In Search of Memory: The Emergence of a New Science of Mind (10 page)

The principles of connection specificity and the one-way flow of signals gave rise to a logical set of rules that has been used ever since to map the flow of signals between nerve cells. Efforts to delineate neural circuits received a further boost when Cajal showed that such circuits in the brain and spinal cord contain three major classes of neurons, each with a specialized function.
Sensory neurons
, which are located in the skin and in various sense organs, respond to a specific type of stimulus from the outside world—mechanical pressure (touch), light (vision), sound waves (hearing), or specific chemicals (smell and taste)—and send this information to the brain.
Motor neurons
send their axons out of the brain stem and spinal cord to effector cells, such as muscle and gland cells, and control the activity of those cells.
Interneurons
, the most numerous class of neurons in the brain, serve as relays between sensory and motor neurons. Thus Cajal was able to trace the flow of information from sensory neurons in the skin to the spinal cord and from there to interneurons and to motor neurons that signal muscle cells to move (figure 4–6). Cajal derived these insights from work on rats, monkeys, and people.

In time, it became clear that each cell type is biochemically distinct and can be affected by distinct disease states. Thus, for example, sensory neurons from the skin and joints are compromised by a late stage of syphilis; Parkinson’s disease attacks a certain class of interneurons; and motor neurons are selectively destroyed by amyotrophic lateral sclerosis and poliomyelitis. Indeed, some diseases are so selective that they affect only specific parts of the neuron: multiple sclerosis affects certain classes of axons; Gaucher’s disease affects the cell body; fragile X syndrome affects dendrites; botulism toxin affects synapses.

4–6 Three major classes of neurons, as identified by Cajal
. Each class of neurons in the brain and spinal cord has a specialized function. Sensory neurons respond to stimuli from the outside world. Motor neurons control the activity of muscle or gland cells. Interneurons serve as relays between sensory and motor neurons.

For his revolutionary insights, Cajal received the Nobel Prize in Physiology or Medicine in 1906, together with Golgi, whose silver stain made Cajal’s discoveries possible.

It is one of the strange twists of the history of science that Golgi, whose technical developments paved the way for Cajal’s brilliant discoveries, continued to disagree vehemently with Cajal’s interpretations and never subscribed to any aspect of the neuron doctrine. Indeed, Golgi used the occasion of his Nobel Prize lecture to renew his attack on the neuron doctrine. He began by asserting once again that he had always been opposed to the neuron doctrine and that “this doctrine is generally recognized as going out of favor.” He went on to say, “In my opinion, we cannot draw any conclusion, one way or the other, from all that has been said…in being for or against the neuron doctrine.” He argued further that the principle of dynamic polarization was wrong and that it was incorrect to think that the elements of a neural circuit connected in precise ways or that different neural circuits had different behavioral functions.

Until his death in 1926, Golgi continued to think, quite erroneously, that nerve cells are not self-contained units. For his part, Cajal later wrote of the shared Nobel Prize, “What a cruel irony of fate to pair, like Siamese twins, united by the shoulders, scientific adversaries of such contrasting character.”

This disagreement reveals several interesting things about the sociology of science that I was to observe repeatedly during my own career. To begin with, there are scientists, like Golgi, who are very strong technically but who do not necessarily have the deepest insights into the biological questions they are studying. Second, even the best scientists can disagree with one another, especially in the early stages of discovery.

Occasionally, disputes that start out as disagreements about science take on a personal, almost vindictive quality, as they did with Golgi. Such disputes reveal that the qualities that characterize competition—ambition, pride, and vindictiveness—are just as evident among scientists as are acts of generosity and sharing. The reason for this is clear. The aim of science is to discover new truths about the world, and discovery means priority, being there first. As Alan Hodgkin, the formulator of the ionic hypothesis, wrote in an autobiographical essay, “If pure scientists were motivated by curiosity alone, they should be delighted when someone else solves the problem they are working on—but that is not the usual reaction.” Recognition by their peers and esteem come only to those who have made original contributions to the common stock of knowledge. This caused Darwin to point out that his “love of natural science…has been much aided by the ambition to be esteemed by my fellow scientists.”

Finally, great controversies often originate when available methodologies are insufficient to provide an unambiguous answer to a key question. It was not until 1955 that Cajal’s intuitions were borne out conclusively. Sanford Palay and George Palade at the Rockefeller Institute used the electron microscope to demonstrate that in the vast majority of cases, a slight space—the synaptic cleft—separates the presynaptic terminal of one cell from the dendrite of another cell. Those new images also revealed that the synapse is asymmetrical, and that the machinery for releasing chemical transmitters, discovered much later, is located only in the presynaptic cell. This explains why information in a neural circuit flows in just one direction.

