Growing 3D Cells

Neurons don't grow in a vacuum. They have white fibers, other neurons, blood vessels and all sorts of other obstacles to grow around.

Some NeuroArt (source)

A recent paper from France details the making of a 3D environment that can facilitate 'realistic' neural growth. Labour et al. (2012) created a collagen biomimetic matrix which contains neural growth factor (NGF). 

Labour et al., (2012) Figure 3

These scanning electron microscope images show the porous fibril texture of the collagen matrix. Most of the paper is spent explaining the methods for making this biomimetic matrix, but they also actually grow some pseudo-neurons (PC-12 cells) on the matrix.

They show that when cultured on top of this collagen surface, the cells extend neurons in three dimensions into the matrices and are affected by the NGF. (when there is no NGF, the neurites don't grow and the cells die.)

This paper is mostly about the methods, but I like the new possibilities that growing 3D cells opens up. With these biomimetic collagen matrices, the factors that cause specific dendritic arborizations in three dimensions can be analyzed. The environment can be completely controlled and the neurons easily visualized during growth. The authors suggest using these matrices to study neurodegeneration as well.

Another interesting thing this paper introduced me to is the 'graphical abstract.' I didn't know that that was a thing, but it seems like a good idea. However, trying to summarize an entire paper in one figure seems pretty difficult. Here is their attempt:

Labour et al. (2012) graphical abstract

I think it does actually get the feel of the paper across pretty well, though it's not really informative without the actual abstract next to it.


© TheCellularScale


Labour MN, Banc A, Tourrette A, Cunin F, Verdier JM, Devoisselle JM, Marcilhac A, & Belamie E (2012). Thick collagen-based 3D matrices including growth factors to induce neurite outgrowth. Acta biomaterialia, 8 (9), 3302-12 PMID: 22617741

The ageless face of an Aes Sedai: Science Edition

How would the brain process a truly 'ageless' face?

Moraine, an ageless Aes Sedai (source)

I am sure this question has plagued many Wheel of Time fans, but only now has an experiment been designed to test it. Just 4 days ago, Homola et al. (2012) published a paper in PLoS ONE in which they have people guess ages of people in pictures and scan their brains. 

Homola et al. (2012) Figure 1A. (Which one looks most Aes Sedai to you?)

The first interesting thing that they found was that the older the person in the picture (either a real picture of a real person, or a hybrid 'morphed' picture like the ones above), the harder it was to tell how old they were. This isn't really that surprising, as the range of ages that can 'look' a certain age gets wider over the years.

Homola et al., (2012) Figure 2B.

Here they plot the standard deviation in years for people's guesses as to the age.

The authors showed videos of the faces morphing from one age to another to volunteers while they were in the fMRI machine.

As a side note: they found that there was no difference between male and female volunteers. If they had I think a big deal would have been made about it. but since they didn't it's just a tiny sentence in a long paper.

Ok, back to the processing of age. They threw out the results from people who were really really bad at rating age because they 'weren't motivated' and weren't really trying apparently. (This could be a bit of cherry picking or data massaging) Then they compared the areas of the brain that were active for people who were really really good at guessing age, and people who were only average.

Homola et al., (2012) Figure 4D

The basic finding was that the posterior angular gyrus area (pANG) in the left hemisphere was 5 times more active for the expert age guessers than it was for average. Conclusion: pANG is important for age-processing. This on its own is good to know, but not amazingly interesting. What I think is cool is the idea that the authors present as a  follow up experiment in their discussion:

"Even though our study highlights pANG as one key component for age processing, its precise role in this context is still speculative and needs further investigation. Our model, illustrated in Figure 7, gives rise to interesting hypotheses: One testable prediction would be that disruption of left pANG activity using transcranial magnetic stimulation (TMS), for example, should impair numerical age but not gender judgements, and that brain lesion-symptom mapping can eventually dissociate the two. " Homola et al., (2012)

So now we know, the Aes Sedai must have some magic that transcranially impairs pANG in everyone around them so they can't guess their age. That is how to stay truly ageless.

© TheCellularScale


Homola GA, Jbabdi S, Beckmann CF, & Bartsch AJ (2012). A Brain Network Processing the Age of Faces PLoS One DOI: 10.1371

Virtual reality for your robot cockroach

I have previously covered some interesting advances in the world of cyborg insects.

