Friday, October 03, 2008

Glutamate and classical conditioning

I had speculated in one of my earlier posts that Glutamate , GABA, Glycine and aspartate may be involved in classical conditioning / avoidance learning.  To quote:

That is it for now; I hope to back up these claims, and extend this to the rest of the 3 traits too in the near future. Some things I am toying with is either classical conditioning and avoidance learning on these higher levels; or behavior remembering (as opposed to learning) at these higher levels. Also other neurotransmitter systems like gluatamete, glycine, GABA and aspartate may be active at the higher levels. Also neuro peptides too are broadly classified in five groups so they too may have some role here. Keep guessing and do contribute to the theory if you can!!

Now, I have discovered an article that links Glutamate to classical conditioning. It is titled Reward-Predictive Cues Enhance Excitatory Synaptic Strength onto Midbrain Dopamine Neurons, and here is the abstract:

Using sensory information for the prediction of future events is essential for survival. Midbrain dopamine neurons are activated by environmental cues that predict rewards, but the cellular mechanisms that underlie this phenomenon remain elusive. We used in vivo voltammetry and in vitro patch-clamp electrophysiology to show that both dopamine release to reward predictive cues and enhanced synaptic strength onto dopamine neurons develop over the course of cue-reward learning. Increased synaptic strength was not observed after stable behavioral responding. Thus, enhanced synaptic strength onto dopamine neurons may act to facilitate the transformation of neutral environmental stimuli to salient reward-predictive cues.

Though the article itself does not talk about glutamate, and nor does this Scicurious article  on Neurotopia, commenting on the same , which focuses more on the dopamine connection, still I believe that we have a Glutamate connection here. First let us see how the artifact under discussion is indeed nothing but classical conditioning:

The basic idea is that, when you get a reward unexpectedly, you get a big spike of DA to make your brain go "sweet!" After a while, you being to recognize the cues behind the reward, and so seeing the wrapper to the candy will make your DA spike in anticipation. But it's only very recently that we've been able to see this change taking place, and there were still lots of questions as to what was happening when these changes happen.

So the authors of this study took a bunch of rats. They implanted fast scan cyclic voltammetry probes into their heads. Voltammetry is a technique that allows you to detect changes in DA levels in brain areas (in this case the nucleus accumbens, an area linked with reward) which represent groups of cells firing. So the rats had probes in their heads detecting their DA, and then they were given a stimulus light (a conditioned stimulus), a nosepoke device, and a sugar pellet. There is nothing that a rat likes more than a sugar pellet, and so there was a nice big spike in DA as it got its reward. So the rats figured out pretty quickly that, when the light came on, you stick your nose in the hole, and sugar was on the way. As they learned the conditioned stimulus, their DA spikes in response to reward SHIFTED, moving backward in time, so that they soon got a spike of DA when they saw the light, without a spike when they got the pellet. This means that the animals had learned to associate a conditioned stimulus with reward. Not only that, the DA spike was higher immediately after learning than the spike in rats who just got rewards without learning.

So, if we consider the dopamine spike as an Unconditioned Response, then what we have is a new CS-> CR pairing or classical conditioning taking place. Now, the crucial study that showed that the learning is mediated by Glutamate: (emphasis mine)

To find out whether or not excitatory synapses were in fact changing, they authors conducted electrophysiology experiments in rats that were either trained or not trained. Electrophysiology is a technique where you actually put a tiny, tiny electrode into a cell membrane. When that cell is then stimulated, you can actually WATCH it fire. It's really very cool to see. Of course all sorts of things are responsible for when a cell fires and how, but what they were looking at here were specific glutamate receptors known as AMPA and NMDA. These are two major receptors that receive glutamate currents, which are excitatory and induce cells downstream to fire. What they found was that, in animals that had been trained to a conditioned stimulus, AMPA and NMDA receptors had a much stronger influence on firing than in non-trained animals, which means that the synaptic strength on DA neurons is getting stronger as animals learn. Not only that, but cells from trained rats already exhibited long-term potentiation, a phenomenon associated with formation of things like learning and memory.

But of course, you have to make sure that glutamate is really the neurotransmitter responsible, and not just a symptom of something else changing. So they ran more rats on voltammetry and trained, and this time put a glutamate antagonist into the brain. The found that a glutamate antagonist completely blocked not only the DA shift to a conditioned stimulus, but the learning itself.

From the above it is clear that Glutamate , and the LTP that it leads to in the mid-brain neurons synapses , is crucial for Classical conditioning learning. Seems that one more puzzle is solved and another jig-jaw piece fits where it should have.

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