Archive for: September, 2010

Neuronistas vs. Reticularistas

Sep 06 2010 Published by under Scientific Practice

Every couple of years I teach an upper-level seminar course which focuses on historical controversies in neuroscience. Typically we read some classic scientific papers describing how a specific bit of knowledge first came to be and then we read some contemporary papers from the scientific literature which either overturn this long-held dogma, or revisit it with more modern experimental techniques. Ideally we'll discuss papers which look at the same question but come up with completely opposing conclusions. We then try and see why this is so – whether it is differences in experimental techniques, or cherry picking of data by a lab looking to support their pet hypothesis.

One of the first discussions we have in class is about a heated controversy that occurred over 100 years ago regarding the fine structure of the nervous system. During the second half of the 19th century, anatomists had been unable to distinguish much in the way of structure in neural tissue. It was simply too dense, too complicated and indistinct, and it was difficult to conclude anything useful about its anatomy from available anatomical and microscopic techniques. In 1872, Italian anatomist Camillo Golgi developed a method to stain brain sections using silver impregnation such that only a few of the brain cells, or neurons, in the tissue were stained, but were stained completely, allowing one to observe their complete structure in relative isolation from other cells. This discovery brought Golgi a good deal of recognition throughout Europe and he became well established at the University of Pavia. One of the conclusions that Golgi drew from observing his anatomical sections was that neurons appeared to have a series of complex appendages, also known as processes, that formed a continuous web, which he called a reticulum, with each other. Thus, the cytoplasm within each neurons was continuous with all other neurons in a given brain region, and somehow neural information flowed through these webs to produce brain function. This idea became fairly entrenched within the scientific circles of the time.

Fig 1. Golgi's interpretation of the hippocampus, a region in the mammalian brain. Notice how all the cells appear to be connected in a reticulum.

Meanwhile in Spain, an obscure anatomist named Santiago Ramón y Cajal had refined Golgi's technique so that neurons were stained even more clearly and he had reached a very different and controversial conclusion. Before I tell you about that, let's first examine how neuron function is currently understood. In today's thinking, the canonical view of a neuron is that it has two types of processes, dendrites and axons. Dendrites are the part of the neuron that receives information from other neurons via specialized junctions known as synapses, while axons are what send information to other neurons via electrical impulses known as action potentials. In a synapse, the end of an axon from one cell ends, releases signaling chemicals known as neurotransmitters, which travel through a gap between the axon terminal and the dendrite of the next neuron. The neurotransmitters activate receptors in the dendrite and ultimately generate further activity. What Cajal claimed to have seen was that in some cells he could see axons terminating in areas where another cell was known to be, but the cell was not stained by the silver stain. From looking at these free terminals, he concluded that neurons were not continuous with each other, but rather individual units, and that somehow, these free terminals made contacts with the dendrites of other neurons to transmit neural information. These contacts were later named synapses by Sherrington, a British physiologist and friend of Cajal. Cajal never actually saw a synapse – the distance between the axon terminal and the dendrite is way too small to be seen by a light microscope. But rather he inferred their existence by studying free terminals. Using these observations he was able to create composite wiring diagrams that showed the flow of information within a given brain region. More importantly, he established that neurons were polarized, with information traveling from dendrites to axons, as opposed to the reticular view, in which information travelled through a web of axons, and dendrites simply were thought to supply nutrients to the reticulum.

Fig 2. The hippocampus according to Cajal. Notice how a circuit diagram is drawn, showing neurons as individual units with information flowing between them.

Cajal published most of his early work in Spain and his views were not widely disseminated through European scientific circles or even accepted by many of his contemporaries. In an attempt to increase dissemination of his work he began to publish in French to reach a wider scientific audience. However the idea of a neural reticulum had taken hold, not only within Italy, but throughout Europe, and for the few that had read Cajal's work, they deeply mistrusted it. Desperate for recognition, Cajal joined the German Anatomical Society and took his slides and a borrowed microscope to their annual meeting in Berlin. Scientific meetings back then were similar to the ones today – there were a series of keynote talks and presentations of papers, followed by scientific demonstrations in a great hall. Rather than posters, people used to bring microscopes and specimens and set up in little tables as people would come by and discuss their findings. Richard Rapport writes in his book "Nerve Endings" that at this meeting Cajal was mostly ignored and scoffed at as he sat in his little table. Thus Cajal took it upon himself to find Albert von Kölliker, one of the most preeminent Swiss neuroanatomists at the time, and dragged him over to his microscope. Kölliker, like most bigwigs today, always had a posse of people following him around, and they all gathered around to see his reaction to this weird Spanish guy's claims. After listening to Cajal explain his theories and clearly demonstrating supporting evidence with his slides, Kölliker realized Cajal had performed a major breakthrough in our understanding of the nervous system. Kölliker worked hard over the next several years to promote and extend Cajal's findings. The idea, that individual neurons are the fundamental units of the nervous system was later dubbed the "Neuron Doctrine". Within 30 years, more and more evidence poured forth supporting the neuron doctrine, establishing it as one of the central tenets of modern neuroscience. In 1906 both Golgi and Cajal received the Nobel Prize for their contributions toward our understanding of the nervous system.