Biobot backpack (cockroach size) (source)

Latif and Bozkurt from North Carolina state university recently presented a paper (though I can't find a peer-reviewed publication on Pubmed), explaining their Biobot. They use the Madacascar hissing cockroach...

Hissing Cockroach (source). Terrifying.

... and attach a electrically stimulating 'backpack' (see first picture). They then stimulate the the antennae in a variety of ways to 'steer' the Biobot.

"In these studies, electrical pulses were applied to the insect to create biomechanical or sensory perturbations in the locomotory control system to steer it in desired directions, similar to steering a horse with bridle and reins." -Latif and Bozkurt

This is very similar to the backyard brains Roboroach, but the system created by Latif and Bozkurt is extremely precise. Rather than just making the Biobot turn when stimulated, Latif and Bozkurt can make the cockroach walk a specified line.





Pretty cool. The authors note that generally the cockroaches want to walk straight until they encounter an obstacle (or stimulation). So, sure, this is sort of like steering a horse with reins, but the horse has to be trained to know what the bridle signals mean. This setup is more like creating a virtual reality for the cockroach, where it thinks that it has 'run into' something at certain points on the line. This is similar to creating a virtual reality for worms by stimulating specific neurons with light.

Of course the practical applications of this are a little iffy. People always seems to say that these little insect-bots could be of use in disaster settings where people need to get some ground level surveillance of a rubble-littered area, but I think the scientific applications for this are what is really exciting. Being able to create a virtual reality of any shape or size could allow for tests of spatial navigation in the cockroach. You could even try to train the cockroach to find something or avoid something and the 'confuse it' by changing the virtual environment suddenly. Could it adapt?

© TheCellularScale

How to Build a Neuron: step 3

Steps 1 and 2 of neuron-building, as well as an important set of shortcuts can be found in the How to Build a Neuron index. Step 3 is deciding which simulation software or programming language you want to use.

Simulated Neuron in Genesis (source)

The big two are Genesis and Neuron. They are pretty similar in a lot of ways, but Genesis runs in Linux and Neuron runs in Windows. However, you can run Genesis in Windows if you install the Linux environment Cygwin.

Both programs can read in morphological data, but they use different syntax and coding procedures. There are other types of neural simulators as well, and an ongoing problem in the field of computational neuroscience is compatibility between programs. If someone has done the work to make a beautiful Purkinje cell in Genesis like the one above, it will take a lot of time and effort to translate that neuron into a different simulator such as Neuron.

Gleeson et al., (2010) explains this problem and presents a possible solution in the form of the "Neuron Open Markup Language" or NeuroML.

"Computer modeling is becoming an increasingly valuable tool in the study of the complex interactions underlying the behavior of the brain. Software applications have been developed which make it easier to create models of neural networks as well as detailed models which replicate the electrical activity of individual neurons. The code formats used by each of these applications are generally incompatible however, making it difficult to exchange models and ideas between researchers....Creating a common, accessible model description format will expose more of the model details to the wider neuroscience community, thus increasing their quality and reliability, as for other Open Source software. NeuroML will also allow a greater “ecosystem” of tools to be developed for building, simulating and analyzing these complex neuronal systems." -Gleeson et al (2010) Author Summary

NeuroML is basically a "simulator-independent" neuronal description language. A neuron built with or converted to NeuroML should be able to run on Neuron, Genesis, and plenty of other platforms. Gleeson et al. validated NeuroML by using a simulated pyramidal neuron converted to NeuroML format and run with several different simulators.

Gleeson et al., (2010) Figure 7

Zooming in:

Neuron, Genesis, Moose, Psics comparison

All the simulators overlay so tightly that you can barely tell that they are separate lines.

So when building you neuron, take care to follow the NeuroML format and then you and others can use it with any simulator you want.

© TheCellularScale


Gleeson P, Crook S, Cannon RC, Hines ML, Billings GO, Farinella M, Morse TM, Davison AP, Ray S, Bhalla US, Barnes SR, Dimitrova YD, & Silver RA (2010). NeuroML: a language for describing data driven models of neurons and networks with a high degree of biological detail. PLoS computational biology, 6 (6) PMID: 20585541

Cut your brain some SLACK

Action potentials are the main means of communication between neurons, and their exact timing can be really important. But the specific timing of action potentials is really important in the auditory system, because the auditory system encodes (among other things) information about sound wave frequency.

