Archive for: September, 2011

A Neuroscience Field Guide: The squid giant axon

Sep 30 2011 Published by under Uncategorized

You are probably wondering where in your nervous system is your squid giant axon, and why I'm writing about it in the Field Guide.  Not to be confused with the giant squid axon (ie. an axon from a giant squid) the squid giant axon is a very large axon that controls escape behaviors in regular squid.  The reason it is relevant, is that it was using the giant axon from common Atlantic squid, Loligo pealeii, that Hodgkin and Huxley, figured out how nerve impulses —known as action potentials— are generated. Why use squid axons? Mainly because they're huge. They can be up to 1 mm in diameter. This allows an experimenter to basically squeeze out the normal cytoplasm from the axon and perfuse the inside with whatever salt solution he or she pleases. Furthermore, a wire can be stuck inside the axon and used to measure electrical currents entering and leaving the axon through its membrane. This experimental preparation was first developed by JZ Young in England and then later refined by Hodgkin and Huxley as well as KS Cole in Woods Hole.

Confused neurophysiologists attempt to extract axon from giant squid.

So why are squid giant axons so large? Mainly because they need to be fast. And this brings up an important principle of what is known as cable theory: that bigger diameter axons conduct current faster. You can think of axons as a sort of leaky hose full of tiny little holes along its length. As water goes in one end of the hose it will leak out of the little holes as well as travel down the length of the tube. The more of these little holes you will have, the lower the water pressure will be at the other end of the tube. If you increase the diameter of the hose, there will be relatively more space for the water to go down the length of the tube. You will also increase the net number of holes but the cross sectional area of the hose will increase at a faster rate as you increase the hoses diameter. In an axon, charge is conducted by the salty solution inside the axon and it also leaks out of the axon through little pores known as ion channels. In a fatter axon you are adding more membrane and thus more channels, decreasing the electrical resistance of the membrane, but at the same time there is more salty solution inside the axon decreasing the electrical resistance along the length of the axon even more. Thus relatively more current will travel down the length of the axon than will leak out via the membrane. In vertebrate axons (and in some invertebrates), the nervous system has developed myelin, which is a fatty coat that covers the axon. This makes the membrane much less leaky and therefore you can have axons that are thin and also fast.

The squid giant axon also facilitated the development of an important neurophysiological technique known as the voltage-clamp. A voltage clamp allows you to set the internal voltage of a cell (or an axon in this case) at a fixed value and then measure the electrical current flowing in or out of the neuron. In order for neurons to generate electrical impulses, they need to be at a voltage which is different than the environment outside of the neuron. They can do this by maintaining a gradient of charged ions which can enter or leave the cell via ion channels, allowing the voltage of the cell to change. These rapid changes in voltage are what constitute an action potential. What the voltage clamp does is that using an electrical wire in side the axon or cell the experimenter can artificially fix the voltage of the inside of the axon and measure the current that flows through the membrane at different voltages. Using this technique Hodgkin and Huxley were able to describe the precise currents entering or leaving the cell as the voltage changed in an action potential. Since they could perfuse any type of salt solution on the inside and the outside of the squid axon, they also determined the type of ions that flux through the membrane. In this case it turned out to be sodium and potassium ions. Apparently H&H travelled to Woods Hole to learn the technique from Cole and afterwards returned to England to do their experiments. Meanwhile there was some trouble with the squid supply in Cape Cod for the remainder of that year and so H&H were able to basically finish their experiments and scoop Cole.

Recordings of voltage changes during an action potential is a squid axon. The top recording is from Curtis and Cole, 1939, and shows that as the voltage changes, the membrane resistance decreases, showing that ion channels are open. The bottom graph is from Hodgkin and Huxley, 1939 and shows the changes in membrane voltage during an action potential. Mind you these are NOT voltage clamp experiments since the voltage is changing. They are recordings of voltage changes inside the axon relative to the outside.

Thus the giant squid axon has been an incredible useful preparation that has helped us understand how nerve impulses are generated. And in addition to the giant axon, it has a giant synapse, where some of the basics underlying synaptic transmission were discovered. So next time you eat your calamari, be sure to thank your squid. And then add lots of hot sauce.

Incidentally, a documentary was made about the squid giant axon in the 70's. The most remarkable thing about it is the hair of all these neurophysiologists. You can see some clips here.


Further Reading

Nobel acceptance speeches of Hodgkin and Huxley.

Nice little primer from the Nobel site about nerve signaling.

Cool paper on the history of electrophysiology (may require subscription).

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You copy, right?