Golgi never did give up the idea of a neural reticulum. Despite the growing evidence against it, he kept generating more and more evidence supporting his views. Which is not hard to do. If you have ever looked at a Golgi stain, it is very easy to see how one would conclude that neurons are continuously connected through their dendrites. Even if only a small percentage of neurons are stained, dendrites are often so extensive that they appear to be completely tangled together between cells. And Cajal never did see connections between neurons, he just inferred their existence by looking at free axon terminals. So both sets of conclusions, based on the available technology were in their own way valid. It just happened that Cajal was right and Golgi refused to give up his pet hypothesis, finding examples to support his view and ignoring those that didn't.

Apparently Cajal and Golgi did not talk to each other when they received their Nobel Prizes.  It is worth reading the Nobel Prize acceptance speeches given by Golgi and Cajal to illustrate the very different approaches of both scientists. It also goes to show that science 100 years ago was, in many ways, much like science today. Furthermore, as any good scientific theory does, the neuron doctrine has significantly evolved in 100 years. In a future post I will write some of the modern challenges that the neuron doctrine has faced over the years.

Further Reading

Ramón y Cajal, S. (1906) The structure and connexions of neurons. Nobel Lectures.

Golgi, C. (1906) The neuron doctrine – theory and facts. Nobel Lectures.

Highly recommended and entertaining book on Cajal and the Neuron Doctrine:

Rapport, R. (2005) Nerve Endings: The discovery of the synapse. Norton, 240 Pages, ISBN: 0393060195

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Zombie for a day

Sep 02 2010 Published by under Uncategorized

You suspected it wasn't a good idea when you decided to wear long pants and a button-down shirt on another ridiculously warm and humid day. But it was the first day of the academic year and the president of the university was holding a reception for faculty that afternoon and you wanted to look somewhat more professorial. Nothing dressy, just not your usual shorts and a T-shirt you would normally wear to work on such a hot day. The main problem was that the president's house is completely across campus from your office and that by the time you got there you were a sweaty and disheveled mess. At the reception you jealously glanced at your colleagues hobnobbing and schmoozing, keeping cool in their shorts and T-shirts. After the event you also realize that not only is the air temperature warmer than when the reception started despite the sun having set, but that your walk home will be twice as long since you are all the way across campus at the president's house. As you walk home grumpy and sweaty, your stomach giving you heartburn from those jalapeño poppers you gobbled down at the reception, you don't pay attention to that hole in the sidewalk. When you step in the hole and twist your ankle you reflexively try to right yourself, which somehow causes the calf muscle in your other leg to painfully cramp. Not sure whether to tend to your ankle or your leg cramp first, you try and stretch out your calf, but to do this you need support from your injured leg, causing you to acquire a strange-looking pose in somebody's front yard. And that somebody is looking at you through her window. So you decide to walk through the pain, knowing you are still a long way from home. You find that the only way to minimize pain is to walk with a limp-like, foot-dragging gait – and as you walk you try and suppress the little grunting noises you have now started to make, hopefully to keep people from staring. But you realize that there's no use, because you already look like some sort of freakish professorial zombie, hobbling along, grunting and twitching, on a hot late summer evening, limping your way home in search for brains.

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The tools of the trade

Sep 01 2010 Published by under Uncategorized

My postdoc and I sat down to discuss our strategy for addressing the reviewer's comments in his latest manuscript. On the table we put out a copy of the reviews, pulled out some new data that we planned on adding to the manuscript, got a pad of paper, I took out my pencil and sharpened it on the electric sharpener on my desk. Then, the postdoc exclaimed with shock and surprise:

"WHAT are you doing?!?"

"What do you mean?"

"That, the pencil thing… I don't think I've sharpened a pencil since the fourth grade."

"Then how do you keep them sharp?"

"I don't USE pencils, NOBODY uses pencils, why would ANYBODY use pencils!"

"I use pencils… all the time. And I need to keep them sharp."

"That's my point, why not use a pen? Or a mechanical pencil?"

"Because pens fucking SUCK!!!!"

OK, so not all pens suck, except that being left handed limits your pen usage to crappy ball-point pens. All nice smooth and inky pens either smudge too much or scratch the paper when you use your left hand. Mechanical pencil tips either break too often or are too thick. Plus you can't vary things such as pressure and line width with a mechanical pencil or a ball point pen. I wouldn't call myself a pencil geek, but I am somewhat picky about my pencils. Ideally, they should be dark and soft. For those of you not "in the know", graphite pencils are graded by a couple of different scales. The more universal scale splits the pencil world into Hard (H) and Soft (B), much like the sciences. Hard pencils are also lighter in tone, soft pencils are darker. Each category is then ranked, typically from 1 to 9, but I've seen higher. The larger the number the harder or softer the pencil is. Thus 9H is the hardest and 9B is the softest. In the middle, you have HB, which is-not-so-hard and not-so-soft. I find HB pencils to be somewhat flaccid. A parallel pencil classification scale exists in which pencils ares simply rated from 1 to 4. A #1 pencil would be a B (or 1B) pencil, while a #2 pencil is an HB pencil. Most generic school and office pencils are #2 (HB) pencils. Hard pencils tend to be used by engineers for generating technical drawings and such, while softer, darker pencils are more common for writing and art. Ideally I prefer a 2B for most things. Its pretty dark and smooth yet tends to keep a sharp tip longer. It's pretty difficult to find 2B pencils with an eraser on them, I usually get Golden Bear pencils, which are quite nice. Sometimes I use 4B's, but then I need to carry around an eraser. So there, Mr. Postdoc, that's why I use pencils. And yes, I do know that I am grossly overpaying for the fancy French notepads with the quad paper that I get from the stationery shop down the street…

Fig 1. My arsenal.

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