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jake-head-shot.jpgJake Young is a MD/PhD student at Mount Sinai School of Medicine focusing in Neuroscience. He is due to graduate in 2032. He received a BS and a MS in Biological Sciences from Stanford University -- where he spent most of his time drinking heavily and building vegetable catapults instead of learning information that would now be eminently useful. When he is not failing terrifically to perform his sworn duties, he enjoys watching bad movies, ethnic food, and running.

Pure Pedantry is a blog about science -- social sciences and otherwise -- as well as academic and scientific culture. No one can live on science alone, so I also like to dwell on pop culture, periodically explore the humanities, and indulge in other types of geeky goodness.

Jake is joined periodically by two wonderful guest bloggers: Kara Contreary and Kate Seip. See the About Page.

DISCLAIMERS: 1) Jake Young is not a licensed physician (yet). He is merely a medical student. The information published on this site is not intended for use in medical decision making. Please seek advice from a licensed, medical professional before making any health decisions. 2) The opinions expressed are my own or those of my co-bloggers. They do not represent the views of SEED magazine or the educational establishments we currently attend.

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LTP observed from learning paradigm in vivo

Category: Learning and MemoryNeuroscience
Posted on: September 5, 2006 10:06 AM, by Jake Young

My suspicion is that the people who know about neuroscience read the title of this and said: "Wow, Jake, there's a shocker. Tell us something we didn't know." Everyone else probably said: "Guh?" Therefore, I should probably explain why I think this finding is cool.

LTP or Long Term Potentiation is an experimental paradigm that is believed to simulate learning in vivo. In the paradigm, an exciting electrode and a recording electrode are placed into the brain of the animal, usually into an area called the hippocampus. The electrodes are position such that the action of the excitation electrode activates the neurons near the recording electrode through a single synapse.

During the experiment, you activate the excitation electrode using what is called High Frequency Stimulation (HFS). HFS is neuroscience code for blasting the bejesus out of that synapse with electricity. The recording electrode is measured using test pulse from the excitation electrode before and after the experiment.

The phenomenon of LTP refers to the observation that after you blast the bejesus out of this synapse, the synapse becomes more effective at activating the next cell over -- near to the recording electrode -- than it was before. This is what is called potentiation at the synapse. Furthermore, potentiation is long lasting, even to the point of months -- hence the long-term part.

It has been the model for many years that LTP across many synapse in the brain -- forming a network -- is the mechanism for learning. However, I emphasize that this is an experimental paradigm because determining whether or not this is the real mechanism of learning is a tricky business. See, ideally, you want to use a physiological activation of the neurons and record potentiation changes from that. Unfortunately this is rather difficult because A) the changes from physiological stimulation are much smaller and B) the neurons form a network and you are never quite sure which synapse is going to potentiated.

Whitlock et al. publishing in Science have solved this problem and verified that LTP caused by learning -- a physiological activation -- causes measurable LTP in the hippocampus of rats. This finding is huge because it confirms how we thought memory works but could never prove.

The researchers solve one of the technical hurdles to measuring LTP using an avoidance learning paradigm. They place an array of electrodes into the hippocampus of rats. Then they place them in a box with a black area and a white area. When allowed to cross into the black area, a foot shock is administered to the rats. It has been shown from a variety of work -- and I think common sense supports -- that rats learn not to go in the black area after a single trial of this paradigm. Since learning is so rapid, it is reasonable to assume that the memory trace only requires one trial as well, and this is what their data shows.

To measure the LTP, the researchers examine many synapses across the hippocampus both before and after learning using the array of electrodes. What they are measuring in this case is what we call the synaptic efficiency -- the ability of a presynaptic neuron to activate a post-synaptic neuron. LTP is detected as an increase in synaptic efficiency.

So here is a figure of their data (click to enlarge):

ltp.jpeg

In the figure, Part A shows the anatomical placement of the array of electrodes in the rat hippocampus. Part B shows what the data for synaptic efficiency looks like. The traces are measures of the depolarization of the postsynaptic neuron on activation by the activating electrode (in this case just being used to measure rather than to potentiate). A more efficient synapse would have a deeper slope to this trace because it would be depolarized more (for those who would catch this, the depolarization of the cell is shown going downwards because the recording electrode is extracellular).

The rest of Part B shows the synaptic efficiencies represented as what are called Excitatory Post-Synaptic Potentials (EPSPs). The number on y-axis is a measure of the slope of the traces above (slope is often used as a measure of the depth of the trace) for repeated time points after the learning paradigm was administered.

You can see that the red-orange is the trace of a synapse that was potentiated. After the learning paradigm the synaptic efficiency has gone up as is shown by the increasing slope of the EPSPs that persists over time. On the other hand, the green-blue is the trace of a synapse that was unaffected.

The blocks of color on the right show the behavior of synapses measured across all the electrodes in the hippocampus with the level of potentiation indicated by color. You can see that after the avoidance learning paradigm many but not all of the synapses in the hippocampus show potentiation. This does not occur either when the rat was just shocked, or when it was allowed to wander around the box without being shocked.

I think this experiment is particularly elegant in verifying that our theory of LTP based learning is correct.

Comments

I also think that this is a particularly elegant paper. What particularly struck me was Fig 3. They didn't put any emphasis on it, but it does appear from that figure that LTD is happening all the time. Perhaps I am overinterpretting that figure, but, I was particularly struck by it.

In the June 16 issue of Science (page 1659) the Sandkuhler lab showed, also quite elegantly, that physiological nociceptive stimuli initiate LTP in a subset of dorsal horn neurons. It is nice to see that these decades of work on LTP really do appear to be representative and generalizable to a physiological state. I'm not sure anyone thought it would not eventually happen but evidence had been rather slow to come along.

Posted by: Theodore Price | September 6, 2006 7:22 AM

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