Sound waves (source)

I've previously written about auditory processing with regards to the wonder that is the chicken brain, but today we will focus on timing-specificity in the mammalian brainstem. Specifically, some weird channels in the Medial Nucleus of the Trapezoid Body (the MNTB).


Mammalian Auditory Brainstem (source)

At the Society for Neuroscience meeting, I learned about the sodium-activated potassium channels which help the electric fish fire super-fast super-large action potentials. I was suprised to learn that sodium-activated potassium channels are located in many parts of the mammalian brain.

A paper from the Kaczmarek lab at Yale explains that these sodium-activated potassium channel (SLICK and SLACK) are present in the mouse auditory brainstem and contribute to the 'temporal accuracy' of the MNTB neurons. Yang et al. (2007) record the action potentials from these neurons at a range of frequencies and show that the neuron can 'keep' up with the frequencies better when more sodium is present.

Yang et al., 2007 Figure 9B

In the figure above, the 'flatter' the line, the better the 'temporal accuracy.' They also made a computational model of this neuron and ran simulations altering the sodium values and reversal potential.

Yang et al., 2007 Figure 9D

Their model simulations are similar to their experimental recordings, in that more sodium results in more temporal accuary of the action potential. They confirmed that this was dues to a sodium-activated potassium channel by directly activating SLACK and seeing a similar improvement in temporal accuracy.

The SLACK channel still blows my mind, but its role in helping the auditory system fire with the utmost precision actually makes a lot of sense.


© TheCellularScale



Yang B, Desai R, & Kaczmarek LK (2007). Slack and Slick K(Na) channels regulate the accuracy of timing of auditory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience, 27 (10), 2617-27 PMID: 17344399

why you shouldn't wash your brain with soap

I can't think of any situation where you might be inclined to soap up your brain (except maybe if you had recently been trepanned), but it is still a bad idea.

you can actually buy soap shaped like a brain here. (It smells like bubble gum!)

When used on say, an oily frying pan, soap + scrubbing will trap the oil in little units which can be rinsed off. Without soap, using only water, the oil which is hydrophobic (meaning it would rather stick to anything besides water) will stick to the pan rather than the water. 

Soap + shaking = trapped oil (source)

How does this relate to the brain? Well the cell membrane which helps give the shape to the neurons is made up of a lipid bilayer. These lipids have a hydrophobic tail (which hides in the middle of the layer) and a hydrophilic head which faces outward, just like the oil particles above.

Cell membrane (source)

So basically if you scrubbed your brain cells with soap, the membrane that holds the neuron together would be disrupted. Scientists actually use this principle to get stuff (like DNA) out of a neuron. In DNA extraction, there is a lysis step in which a detergent (like SDS) is applied to the tissue and given a good shake. This disrupts the membrane and allows access to the contents of the neuron.

You can wash your skin with soap because the living skin cells are protected by an outer dead skin cell layer. Though if you soap up too much, you can actually dry out yours skin by stripping it of lipids faster that they can be replenished. See "How much should you shower" for an excuse to stay in bed tomorrow morning rather than get up and shower.


© TheCellularScale

Ketamine for depression via neurogenesis?

A lot of fuss has been made recently about the street drug "Special K" (ketamine). It's basically an anesthetic used in labs and veterinary offices to tranquilize mice, rats, cats, and (famously) horses, but recently its been lauded as a newer faster anti-depressant.


Ketamine: from the dealer or from the doctor? (image source)

The possibility that it might have near immediate anti-depressant effects on humans has been around for a little while, but the concept is picking up steam as new research finds mechanisms for how it might actually work in depressed patients. (I briefly mention one new study in an SfN neuroblogging post. )

An emerging theory is that depression is not so much a chemical imbalance as it is a loss of neurons. Thus the cure for depression is not restoring the balance of serotonin or dopamine, but restoring the growth of new neurons. Some suggest that this is how classic anti-depressants (like Zoloft) work, by fixing the neuron atrophy problem. This could also explain why these anti-depressants take so long to work, though I have expressed skepticism about this hypothesis.

