) wrote about the plastic properties of synapses as follows: The application of a stimulus… leads to changes of a two-fold kind in the nervous system… The first property by virtue which nerve cells react to the incoming impulses with certain cycles of changes we call excitability, and that changes arising in the centers because of this property we should call changes due to excitability. The second property, by virtue of which certain permanent functional transformations arise in particular systems of neurons, as a result of appropriate stimuli or combinations, we shall call plasticity, and the corresponding changes plastic changes. Hebb and Konorski as quoted in Cowen, Maxwell W., Thomas Südhof and Charles F. Stevens, eds,. Synapses (Baltimore: The John Hopkins University Press, 2001), 68. Hebb used these ideas about neuroplasticity and neurogenesis in his book The Organization of Behavior: A Neuropsychological Theory. This groundbreaking book set forth the theory that the only way to explain behavior was in terms of brain function. Hebb was one of many psychologists who based explanations of human behavior on new discoveries about the nervous system. The American pscychologist John Watson (1878-1958) did his research on dogs’ brains to support his theories of behaviorism in humans. Like other behaviorists, Watson believed that outside stimuli program our actions. Watson proposed that with proper stimuli given to the brain and infant could be formed into any type of person. He famously said that if he were given twelve normal infants, he could make them into any type of specialist he might select, lawyer, artist beggar or thief. Wikipedia <www.wikipedia.com> Better understanding of what started as “wild speculation” when nerve growth was first observed, became an integral tenet of new psychological theories. Efforts to increase synaptic strength and proliferation even made their way into the popular culture with techniques targeted to increase brainpower through exercises, meditation, enriched environments and neurofeedback. All the current research and interest in the fields of neuroplasticity and neurogenesis have their roots in the work done by scientists of the 19th century who debated the reticular and neueonal theories of the nervous system and who began to envision neurons as dynamic. References Bennett, M. R. and P. M. S. Hacker, Philosophical Foundations of Neuroscience (Malden MA: Blackwell Publishing, 2003). Brazier, Mary A.B, A History of Neuropysiology in the 19th Century (New York: Raven Press, 1988). Cajal, Santiago Cajal y, “The Croonian Lecture: La fine structure des centres nerveau” Proceeding of the Royal Society of London, Series B, 55 (1894): 444-467. —— Recuerdos de Mi Vida (Madrid” Juan Pueyo, 1923). Clark, Edwin and L.S. Jacyna, Nineteenth Century Origins of Neuroscientific Concepts (Berkley: University of California Press, 1987). Cowen, Maxwell W., Thomas Südhof and Charles F. Stevens, eds., Synapses (Baltimore: The John Hopkins University Press, 2001). Davies, R.W., B.J. Morris, Molecular Biology of the Neuron (Oxford: Oxford University Press, 2004). Finger, Stanley, The Minds Behind the Brain (Oxford: Oxford University Press, 2000). Gazzaniga, Michael et al., eds., The Cognitive Neurosciences III (Cambridge: MIT Press, 2004). Konorski, Jerzy, Conditioned Reflexes and Neuron Organization (Cambridge: Cambridge University Press, 1948). Levian, Irwin B., Leonard K. Kaczmarek, eds., The Neuron: Cell and Molecular Biology (Oxford: Oxford University Press, 2002). Llinás, Rudolfo R, The Giant Squid Synapse: A Model for Chemical Transmission (Oxford: Oxford University Press, 1999). Lugaro, Ernesto, “La fonction de la cellule nerveuse,” XVIe Congrés International de Médecine, 11e Session (Budapest, 1909, 5-57). Rapport, Richard, Nerve Endings: The Discovery of the Synapse (New York: W.W. Norton and Company, Ltd., 2005). Uttal, William R, Neural Theories of Mind (New Jersey: Lawrence Erlbaum Associated, Publishers, 2005). Willis, Thomas, Two Discourses Concerning the Soul of Brutes, facsimile of the1683 translation by S. Pordage (Gainesville: Scholars’ Facsimiles & Reprints, 1971). Young, Robert M., Mind, Brain and Adaptation in the Nineteenth Century (Oxford: Clarendon Press, 1970). PAGE 11