Sep 28 2011 Published by under Uncategorized

OK that was a crappy blog post title. But anyway, I was just reading about a new policy from Princeton University that forbids faculty from assigning all copyrights of their published work to journals. They will also support faculty who want to put copies of their published work on their web pages. Apparently other universities are implementing similar policies. This is to assure open access to work published by their faculty and particularly of federally funded research. I think this is a great goal, but I suspect that this policy might make it difficult to publish in certain journals. Many journals, including for-profit glamour magz require that you assign copyright to them, or else pay a ridiculous amount of money in order for the author to retain the copyright. Publishing in open access journals is also expensive. Will Princeton assist with these charges? The article claims that waivers will occasionally be granted, if so then this will strip the policy of any value that it has. Will it be OK if open access is made available after a few months as many journals do? This might all be a moot point anyway since the NIH and other agencies already require that you deposit an copy of your published manuscripts in PubMed Central, which is an open access database of NIH-funded articles. I wonder if this will be sufficient to fulfill Princeton's requirement. It will be interesting to see how this pans out.

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A Neuroscience FIeld Guide: The Purkinje Cell

Sep 26 2011 Published by under Uncategorized

Whenever neuroscientists want to talk about dendrites — the part of a neuron that typically is used for receiving information from other neurons — neuroscientists will almost always show a picture of a Purkinje cell. I'm sure you've seen it before, you know, those big cells with the giant, branching beautiful dendrites that look like this:

Purkinje cells from pigeon cerebellum by Santiago Ramón y Cajal, 1899.

And that's pretty much where things end. You never hear about what these peacocky cells do, where they live, how they act. But in fact they do a lot and are very unique among neurons.

Purkinje cells were discovered in 1837 by Bohemian (as in Czech, not as in Kerouac) anatomist Jan Evangelista Purkyně, who among other things, discovered that you could get high on nutmeg. As you can see from the picture above, Purkinje cells have a very large and branchy and practically two-dimensional (ie. flat) dendrtic arbor, studded with little things called spines. The dendritic arbor stems from a primary dendrite which emerges from a roundish cell body which has a single axon emerging from the other end. Purkinje cells are in a part of the brain known as the cerebellum, more specifically the cerebellar cortex, and in fact they are the only source of output for the entire cerebellar cortex. Purkinje cells send their axons to a region of the cerebellum know as the deep cerebellar nuclei, a dark and obscure place where you don't want to go, but that's another story. Purkinje cells sit nicely aligned to each other in one layer, with their dendrites forming these parallel arrays along the cerebellar cortex. This architecture is basically maintained in most vertebrates, and constitutes an evolutionarily old part of the brain.

One of the things that makes Purkinje cells unusual is that they are inhibitory, meaning that when they are active, their targets stop being active, or are inhibited. In the nervous system, for the most part, neurons that connect one area of the brain or nervous system to another, also known as projection neurons, tend to be excitatory. Meaning that they activate their targets. In contrast, neurons that connect to nearby neurons in the same brain region can be either excitatory or inhibitory; these are known as interneurons.  Purkinje cells, are inhibitory projection neurons, which is unusual.

Another nifty thing about Purkinje cells, is that they have active dendrites. Meaning dendrites that can generate electrical impulses, or action potentials. Most basic neuroscience textbooks will tell you that axons generate action potentials to communicate with target cells, while dendrites passively integrate information from other neurons. However, Purkinje cell dendrites can also generate action potentials. Actually it turns out almost all dendrites can generate action potentials, but this was first discovered in Purkinje cells by neuroscientist Rodolfo Llinás and colleagues. Since Purkinje cells have such big-ass dendrites, they were able to record electrical activity from directly inside the dendrite, as well as from the cell body. What they observed was that the dendrites could generate action potentials, but in contrast to action potentials generated by axons, which are usually mediate by influxes of sodium ions into the cell, the dendritic ones were mediated by calcium. This was a remarkable finding that changed the way we thought of neuron function, and way cool. You can see their results below.

Electrical recording from different parts of the Purkinje cell show that dendrites can generate action potentials. This is from the classic paper from Llinás and Sugimori, J. Physiology, 1980. This paper ushered in a new era of dendritic research.

So why the big dendrites? Typically cells have big dendrites in order to receive information from many other neurons. The larger your dendritic tree, the more cells will tend to project to it. Purkinje cells recieve two types of excitatory inputs in their dendrites. Most of them come from a shitload of so-called granule cells. Granule cells are another type of cerebellar neuron which constitute half, yes half, of the total number of neurons in the brain. They have these axons called parallel fibers that make contacts throughout the arrays of Purkinje cells. Each Purkinje cells receive inputs from up to 200,000 parallel fibers, but each input by itself is very weak. The other type of excitatory input comes from what are known as climbing fibers. Climbing fibers are the axons from neurons which reside in another brain region known as the inferior olive. What's cool is that each Purkinje cell receives input from only one climbing fiber, but this input is incredibly powerful. These two types of inputs thus activate Purkinje cells very differently.

