20 SCIENTIFIC AMERICAN MIND June/July 2006 ESSAY

Beyond the Doctrine New experiments sliced the heart in two with a big kitchen knife. All was revealed—the four chambers separated by moist, are settling gristly valves that suck blood into auricles and a century-long squeeze it out ventricles. Eleven years old and fasci- debate between nated, I asked my mother if, next time, she could Ibring me a brain. When she returned from the butcher shop two camps over with a calf brain, I beamed and cleaved the melon in two. how But inside I saw nothing notable. Just a hollow cavity at the core of a fl eshy mush.

communicate. AS How did it work? Books offered names for its bumps and

The surprise: M both sides folds but failed to provide a detailed explanation for how this supreme organ functioned. My parents, teachers—no are right one seemed to have the answer. Today we know the brain’s power comes from compo- nents so miniaturized they are invisible. But even though technology now allows us to see individual neurons, our VOL. 310; NOVEMBER 4, 2005, © AA , models of how they function en masse are still inadequate. REPRINTED PERMISSION WITH FRO We like to think of each cell as a microprocessor linked to billions of others. But how sure can we be that this analogy is accurate? Are we held captive by our analogies just as tightly as the scientists who preceded us were bound by their own now obsolete ideas?

DON BLISS Arts, Medical NIH T. H. BULLOCK ET AL. IN SCIENCE By R. Douglas Fields

www.sciammind.com SCIENTIFIC AMERICAN MIND 21 Santiago Ramón y Cajal

The answer is yes. The discoveries are con- One man looking at this world saw some- vincing that our fundamental thing different, however. The great Spanish anat- concept of how the brain works is naive. Yet iron- omist Santiago Ramón y Cajal was at heart an ically, the two prevailing models, which have artist. As a boy, he sketched cadavers dissected been at odds since their founders were jointly by his physician father before he, too, became a awarded the Nobel Prize 100 years ago, are both doctor. With an artist’s ability to see motion in relevant. Indeed, by joining the models and add- the curve of a line, Ramón y Cajal began to see a ing a third, yet unanswered piece to the puzzle logic in the tangle of cells and pipes. His vision, raised by recent research—how brain cells give hotly contested for the next 50 years, became rise to brain waves—we can fi nally explain not known as the neuron doctrine. only how the works but also what Ramón y Cajal observed that a single, long

makes it unique in the animal world. running from one neuron tended to end in right ) a fi eld of —other, short tubes attached Networked or Isolated to another neuron. He maintained, however, that Analogies are helpful because they make com- the tubes were not interconnected everywhere. In plicated situations more accessible. But such sim- a brilliant deduction, Ramón y Cajal concluded plifi cation also encourages rigid thinking. As the that each neuron was an island unto itself, not a 20th century approached, anatomists probed the node in a network. Moreover, he surmised that brain with the most powerful instrument avail- information fl owed in one direction: into den- able: the newly perfected microscope. They drites, then through a neuron cell body, and out ); THE NOBEL FOUNDATION ( left peered into an invisible world of baffl ing com- its axon. plexity, a densely tangled mass of microscopic, Furthermore, the axon did not connect with interconnected fi bers. Anatomists naturally pre- the dendrites. It remained separated by a minus- sumed that these tiny tubes, called , were cule gap, or . This gap functioned as a like pipes, plumbed into a Byzantine network that switch that allowed information to pass to the allowed sensations and commands to fl ow freely next neuron—or not. The space of separation to wherever they were required. The neuron was was so small it was beyond the resolution of the

simply a node in the interconnected network. best microscopes. Scientists would not get their RESEARCHERS,PHOTO ( INC.

22 SCIENTIFIC AMERICAN MIND June/July 2006 fi rst fuzzy glimpse of the synapse until the 1950s, connection appeared to be direct and electrical. when focused electron beams replaced light When the electron microscope finally re- beams in microscopes. vealed the synapse in 1955, scientists again were In 1906 the Nobel Prize in Physiology or faced with evidence for both sides. There was no Medicine was awarded jointly to Ramón y Cajal longer any doubt that neurons were stand-alone and his rival, Italian physician Camillo Golgi. entities or that they communicated across the gap The unusual pairing sparked a standoff in mod- using chemical messengers. But some images eling how the brain works that is only being set- showed individual neurons to be connected to tled today, on the award’s centennial. Like many one another, as though spot-welded. Researchers others, Golgi assailed the validity of the neuron soon determined that protein channels, called doctrine and vigorously defended the free-fl ow- gap junctions, formed these welds—like a short ing network view of the brain. The great irony coupling that joins two hoses. Ions and organic was that Ramón y Cajal used an ingenious lab molecules passed freely, allowing impulses to technique Golgi had invented to provide evidence speed directly from one neuron to the next. Neurons can release neurotransmitters far away from (), an overlooked form of communication.