So the question is: Does ketamine cause the growth of new neurons, help in their maturation, or prevent neuronal atrophy? Ketamine is an NMDA receptor antagonist, so it inhibits synaptic transmission. It doesn't inhibit all synaptic transmission like deadly poisons do (tetrodotoxin for example), but enough of it to change something in the brain. Knowing something about NMDA receptors, it was still hard for me to conceive of a connection between blocking them and neuronal growth.

A nice review by Duman and Li (2012) spells it out for me, explaining new research that links ketamine with the growth of new synapses.

Duman and Li 2012 figure 3

The idea is that ketamine blocks the NMDA receptors on the GABAergic (inhibitory) neurons, so there is less inhibition and more glutamate. When there is more glutamate, there is more BDNF (brain derived neurotrophic factor). BDNF helps synapsse grow by triggering a cascade of events (via mTOR) which causes more AMPA receptors to be inserted into the synapse, making the synapse stronger, more stable, and more mature.

The authors cite their previous Li et al., 2010 Science paper explaining that when they block mTOR with the drug rapamycin, the effects of ketamine on new spine growth disappear and its anti-depressant effects disappear. However, this is a study in rats and assessing the depressed state of a rat is as tricky as assessing a rat's post-traumatic stress. So the claim here isn't so much that ketamine causes neurogenesis, but that it could help new neurons become synaptically mature, and thus functionally useful. (Carter et al. is investigating this further)

As shiny and interesting as this is, I am not quite sold on it. I don't see how the NMDA antagonist is going to inhibit the inhibitory neurons more than the excitatory neurons, and I would love to see research showing how ketamine causes glutamate accumulation.

And as far as actually using it as a treatment for depression, there are some serious side-effects. Ketamine is a hallucinagenic street drug which can cause a schizophrenia-like state. Therefore, it seems unlikely that ketamine itself will ever be prescribed as an anti-depressant, but new research could reveal (or synthesize) other molecules that activate mTOR directly or somehow bypass the hallucinogenic aspect of ketamine.

For more, see some skeptical and critical analyses of human ketamine studies.

© TheCellularScale

Duman RS, & Li N (2012). A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367 (1601), 2475-84 PMID: 22826346

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, & Duman RS (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science (New York, N.Y.), 329 (5994), 959-64 PMID: 20724638

LMAYQ: How to do things

Time to get back to Answering Your Questions.  It has been a whole month, and I have had some great search engine queries lead to The Cellular Scale. As always, I am pretty sure whoever asked The Internet these questions did not find an answer on this blog. Since I hate to disappoint, here are some real answers to some real questions:

1. "How to make a football out of construction paper"

 I did write about how bipolar neurons look like footballs, but never explained how to make a football yourself. You take a piece of construction paper or notebook paper and fold as diagrammed in the following image.

How to make a paper football, from A Crisp Fold

Then you hold it between two fingers and flick it with your other hand, trying to get it between some arbitrary goal posts, or to the back of your classmate's head.

2. "How to beat Mass Effect without Shepard dying."

1. You have to have the majority of the 'War Assets'
2. You have to choose "destroy the reapers" at the very end.

But it's not like Shepard gets up and walks around or anything, you just get to see an N7 chest plate take a single tantalizing gasp.

3. "How to draw a Pokemon character."

I put one little picture of one little Pokemon character in a post about how the Axolotl nose can help us understand how the brain modulates odor receptors. And boy, people must search for "pokemon" on a lot. Some unlucky kid found an article about smell when what she really wanted to learn was:

 how to draw Psyduck (source)

Well, there you go, now you can draw the vacant-staring psychic platypus-duck from Pokemon. Here's a little more about Psyduck:

Psyduck is constantly stunned by its headache. It usually stands immobile, with a vacant expression, trying to calm its headache. However, when its headache becomes too severe, it releases tension in the form of strong psychic powers. (from Bulbapedia)

For the record, I do not endorse the scientific validity of the Bulbapedia website.


4. "How to kill a small man."

Hmmm. This is a tough one. How small is this man? If he is very very small, you could put him in a tupperware container without poking air holes. If he is a little bigger, you could probably stuff him in the refrigerator. That's fatal, right?

I suppose I am glad you did not find an answer to this particular question at The Cellular Scale.


© TheCellularScale