Saturday, October 17, 2009

I have for long thought Ivan Pavlov and his dogged experiments were too old to give a fresh thought. Just to recollect, Pavlov trained dogs to salivate on hearing a bell (the stimulus), as food would follow. This is now known as classical conditioning and one that many mammals do very well. Pair a stimulus (like a light or tone) with a condition (like food or something aversive, like a bad taste or smell). Pretty soon, the animal (or human) will react to the stimulus alone, even if the condition doesn't materialize.

In my recent reads, I found out one startling thing after another. I know that neurons are the cells in the brain, numbering around a trillion. But never knew that neurons whose primary neurotransmitter is say, dopamine, are called dopmaminergic neurons. These neurons are primarily present in the ventral tagment area of the midbrain, the substantia nigra (whose loss is said to cause Parkinson’s) and the arcuate nucleus of the hypothalamus. Dopamine is a notable neurotransmitter having many functions in the brain, including “important roles in behavior and cognition, voluntary movement, motivation and reward, inhibition of prolactin production (involved in lactation), sleep, mood, attention, and learning.”

Then, I read about two research studies done on rhesus monkeys, one voluntarily and the other accidentally. I’ll first cover the accidental one.

Monkeys were subjected to both positive and negative rewards. Show them a spot (●) and they will surely (100%) get juice; a + sign meant 50% chance or no juice; and a square (□) meant no juice. This was the positive side of it.

Then, seeing an open circle (O), an air puff was blown into the eye of the monkey—irritating it. A triangle (Δ) meant 50% chance of air puff or nothing; and a square meant no air puff at all.

Researchers plugged electrodes on the brains of the monkeys and tracked the dopaminergic neurons. It seems we can trace these neurons through an “electrophysiological trace, which will be different from that of the surrounding neurons, most of which are GABA [an inhibitory neurotransmitter, implicated in exciting the entire nervous system as well as regulating muscle tone] cell bodies.”

Here’s the verbatim reproduction of what Scienceblogs.com wrote about this study:

“Not surprisingly, the animals' behavior soon corresponded closely with the signals it was getting. If it saw the spot and knew it was getting juice, licking at the spout would increase in anticipation. If it saw the open circle and knew it was getting an air puff, it would blink to try and avoid the air puff.

Ok fine, Pavlovian conditioning. But remember those electrodes in the brain? Those electrodes attached to...dopamine neurons? Well, it turns out that all the neurons responded to stimuli, but they broke down into two distinct categories when it came to WHICH stimuli they responded to. The first set were clearly responding to the positive reward, the juice:





You can see there, ,starting in the upper right, the dopamine cells spiking in response to stimuli. Because they are trained to the reward and the stimulus, the monkeys are no longer responding to the reward itself, but rather to the stimulus, which, in the case of juice, will trigger behaviors like licking at the juice spout in anticipation. On the left, you can see the spike when the monkeys the the spot, 100% chance of juice showers, let the licking begin! In the center panel, there is still a spike, but it's a much smaller one, there's only a 50% chance of juice, and so their brains are weighing the chances. In the far right, you can see the sign for no juice. The neurons aren't just quiet or baseline, they're inhibited, no chance of reward here.

And this first set of neurons responded in the opposite manner to the chance of an airpuff:

On the left we have 100% chance of an air puff, and totally inhibited neuronal activity. Clearly, no chance for juice. On the right, however, there is the 0% air puff stimulus, and the neurons fire. *phew* escaped the air puff to the face!

But then, there was a SECOND set of neurons. In the reward paradigm, they look just the same as the first set. But in the airpuff paradigm, you see something different:


These neurons, as you can see on the left side, respond to a certain air puff, which is known to be no kind of rewarding stimulus, are are actually inhibited when there is no chance of an air puff. But they respond to juice in a normal manner. WTF?

So they did the experiment again, only this time, they recorded neurons when the animals got an unexpected freebie, either free juice, or free air puff. This time the neurons organized themselves into two groups again (though slightly different groups), and the same thing happened:

Here you can see that first set of neurons. When you're just looking at juice presentation, and NOT at the stimulus, the neurons don't fire (on the top left) even though there's 100% chance of reward. Instead, they fire in response to the stimulus, as you saw in the first figure. But on the top right, you can see the strong response when they just get some free juice. When it's not connected with a stimulus, that juice will still make those neurons fire all day long. In contrast, on the bottom right, when the monkeys get a free air puff, the neurons go silent. Stimulus or not, those particular dopamine neurons do not appreciate that air puff.

But what about the second set?

Same thing as in the first paradigm, they still respond well to a free reward (top right), but they ALSO respond to a free air puff.

What does this mean? It means that though there is a set of dopamine neurons that responds to value-related stimuli (the juice only), there is ALSO a set of neurons that just responds to salience, something you need to be paying attention to, and thus they would respond to both the juice AND the air puff.

But the coolest part was yet to come. Not only were the researchers able to identify two distinct populations of neurons, those neurons were grouped clearly in different places!

The dots you can see in red are the ones that responded to both the juice and the air puff, while the ones in the blue responded only to the juice. And a pattern emerges. The red neurons are much more dorsolaterally located, ending up in the substantia nigra, while the blue ones which appear to code for value only were in the ventral tegmental area.

This has some big implications. First of all, it shows conclusively that not all dopamine neurons will respond only to positive stimuli and show inhibition to negative stimuli, some will respond to both. Secondly, it shows that these neurons can be localized to distinct populations, which give some clues as to their function. The substantia nigra pars compacta is an area of dopamine cell bodies that is known to degenerate in diseases like Parkinson's, while the ventral tegmental area is related to the mesoaccumbens dopamine circuit thought to be involved in things like motivation and addictions. Thus, it makes more sense for the value-only related neurons to be localized to the ventral tegmental area, while the others, which appear to encode salience rather than value AND salience, are localized to the substantia nigra, which is known to have a myriad of functions.

So why is this important? Understanding how we pay attention to things and encode things like value responding in the brain can play a big role in how we target treatments for things like addiction, which dramatically changes the firing activity of some of these neurons. Not only that, it could help find treatments for other disorders of motivation and salience, particularly things like Obsessive-Compulsive disorder and kleptomania. It's amazing what you can do with two monkeys, some juice, and some air.”

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