for his neuron doctrine. Golgi had devised a way Transmission of signals across “chemical” to stain nerve cells with silver nitrate, making synapses—the basis for learning and memory— their features visible against background tissue. could be regulated by the release or uptake of For reasons that are still not understood, the Gol- neurotransmitters, so they drew most of the at- gi method stains only a fraction of neurons in a tention from neuroscientists. In contrast, “elec- sample, but the neurons that absorb the stain are trical” synapses appeared static, and their role in revealed in exquisite detail. Ramón y Cajal’s pen- brain function was much less interesting. Electri- and-ink drawings of Golgi-stained neurons were cal synapses seemed peculiar, relevant only when the basis of his theory. Golgi was backed into the very rapid communication was necessary or uncomfortable predicament of arguing that his when a bunch of neurons needed to be tethered marvelous Nobel Prize–winning procedure was to a group. merely producing an artifact when it showed Yet recent work by Michael neurons as individual cells. V. L. Bennett of Albert Einstein College of Med- icine and others shows that simple view to be Welded Together wrong: conduction through gap junctions can be The debate between doctrinaires who support- regulated by changes in the voltage of cell mem- ed Ramón y Cajal’s neuron doctrine and reticular- branes and by biochemical reactions that control ists (from the Latin for “network”) who supported the size of the channel through the junction. Golgi’s scheme raged for decades because every There are even cases where chemical and electri- new tool turned up evidence fueling both argu- cal synapses form together at the same junction. ments. For example, electrophysiologists, using One thing is certain: Golgi was right. Neurons electrodes and electronic amplifi ers to study the can be networked together. transmission of electrical signals from axon to , proved in fi ne detail that when an im- A Changing Tide pulse reached the end of an axon, the axon re- Whether signals travel one way down a chain leased chemical substances called neurotransmit- of neurons or back and forth across a network, ters. This event was followed by a delay of about using chemical or electrical messengers, even 1/1,000 of a second, as the substances diffused more fundamental questions remain: What do across the tiny synapse and stimulated an electri- the signals mean? How do traveling impulses cal response in the neighboring dendrite. Yet in translate into a visual image, a feeling, a thought? some cases, the recordings showed that an electri- What’s the code? Neither model has provided an- cal signal swept from axon to dendrite with no swers, yet proponents have generated surprising delay at all, as if the two nerve cells were fused. insights that undermine the exclusivity of each No neurotransmitters were involved, and the theory.

www.sciammind.com SCIENTIFIC AMERICAN MIND 23 One of the great discoveries made in examin- firmed that many such neurons did not emit ing the neuron doctrine is that neural impulses sharp, spiked impulses at all. (called action potentials) carry information in These small, tightly packed “interneurons” one direction, from the cell body to the axon tip. process information within internal circuits of Every morsel we taste, every idea we have, is de- the brain, rather than communicating directly scribed by a pattern of impulses fi ring through with the body or environment as motor and sen- axons. Neuroscientists were eager to decipher sory neurons do. Interneurons are concerned this code, and they did. They found that the with the fundamental, internal workings of the codebook changes constantly depending on the brain rather than with transmitting commands

Glia broadcast signals across hardwired neurons, ()coupling them together into functional groups.

prior history of stimulation. The same frequency or sensations, and the neuron doctrine did not fi t of impulses might signify very bright light when well for many of these internal processors. we are outside during the day and relatively dim Roughly 100 billion interneurons in the human light when we are inside at night. That is because brain control information processing in learning the impulse code is concerned with reporting and memory and are implicated in diseases such changes of state, rather than slavishly transcrib- as epilepsy and Parkinson’s. ing our every sensation. This phenomenon ex- plains why when you pop your head through a Leaks and Backfl ow fresh cotton T-shirt in the morning, you are As Bullock further defi ned the workings of fl ooded with sensations about the soft fabric, but interneurons, other researchers exposed addi- soon afterward you are not aware of feeling the tional shortcomings of the neuron doctrine. cloth at all. Neuroscientist Daniel Johnston of the Univer- Action potential coding explains a great deal, sity of Texas at Austin inserted microelectrodes but it only goes so far. The same rules for im- inside dendrites in the rat hippocampus and pulses are used by animals down to the lowly found two events that would have surprised earthworm. There must be more. American The- Ramón y Cajal. In some circumstances, action odore H. Bullock, one of the grand men of 20th- potentials traveled not only down the axon but century , fl eshed out the code more also “backward” into the cell body and down than any other individual. The electrophysiolo- the dendrites. Moreover, dendrites did not sim- gist and comparative neuroanatomist was inter- ply collect incoming signals; in some instances, ested in how information is coded in the nervous they fi red impulses of their own. We now know system in all types of animals, from snails to it is likely that dendritic processing is part of the whales. He traveled from the Amazon rain forest mechanism for learning and memory. Dendrites to tidal pools everywhere with his electrodes and are more than passive conductors; they integrate microscope. In 1959 Bullock published a paper and transmit information. in Science stating that in addition to high-speed A recent surprise is that dendrites can also nerve impulses fi ring through axons, many other release hormones and peptides that infl uence the electrical events were playing out in the back- slow voltage changes on neuronal membranes, ground, deviating from the neuron doctrine. In which affect whether a neuron fi res a single im- particular, he observed slow surges and wanes in pulse or bursts of impulses. Eve Marder of the voltage on nerve cell membranes. These po- Brandeis University has found that these neuro- tentials strongly infl uenced how many impulses modulators work when applied to axons, the an axon would fi re in a burst and the probability neuron cell body, or dendrites, scrambling the that an axon would fi re at all. orderly one-way information fl ow Ramón y Cajal Moreover, a sharp impulse was needed only perceived. Neuromodulators can even cause neu- to transmit information over long distances. The rons to fi re in rhythmic burst patterns; this fi ring slow voltage waves could easily spread in all di- forces ensembles of neurons to work in synchro- rections across small, closely spaced neurons, ny, like musicians playing in tempo. and Bullock’s electrophysiological records con- Even the synapse proved less simple to under-

