Tag Archives: dendritic spine

The neuron as motherboard

Back in the day when transistors were fairly large and the techniques for putting them together on silicon were primitive by today’s standards, each functionality was put on a separate component which was then placed on a substrate called the motherboard. Memory was one component, the central processing unit (CPU) another, each about the size of a small cellphone today. Later on as more and more transistors could be packed on a chip, functionality such as memory could be embedded in the CPU chip. We still have motherboards today as functionality undreamed of back then (graphic processors, disc drives) can be placed on them.

It’s time to look at individual neurons as motherboards rather than as CPUs which sum outputs and then fire. The old model was to have a neuron look like an oak tree, with each leaf functioning as an input device (dendritic spine). If enough of them were stimulated at once, a nerve impulse would occur at the trunk (the axon). To pursue the analogy a bit further, the axon has zillions of side branches (e.g,. the underground roots) which than contact other neurons. Probably the best example of this are the mangrove trees I saw in China, where the roots are above ground.

How would a contraption like this learn anything? If an impulse arrives at an axonal branch touching a leaf (dendritic spine) — e.g. a synapse, the spine doesn’t always respond. The more times impulses hit the leaf when it is responding to something else, the more likely the spine is to respond (this is called long term potentiation aka LTP).

We’ve always thought that different parts of the dendritic tree (leaves and branches) receive different sorts of information, and can remember (by LTP). Only recently have we been able to study different leaves and branches of the same neuron and record from them in a living intact animal. Well we can, and what the following rather technical description says, its that different areas of a single neuron are ‘trained’ for different tasks. So a single neuron is far more than a transistor or even a collection of switches. It’s an entire motherboard (full fledged computer to you).

Presently Intel can put billions of transistors on a chip. But we have billions of neurons, each of which has tends of thousands of leaves (synapses) impinging on it, along with memory of what happened at each leaf.

That’s a metaphorical way of describing the results of the following paper (given in full jargon mode).

[ Nature vol. 520 pp. 180 – 185 ’15 ] Different motor learning tasks induce dendritic calcium spikes on different apical tuft branches of individual layer V pyramidal neurons in mouse motor cortex. These branch specific calcium spikes cause long lasting potentiation of postsynaptic dendritic spines active at the time of spike generation.

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Is it conceivable that that dementia of Alzheimer’s disease could be reversed (and quickly)?

I saw people get out wheelchairs in 1970 in just a few weeks after starting L-DOPA (which had just been released in the USA) for their Parkinson’s disease.  Could anything remotely similar happen in Alzheimer’s disease?  I think it’s possible if the problems with thinking and forming new memories are due to the senile cluttering up the brain (a very big if).  First, more than just a little bit of neuroanatomic and neurophysiologic background.

As recently as 1900,  it was far from clear that the brain was actually made of cells, unlike every other tissue in the body.  Why?  Because the smallest wavelength of visible light is 4000 Angstroms, and nerve cells in the brain  are mushed together far more closely than that.  With the invention of the electron microscope we could see nerve processes, including dendrites and dendritic spines in glorious detail. Dendritic spines are the major place in the brain where neurons communicate with each other (the synapse between axon and dendrite).  The latest estimate is that we have trillions of dendritic spines on our billions of neurons.  People have been able to see dendritic spines even at the resolution of the light microscope for the past century using silver staining techniques. But to see them, you had to kill the animal, fix the brain and make microscope slide.

Subsequently it became possible to watch dendritic spines form between neurons in tissue culture using various fancy types of microscopy (confocal laser microscopy etc. etc. ).

For about the past 10 years we’ve been able to observe dendritic spines for months in the living (rodent) brain.  In 1970, if you told me that, I’d have said you were smoking something.  The surprising finding is that dendritic spines are a work in progress, being newly formed and removed all the time.  The early literature (e.g. 10 years ago) is contentious about how long a given spine lasts, but most agree that spine plasticity is present every time it’s looked for.  Here are a few references [ Neuron vol. 69 pp. 1039 – 1041 ’11, ibid vol. 49 pp. 780 – 783, 877 – 887 ’06 ].

What does this have to do with Alzheimer’s? It seems likely that learning new things involves not just the strengthening of synapses (making them more likely to transmit information), a concept going back 50 or so years to Hebb, but the formation of new ones. Here are a bunch of pictures of such plaques http://www.google.com/images?client=safari&rls=en&q=senile+plaque&ie=UTF-8&oe=UTF-8&oi=image_result_group&sa=X.

There has been a huge amount of discussion about how (and even if) the senile plaque causes the cognitive problems of Alzheimer’s.  Most of the dementia of Alzheimer’s has been attributed to the loss of neurons.  The plaques are thought (by some) to cause the neuronal loss.  Perhaps they do, but what if the plaques are causing cognitive problems by simply getting in the way of new synapse formation (e.g. sand in the gears of the brain).  Then getting rid of the plaques should help cognition.

Alzheimer therapy is ineffectual at best, but it isn’t from lack of trying to get rid of plaques.  Antibodies against the major protein component of the plaque (Abeta peptide) unfortunately caused inflammation of the brain in some patients and had to be abandoned.  Bapineuzumab  has shown minimal results so far. In mice Bexarotene (Targretin)  looks promising, but here   the mechanism involves a protein (apolipoprotein E) which is quite different in mouse than man.

This brings us to an older post — https://luysii.wordpress.com/2012/03/04/could-le-chateliers-principle-be-the-answer-to-alzheimers-disease/.  Again, the work is in the mouse, but the preparation causes an enzyme in the liver to chew up Abeta peptide, with a marked decrease in plaque numbers and size and improvement in mental functioning in the mice (assuming you can actually measure such things).  The nice thing about this work, is that the preparation doesn’t even have to get into the brain.

We’re not going to raise neurons from the dead.  New neurons form in the human brain quite rarely (despite claims to the contrary – I frankly don’t believe Gage’s work), but hopefully we might be able to make those left function better.  The preparation is from Ayurvedic medicine, and people have been taking the stuff for millenia without dying on the spot.  It’s time to find out what the active principle actually is in the preparation, and get to work.

Addendum 11 Apr ’12:  Cell vol. 148 p. 1204 ’12 — tending to cast a favorable light on the hypothesis above — “Although Alzheimer’s disease clearly causes loss of neurons in specific brain regions  . . . .  much of the overall loss of brain volume appears o be due to the shrinkage and loss of neuronal processes.”  So if there hasn’t been that much death, the possibility of rejuvenating the survivors looms larger.

Against my idea is that fact that a cognitively intact individual can have tons of  senile plaques at autopsy.