When parallel fibers are active, Purkinje cells will fire action potentials at a rate proportional to the number of parallel fiber activated, yet when the climbing fiber is active, the Purkinje cell will generate a burst of action potentials occurring at a really high rate, and then will stop firing altogether. This is called a complex spike. If this is sounding a bit like a computer is because that's what it is. The cerebellum is basically an error correction machine. Whenever you perform a motor action, such as picking your nose, your cerebellum is continuously adjusting your arm movement to make sure that your finger expertly reaches your nostril, and doesn't, for example, poke your eye. Thus your cerebellum is constantly comparing the movement that you intended to do with what you are actually doing and makes little adjustments such that the two match as best as possible. Parallel fibers continuously set the gain of this adjustment, while climbing fibers are active when an error is detected. So without a cerebellum, you'd be mostly fine, but would be highly uncoordinated to say the least. And at the center of this computation is the Purkinje cell. This type of adjustment is also useful for mediating certain types of associative learning, such as classical conditioning, but that's the topic for another post.

So to summarize: Purkinje cells are nifty because they have cool dendrites, are inhibitory projection neurons, generate action potentials in their dendrites, and allow you to pick your nose without poking your eyes out. And be thankful for that.

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A Neuroscience Field Guide: Introduction

Sep 26 2011 Published by under Uncategorized

This is the first of a series of occasional posts where I will write a bout interesting things in the nervous system. After all I did say at some point that I would occasionally write about science, as opposed to whatever I can pull out my wazoo. It is not intended to be a comprehensive survey, but rather a tour of some quirky and more unusual parts of the nervous system that you wouldn't necessarily hear about in a brain primer or basic neuroscience textbook. Hopefully you'll find them informative, fun to read and maybe you can impress your friends with your knowledge of neuroscience marginalia. The first post will be on the not so obscure, but also not so often talked about, neuron know as a Purkinje cell, which resides in one of my favorite brain regions, the cerebellum. Also, if there's a specific part of the brain you would like me to write about in the field guide, please send me a note or write it in the comments. I'll do my best to write an entertaining and informative post about it. Enjoy!

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The blogger lifestyle

Sep 26 2011 Published by under Uncategorized

So apparently if I want to be a successful blogger, I need to write at least 1000 words a day. Otherwise, I will lose all my readers and be shunned as a wannabe blogger. The writer of that piece of advice apparently suffered a heart attack as a result from the stress that accompanied his "blogger lifestyle". Whatever that means.

Alternatively I can post whenever the fuck I want, and have fun while doing so. A successful blog is not one that has a gazzillion readers, but rather one that serves as a mode of effective self expression and of reflection, and that benefits the blogger as much as it does its readers. And certainly should never be a source of stress. It's a hobby fer cryin' out loud!

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Cursive curses

Sep 07 2011 Published by under Uncategorized

I never understood cursive writing. To me it has always seemed clumsy and forced and not a natural way of writing. Cursive was originally inventeed to facilitate writing with a quill, in which lifting the nib up and down was apparently messy, so it was better to link the letters in a word together. Later is was promoted as a method for writing quickly or more naturally. To me though, cursive is a slow, cumbersome and ugly way of writing. And probably this is due to the fact that I'm left-handed. It seems like cursive was really designed for right-handed folks. The letters and motions feel incredibly forced, and it is impossible to arrange your hand in such a way that you don't create a smudgy mess. That's why in around fourth grade I stopped using cursive and thus my cursive writing looks like a fourth grader's. Here's an example:

My chicken scrawls.

Not that my regular handwriting is any neater, but at least it doesn't look as lame. It's a bit of a hybrid between cursive and block letters. In my normal writing I do everything backwards, including writing vertical lines from the bottom up and making the "o" counterclockwise. From what I can gather, the cursive method I learned was the so-called D'Nealian Script which is supposed to look like this:

D'Nealian Script

Which to my eye looks different to the cursive that my parents used. It was invented in the 70's and might explain why my script looks even more dated. In my kids school they still teach cursive, which is good , I guess. At least they will be able to read it when they come across it, and neither of my kids are lefties, so they might take to it more than I. I wonder if there's a cursive designed for lefties. How about you all, what's your handwriting like?


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