24 SCIENTIFIC AMERICAN MIND June/July 2006 stand than originally suspected. Synapses did not with thousands of these packets throughout their form just between an axon and surrounding den- cell bodies. Suddenly, the model of how the brain drites. Refi ned electron microscopes showed that processes information has become much more synapses often appeared on the cell body of a complicated. neuron, on its dendrites, and from axon to axon and dendrite to dendrite. Neurons, it seemed, The Glia Factor might indeed be connected in multidirectional Neuroscientists may be more willing to accept networks much the way Golgi and the reticular- such heresy because of a startling expansion in ists had imagined. thinking beyond the neuron doctrine in the early What is more, molecular neurobiologist Craig 1990s: most of the cells in the human brain are Jahr of the Vollum Institute at the Oregon Health not neurons. Nearly 10 times as many cells, called & Science University recently proved that fast glia, fi ll the space between neurons, and the ratio transmission using neurotransmitters can occur of glia to neurons increases in animals “higher” without any need for a synapse. At fi rst, Jahr pre- on the evolutionary tree. The very label “neuron sumed that the neurotransmitters had seeped out doctrine” implies that neither Golgi nor Ramón of a nearby synapse, but his measurements indi- y Cajal imagined that these cells had any informa- cated that neurons released the neurotransmit- tion-processing function. For most of the 20th ters through their cell membranes, far away from century, scientists believed glia provided only synapses. In 2005 computational neuroscientist physical and nutritional support for neurons. But Terrence J. Sejnowski of the Salk Institute for closer examination during the past decade has chers, Inc. Biological Studies in La Jolla, Calif., and electron shown that glia have been listening in on conver- microscopist Mark H. Ellisman of the University sations among neurons all along. Also astonishing of California, San Diego, concluded that this “ec- has been the discovery that glia can communicate topic” release of neurotransmitters outside syn- apses was an important and overlooked means of (The Author) communication. If a neuron releases a single packet of neurotransmitters anywhere from its R. DOUGLAS FIELDS is adjunct professor at the University of Maryland membrane, an adjacent neuron can detect it if it and wrote about the Dalai Lama’s interest in neuroscience in the Scien- has neurotransmitter receptors in the vicinity. tifi c American Mind February/March issue. He dedicates this article to

ROBERT BROCKSMITH Resear Photo Today’s best electron microscopes show neurons the memory of Theodore H. Bullock.

www.sciammind.com SCIENTIFIC AMERICAN MIND 25 among themselves using chemical signaling (and To the neuron doctrine we now must add the no synapses are involved). glia doctrine: glia are equal partners in infor- In addition, as glia eavesdrop they can con- mation processing. Glia intervene not only at trol the fl ow of information among neurons. synapses but also along axons by sensing im- They perform this function by releasing or ab- pulses fl owing through them. When axons fi re sorbing neurotransmitters or by controlling the bursts of action potentials, they release adeno- concentration of ions surrounding neurons. Glia sine triphosphate (ATP) molecules, which are can also make and break connections between detected by receptors on all four types of glia. individual neurons. This information turns on and off genes in glia, Glia’s habits violate the neuron doctrine in affecting how they form layers of insulation two ways. First, information fl ows through cells around axons, which in turn affects how fast axons can conduct impulses. All of this com-

in the brain that are not neurons. Second, unlike neurons, which communicate through a series munication moves along without synapses—a of links akin to telephone wires, glia communi- completely different channel of information cate by broadcasting signals, the way cell phones fl ow in the brain.

do. Glia make shapeless connections that fl ow Getty Images VAY VAY

across the hardwired connections among neu- Beyond Doctrine C rons. In this way, glia can couple neurons to- Neuroscience has drifted well beyond the gether into functional groups. They communi- limits of the neuron doctrine. So where will this cate much more slowly than neurons do, but the new course lead? In 2005, 46 years after his Sci- speed may be adequate for many cognitive pro- ence paper shot the fi rst hole in the doctrine, cesses that do not require lightning-quick mes- Bullock raised an intriguing question in another sages, such as the mechanisms that regulate article in the same magazine: Why are the capa-

mood and behavior. bilities of the human brain so superior to those of CHAD BAKER AND RYAN M

26 SCIENTIFIC AMERICAN MIND June/July 2006 all other animals? The neurons in animals’ brains probability that neurons will fi re at the same time. are not all that different; even the fl y exploits the John J. Greer and his colleagues at the Uni- same neurotransmitters. Careful anatomical versity of Alberta in Edmonton reported this past study does not support the notion that bigger February that when they bathed a fetal rat in a brains or more neurons are the answer either. solution that stopped all synaptic transmission, Bullock (who passed away in December 2005 at neural circuits in its spinal cord and developing age 90) suggested that the answer lay in some brain continued to fi re rhythmically and in con- property that allows neurons to operate as a net- cert. Somehow, without any neurotransmitters work. Golgi would be proud. in motion, neurons found a way to fi re coher- The unparalleled abilities of the human mind arise ()not from neurons but from the coherence of brain waves.

Bullock had begun to explore brain waves in ently. Using similar methods over the past 20 a variety of animals as simple as crabs and as years, F. Edward Dudek, now at the University of complex as dolphins. He determined that pat- Utah, has found that electrical coupling synchro- terns of brain waves in humans differed mark- nizes impulse fi ring during brain seizures and edly from those in simpler animals. Brain waves that ephaptic transmission couples fi ring of neu- arise from the collective activity of thousands of rons in the hippocampus, a part of the brain es- neurons working together, much like the din of a sential for memory. Ephaptic transmission, gap crowd at a baseball stadium. When Bullock ex- junctions, neuromodulators and glia are all ways amined the power spectrum of brain waves, he of making neurons work together in groups. This saw that waves belonging to animals that ap- cooperation increases coherent activity in the peared earlier on the evolutionary ladder tended brain, and all these processes operate outside the to have more high-frequency components, where- neuron doctrine. as mammalian brain waves were shifted toward So both Golgi and Ramón y Cajal were right, lower frequencies. yet neither they nor their followers succeeded in Work by Bullock and others also showed that explaining the entire universe inside our heads. the electrical activity in different groups of neu- Furthermore, the point of the century-long de- rons is often coupled, even though the neurons bate between the doctrinaires and reticularists are not physically connected. It is as though peo- is not to crown a victor but to hone our thinking ple in different parts of a stadium are carrying on and inspire new experiments to explore one of a single, coherent conversation. This coherence nature’s greatest mysteries: how the human of activity in brain waves increases in animals mind functions. with more powerful brains. Perhaps, Bullock The question for the future is: How are brain suggested, the unparalleled abilities of the hu- waves so well coordinated in the brain? To many man mind arise not as a unique property of our neuroscientists, the answer lies just over the ho- neurons or brain circuitry but as an emergent rizon, just beyond the concept of neurons acting property of the way its billions of neurons oper- as single functional units. Perhaps our present ate cooperatively. instruments are inadequate to provide the essen- But how is activity in different neurons coor- tial data. Or perhaps, recalling Ramón y Cajal, dinated? Part of the answer may lie in a phenom- the answer is already here waiting for someone enon we are all familiar with from listening to the to see it. M radio. Sometimes frequencies from one radio sta- tion bleed over to the frequencies of another. Sim- (Further Reading) ilarly, electrical signals transmitted through near- by axons are sometimes picked up as weak signals ◆ Histology of the of Man and Vertebrates. S. Ramón y Cajal. Translated by N. Swanson and L. W. Swanson. Oxford University in adjacent axons. This unruly behavior, called Press, 1995. ephaptic transmission, may be simply an unavoid- ◆ The Other Half of the Brain. R. Douglas Fields in Scientifi c American, able characteristic of electricity. And the brain may Vol. 290, No. 4, pages 54–61; April 2004. tap into it to coordinate brain waves. The voltages ◆ The Neuron Doctrine, Redux. Theodore H. Bullock et al. in Science, from the intruding electrical signals heighten the Vol. 310, pages 791–793; November 4, 2005.

www.sciammind.com SCIENTIFIC AMERICAN MIND 27