In Search of Memory: The Emergence of a New Science of Mind (9 page)

Grundfest’s emphasis on the importance of understanding how nerve cells function was fundamental to my later studies of learning and memory, and his insistence on a cellular approach to brain function was critical to the emergence of the new science of mind. In retrospect, considering that the human brain is made up of about 100 billion nerve cells, it is remarkable how much scientists have learned about mental activity in the last half century by examining individual cells in the brain. Cellular studies have provided the first glimpse into the biological basis of perception, voluntary movement, attention, learning, and memory storage.

THE BIOLOGY OF NERVE CELLS IS GROUNDED IN THREE PRINCIPLES
that emerged for the most part during the first half of the twentieth century and that form to this day the core of our understanding of the brain’s functional organization. The
neuron doctrine
(the cell theory as it applies to the brain) states that the nerve cell, or neuron, is the fundamental building block and elementary signaling unit of the brain. The
ionic hypothesis
focuses on the transmission of information within the nerve cell. It describes the mechanisms whereby individual nerve cells generate electrical signals, called action potentials, that can propagate over a considerable distance within a given nerve cell. The
chemical theory of synaptic transmission
focuses on the transmission of information between nerve cells. It describes how one nerve cell communicates with another by releasing a chemical signal called a neurotransmitter; the second cell recognizes the signal and responds by means of a specific molecule in its surface membrane called a receptor. All three concepts focus on individual nerve cells.

4–3
Santiago Ramón y Cajal (1852–1934), the great Spanish anatomist, formulated the neuron doctrine, the basis for all modern thinking about the nervous system. (Courtesy of the Cajal Institute.)

The person who made this cellular study of mental life possible was Santiago Ramón y Cajal, a neuroanatomist who was a contemporary of Freud (figure 4–3). Cajal laid the foundation for the modern study of the nervous system and is arguably the most important brain scientist who ever lived. He had originally aspired to be a painter. To become familiar with the human body, he studied anatomy with his father, a surgeon, who taught him by using bones unearthed from an ancient cemetery. A fascination with these skeletal remains ultimately led Cajal from painting to anatomy, and then specifically to the anatomy of the brain. In turning to the brain, he was driven by the same curiosity that drove Freud and that many years later drove me. Cajal wanted to develop a “rational psychology.” He thought the first step was to have detailed knowledge of the cellular anatomy of the brain.

He brought to his task an uncanny ability to infer the properties of living nerve cells from static images of dead nerve cells. This leap of the imagination, perhaps derived from his artistic bent, enabled him to capture and describe in vivid terms and in beautiful drawings the essential nature of any observation he made. The noted British physiologist Charles Sherrington would later write of him, “in describing what the microscope showed, [Cajal] spoke habitually as though it were a living scene. This was perhaps the more striking because…his preparations [were] all dead and fixed.” Sherrington went on to say:

Prior to Cajal’s entry into the field, biologists were thoroughly confused by the shape of nerve cells. Unlike most other cells of the body which have a simple shape, nerve cells have highly irregular shapes and are surrounded by a multitude of exceedingly fine extensions known at that time as processes. Biologists did not know whether those processes were part of the nerve cell or not, because there was no way of tracing them back to one cell body or forward to another and thus no way of knowing where they came from or where they led. In addition, because the processes are extremely thin (about one-hundredth the thickness of a human hair), no one could see and resolve their surface membrane. This led many biologists, including the great Italian anatomist Camillo Golgi, to conclude that the processes lack a surface membrane. Moreover, because the processes surrounding one nerve cell come in close apposition to the processes surrounding other nerve cells, it appeared to Golgi that the cytoplasm inside the processes intermingles freely, creating a continuously connected nerve net much like the web of a spider, in which signals can be sent in all directions at once. Therefore, Golgi argued, the fundamental unit of the nervous system must be the freely communicating nerve net, not the single nerve cell.

In the 1890s Cajal tried to find a better way to visualize the nerve cell in its entirety. He did so by combining two research strategies. The first was to study the brain in newborn rather than adult animals. In newborns, the number of nerve cells is small, the cells are packed less densely, and the processes are shorter. This enabled Cajal to see single trees in the cellular forest of the brain. The second strategy was to use a specialized silver staining method developed by Golgi. The method is quite capricious and marks, on a fairly random basis, only an occasional neuron—less than 1 percent of the total number. But each neuron that is labeled is labeled in its entirety, permitting the viewer to see the nerve cell body and all the processes. In the newborn brain, the occasionally labeled cell stood out in the unlabeled forest like a lighted Christmas tree. Thus Cajal wrote:

4–4 A neuron in the hippocampus, as drawn by Cajal.
Cajal realized that both the dendrites (top) and the axon (bottom) of a cell extend from the cell body and that information flows from the dendrites to the axon. This drawing is modified from Cajal. (Adapted from “Figure 23,”
Cajal on the Cerebral Cortex
, edited by Javier DeFelipe and Edward Jones, translated by Javier DeFelipe and Edward Jones, © 1988 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc.)

These two strategies revealed that, despite their complex shape, nerve cells are single, coherent entities (figure 4–4). The fine processes surrounding them are not independent but emanate directly from the cell body. Moreover, the entire nerve cell, including the processes, is fully enclosed by a surface membrane, consistent with the cell theory. Cajal went on to distinguish two sorts of processes, axons and dendrites. He named this three-component view of the nerve cell the neuron. With rare exceptions, all nerve cells in the brain have a cell body that contains a nucleus, a single axon, and many fine dendrites.

4–5 Cajal’s four principles of neural organization.

The axon of a typical neuron emerges at one end of the cell body and can extend up to several feet. The axon often splits into one or more branches along its length; at the end of each of these branches are many tiny axon terminals. The several dendrites usually emerge on the opposite side of the cell body (figure 4–5-A). They branch extensively, forming a treelike structure that grows out from the cell body and spreads over a large area. Some neurons in the human brain have as many as forty dendritic branches.

In the 1890s Cajal pulled his observations together and formulated the four principles that make up the neuron doctrine, the theory of neural organization that has governed our understanding of the brain ever since.

The first principle is that the neuron is the fundamental structural and functional element of the brain—that is, both the basic building block and the elementary signaling unit of the brain. Moreover, Cajal inferred that the axons and dendrites play quite different roles in this signaling process. A neuron uses its dendrites to receive signals from other nerve cells and its axon to send information to other cells.

Second, he inferred that the terminals of one neuron’s axon communicate with the dendrites of another neuron only at specialized sites, later named synapses by Sherrington (from the Greek
synaptein
, meaning to bind together). Cajal further inferred that the synapse between two neurons is characterized by a small gap, now called the synaptic cleft, where the axon terminals of one nerve cell—which Cajal called the presynaptic terminals—reach out to, but do not quite touch, the dendrites of another nerve cell (figure 4–5-B). Thus, like lips whispering very close to an ear, synaptic communication between neurons has three basic components: the presynaptic terminal of the axon, which sends signals (corresponding to the lips in our analogy); the synaptic cleft (the space between lips and ear); and the postsynaptic site on the dendrite that receives signals (the ear).

Third, Cajal inferred the principle of connection specificity, which holds that neurons do not form connections indiscriminately. Rather, each nerve cell forms synapses and communicates with certain nerve cells and not with others (figure 4–5-C). He used the principle of connection specificity to show that nerve cells are linked in specific pathways he called neural circuits; signals travel along these circuits in a predictable pattern.

Typically, a single neuron makes contact through its many presynaptic terminals with the dendrites of many target cells. In this way, a single neuron can disseminate the information it receives widely to different target neurons, sometimes located in different regions of the brain. Conversely, the dendrites of a target nerve cell can receive information from the presynaptic terminals of a number of different neurons. In this way a neuron can integrate information from a number of different neurons, even those located in different areas of the brain.

Based on his analysis of signaling, Cajal conceived of the brain as an organ constructed of specific, predictable circuits, unlike the prevailing view, which saw the brain as a diffuse nerve net in which every imaginable type of interaction occurred everywhere.

With an amazing leap of intuition, Cajal arrived at the fourth principle, dynamic polarization. This principle holds that signals in a neural circuit travel in only one direction (figure 4–5-D). Information flows, from the dendrites of a given cell to the cell body along the axon to the presynaptic terminals and then across the synaptic cleft to the dendrites of the next cell, and so on. The principle of the one-way flow of signals was enormously important because it related all components of the nerve cell to a single function—signaling.