A Brief History of the Neuron (by Danielle Steinbach)

At the dawn of the late 1800’s, as the industrial revolution changed the face of the world, the most common professions included the following: farmer, factory worker, merchant, clerk, and store owner. Life generally revolved around a schedule dictated by corporate bosses, market demand, and railroad hours. All this is to say, very rarely did someone’s days consist of probing masses of preserved human brain tissue. 

And yet, in an era renowned for a surge of inventions and discoveries – from electricity to internal combustion engines to steam turbines – people so often overlook a discovery that sprung from a laboratory in Madrid, Spain. Holding vials of silver nitrate, Santiago Ramón y Cajal carefully dispensed the staining chemical over samples of brain tissue lined up on his work table. What he observed under his crude 19th century microscope marked the beginning of modern neuroscience. With a steady hand and an eye for the natural beauty that is the order of the brain, Ramón y Cajal drew elaborate sketches of the miniscule units and webs that comprised the tissues before him. Such strangely-shaped cells, so distinct from anything else that had been uncovered under the lens of the microscope at that time. What he saw appeared less like clusters of amorphous cells and more like an interconnected web of trees with fragile branches and single roots extending from small grey nodes. What he saw was the neuron. 

And from there the Nobel-prize winning neuron doctrine was born, the theory that the brain is composed of individual subunit cells that act on their own but influence each other’s behavior. This doctrine represented a complete paradigm shift from the earlier reticular theory, which suggested that nervous tissue was built from masses of interconnected filaments. You may ask why this distinction is so important for understanding the brain. Well, in order to truly understand something at a macroscopic level and interpret the behaviors of the brain, it is important to understand the microscopic underpinnings and mechanisms that aggregate to create this broad neuronal activity. 

That brings us to the next stop in our history of the neuron. At this point, all researchers know is that nervous tissue is built from networks of peculiarly-shaped cells and somehow these small structures are supposed to give rise to the most advanced kind of intelligence that exists on Earth. From these tree-like structures arise the entirety of our human existence – our love for our family, our ambition to make something remarkable of our lives, our memories of our triumphs and tragedies, smell, taste, sight, touch, and just about everything else. 

So where do we go from here? 

We go to the city of Plymouth, England in the 1950s. To Citadel Hill, where Andrew Huxley and Alan Hodgkin presided over a laboratory dedicated to taking the next steps in clarifying the workings of the nervous system. The main challenge with continuing the exploration of the neuron at the time was that relatively few technologies existed that could detect activity of structures at a microscopic resolution. This difficulty led Huxley and Hodgkin to pivot towards investigating a species whose neurons existed at a macroscopic scale – that is, they began probing the neurons of giant squid. With a size ranging from 0.5 mm to 1.5 mm, giant squid neurons are large enough to be observed with the human eye. Previous studies of the past century had uncovered electrical current changes in nervous tissue under different conditions of stimulation. However, the nature of this electrical activity as well as the factors influencing this electrical activity remained elusive. 

Huxley and Hodgkins began by placing microelectrodes in the axons of the squids and measuring the way that different ionic environments altered the electrical current they measured using the voltage-clamp. After numerous trials and long hours spent investigating how different combinations of ionic environments altered the electrical potential of the axons, they stumbled upon a shocking reading. Looking at their voltage-clamp, they found that modulating sodium (Na+) and potassium (K+) in the space surrounding the neuron led to a sudden, unmistakable series of voltage gradient changes across the membrane of the neuron. The two researchers, wanting to characterize the brain in ways beyond qualitative observation, wrote and published a series of differential equations demonstrating how fluctuations in ion concentration triggered an electrical impulse in the neuron, specifically along the axon. The researchers further wished to explain why only variations in levels of specific ions – sodium, potassium, and chloride – seemed to trigger this electrical impulse. From there, Huxley and Hodgkins theorized that small protein channels existed in the wall of the axon, allowing only certain ions to enter and exit the cell to alter the membrane voltage. 

The world recognized this discovery for its groundbreaking implications, and the 1963 Nobel Prize in medicine was promptly awarded for the Hodgkin-Huxley model of the mechanism of the action potentials. 

Standing over the miniscule axons of squid, these researchers had uncovered the unique ways in which neurons, the independent subunits of the brain, support differential responses and activities in response to stimulation. Another piece of the puzzle had been added to the broader understanding of the principles guiding these cells in supporting the evolutionary miracle of the human brain. 

As always in science though, once one question is resolved, a flood of new ones takes its place. We know by this point in our history that neurons operate with electrical signals and these signals dictate the activity of those individual neurons. But does that mean that neurons then transmit electrical signals to each other to pass messages amongst themselves? Or, rather, do these electrical signals merely stimulate neurons to pass signals to each other in some other form? 

This question would remain unanswered for seven years. Those seven years that passed were filled with the work of Sir Bernard Katz, Ulf von Euler, and Julius Axelrod, a trio of scientists that had never met until they all found themselves accepting the 1970 Nobel Prize in Medicine for their separate discoveries concerning chemical neurotransmission. It’s a rather exciting way to meet someone new. 

These researchers had all brought to light different corners of the larger picture of neurotransmitters. Bernard Keltz had become an esteemed professor at University College London after his 1935 escape from Nazi Germany. Years of research there led him to unveil the “quantal release” of chemical signals between neurons – essentially, Katz had followed action potential to the end of the axon and found that, from there, the electrical signals induced the release of “packages” (or vesicles) from the end of the axon. Within these packages were chemicals that could induce voltage changes in neighboring neurons, allowing for the relaying of signals across neural circuits. Specifically, Katz had been studying neuromuscular junctions, the spaces between motor nerves and skeletal muscles, and so the specific neurotransmitter he had observed was acetylcholine. Simultaneous work from other scientists using electron microscopy had verified the presence of these vesicles at the ends of axons triggered into firing an action potential. Meanwhile, in Stockholm, Ulf von Euler had confirmed that norepinephrine served to mediate symptoms seen in the stress response, boosting heart rate, blood pressure, and blood sugar levels. These findings converged neatly with those of Julius Axelrod, a researcher of the National Institute of Mental Health (NIMH), who had found that neurotransmitters were indeed released into the synapse but added an important caveat. Although these chemical signals were emitted into the space between neurons, not all these signals would end up binding to the postsynaptic neuron. Rather, Axelrod proposed, a process of reuptake occurred, leading to some neurotransmitters being “re-absorbed” by the presynaptic neuron. Although this process allowed for the conservation of neurotransmitters, the downside was that, if done in excess, reuptake could prevent sufficient excitation of postsynaptic neurons. Axelrod’s studies, which had specifically focused on epinephrine and norepinephrine, would later be confirmed as broadly applicable to other neurotransmitters. 

And so, the fundamental framework for the operation of neurons had been laid out: first in 1906 with the discovery of cellular subunits in the brain, then in 1963 with the advent of Hodgkin-Huxley model of action potentials, and finally in 1970 with the establishment of the neurotransmission that occurs when that action potential reaches axon terminals. 

Since the beginning of our journey in the 1880s with Ramón y Cajal, the number of research groups that have taken an interest in studying the mechanisms of the brain has multiplied exponentially. A fountain of new discoveries have of course been made since 1970. And yet, more exciting, is the fountain of new discoveries yet to come as more scientists grapple with the extraordinary reality of the human brain and work in the hopes of being able to mark their contributions down in the brief history of the neuron. 

– Danielle Steinbach 

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