PHYSIOLOGISTS WERE QUICK TO SEE THE IMPORTANCE OF
Cajal’s contributions. Charles Sherrington (figure 4–7) became one of Cajal’s greatest supporters and invited him to England in 1894 to give the Croonian Lecture to the Royal Society in London, one of the most distinguished honors Great Britain can bestow on a biologist.

In his memorial to Cajal in 1949, Sherrington wrote:

In his own influential book,
The Integrative Action of the Nervous System
, Sherrington built on Cajal’s findings about the structure of nerve cells and succeeded in linking structure to physiology and to behavior.

4–7
Charles Sherrington (1857–1952) studied the neural basis of reflex behavior. He discovered that neurons can be inhibited as well as excited and that integration of these signals determines the actions of the nervous system. (Reprinted from
The Integrative Action of the Nervous System
, Cambridge University Press, 1947.)

He did this by examining the spinal cord of cats. The spinal cord receives and processes sensory information from the skin, joints, and muscles of the limbs and trunk. It contains within itself much of the basic neuronal machinery for controlling the movement of the limbs and the trunk, including the movements involved in walking and running. Trying to understand simple neural circuits, Sherrington studied two reflex behaviors—the cat’s equivalent of the human knee jerk and the withdrawal response of the cat’s paw when exposed to a stimulus that causes an unpleasant sensation. Such innate reflexes require no learning. Moreover, they are intrinsic to the spinal cord and do not require that messages be sent to the brain. Instead, they are elicited instantly by an appropriate stimulus, such as a tap on the knee or exposure of the paw to a shock or a hot surface.

In the course of his research on reflexes, Sherrington discovered something that Cajal could not have anticipated from anatomical studies alone—namely, that not all nervous action is excitatory—that is, not all nerve cells use their presynaptic terminals to stimulate the next receiving cells in line to transmit information onward. Some cells are inhibitory; they use their terminals to stop the receiving cells from relaying information. Sherrington made this discovery while studying how different reflexes are coordinated to yield a coherent behavioral response. He found that when a particular site is stimulated so as to elicit a specific reflex response, only that reflex is elicited; other, opposing reflexes are inhibited. Thus a tap on the tendon of the kneecap elicits one reflex action—an extension of the leg, a kick. That tap simultaneously inhibits the opposing reflex action—flexion, the drawing backward of the leg.

Sherrington then explored what was happening to the motor neurons during this coordinated reflex response. He found that when he tapped on the tendon of the kneecap, the motor neurons that extend the limb (the extensors) were actively excited, while the motor neurons that flex the limbs (the flexors) were actively inhibited. Sherrington called the cells that inhibit the flexors
inhibitory neurons
. Later work found that almost all inhibitory neurons are interneurons.

Sherrington immediately appreciated the importance of inhibition not only for coordinating reflex responses but also for increasing the stability of a response. Animals are often exposed to stimuli that may elicit contradictory reflexes. Inhibitory neurons bring about a stable, predictable, coordinated response to a particular stimulus by inhibiting all but one of those competing reflexes, a mechanism called reciprocal control. For example, extension of the leg is invariably accompanied by inhibition of flexion, and flexion of the leg is invariably accompanied by inhibition of extension. Through reciprocal control, inhibitory neurons select among competing reflexes and ensure that only one of two or even several possible responses is expressed as behavior.

Integration of reflexes and the decision-making capabilities of the spinal cord and brain derive from the integrative features of individual motor neurons. A motor neuron totals up all the excitatory and inhibitory signals it receives from the other neurons that converge upon it and then carries out an appropriate course of action based on that calculation. If and only if the sum of excitation exceeds that of inhibition by a critical minimum will the motor neuron signal the target muscle to contract.

Sherrington saw reciprocal control as a general means of coordinating priorities to achieve the singleness of action and purpose required for behavior. His work on the spinal cord revealed principles of neuronal integration that were likely to underlie some of the brain’s higher cognitive decision making as well. Each perception and thought we have, each movement we make, is the outcome of a vast multitude of basically similar neural calculations.

Some of the details of the neuron doctrine and its implications for physiology had yet to be established in the mid-1880s, when Freud abandoned his basic research studies of nerve cells and their connections. However, he kept abreast of neurobiology and tried to incorporate some of Cajal’s new ideas about neurons in an unpublished manuscript, “Project for a Scientific Psychology,” written in late 1895, after he had begun to use psychoanalysis to treat patients and had uncovered the unconscious meaning of dreams. Even though Freud became fully immersed in psychoanalysis, his earlier experimental work had a lasting influence on his thought, and therefore on the evolution of psychoanalytic thought. Robert Holt, a psychologist interested in psychoanalysis, has put it this way: