If you can’t tell by now, Sci is something of a dopamine junkie.
Anyway, when one first learns about dopamine, you learn about a “reward” molecule, the one that makes you feel good. Sounds like dope for a reason. But over time, scientist have found that it’s not just about reward with dopamine. Dopamine has a lot more to do with things we like to call salience and value. The salience of a cue is in part related to its strength, and it part related to what its connected with. Basically, a cue is high salience if it gives you a good reason to pay attention. It isn’t attention itself, it’s being connected to something worth paying attention to. This is connected to the item’s value. After all, if it’s something I don’t value, the article isn’t going to be very salient to me, it won’t be worth paying attention to.
So as of recently, it’s been assumed that dopamine neurons fire in response to value-related signals. Sci’s dopamine neurons fire in response to pizza, and a crack addict’s neurons fire in response to cocaine. And of course, if they encode value-related stimuli, dopamine neurons should be inhibited by aversive stimuli, because those have negative value. So while my dopamine neurons fire in response to pizza, they should be really inhibited in response to brussels sprouts.
Right? Well…wrong. And this is something that has puzzled scientists for a while. Some studies show inhibition of dopamine neurons in response to negative stimuli, and some show both negative and POSITIVE dopamine response to negative stimuli. So what’s up with that? Are the neurons firing for negative stimuli just some random wackos that get off on brussels sprouts?
Well, it’s possible that they aren’t wackos. It’s possible that the dopamine neurons really do just encode value-relation. Not whether that value is positive or negative. Scientists recently have tried to test this, and what they found clarifies a lot of things we didn’t know about the firing of dopamine neurons.
So what do you need to make a groundbreaking paper (in this case a paper in Nature)? Some juice, some air, and a couple of monkeys.
Matsumoto and Hikosaka. “Two types of dopamine neuron distinctly convey positive and negative motivational signals” Nature, 2009.
Let me just say here. One of the things I love about papers in Nature and Science is the fact they they are limited with regard to space. I know from experience, however, that writing a paper when you’re limited on space is teh suxxors. Only allowed 40 references?! WHAT?! How can they expect me to place this paper in the context of the literature correctly if I only get 40 references?!
But really, some of the space limitations (NOT the references, in my opinion), are a good thing. When you only have 8 columns of space (including figures) to write intro, results, and discussion, you’ve got to be CLEAR. You have to be CONCISE. You gotta tell your story and tell it straight. And what this often results in…is crap. Completely illegible crap where scientists feel they have to use torturous expressions and excessive use of long words to convey something that is often relatively basic. Tell it to me straight. Please. Pretend I’m stupid and don’t know what you’re talking about. Chances are, you’re right.
But though the result is often crap, it’s not always. And this is what I love about this paper. It’s short, and it’s SWEET. Clear and concisely written. I applaud these guys (or girls, they could be girls, unfortunately, I am not well versed enough in Japanese to know whether “Masayuki” and “Okihide” are male or female names). They have the courage and talent to do what many scientists cannot: write a straight story.
And here it is:
Take two monkeys. Implant a TON of electrodes into the substantia nigra and the ventral tegmental area, and capture a whole bunch of neurons (103 to be exact). Make sure they are dopamine neurons (you can tell this by the electrophysiological trace, which will be different from that of the surrounding neurons, most of which are GABA cell bodies).
Then, once the monkeys are recovered from surgery, start training them on a simple task. A Pavlovian response. Pavlov, for those not versed in this class experiment, trained dogs to expect treats at the sound of a bell. After a while, when the bell was rung, the dogs would start salivating massively in expectation of their food. This is a phenomenon 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.
So in this case, with the monkeys, they used positive and negative conditions. One set of signals indicated a certain probability of a juice reward. A spot meant 100{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} chance of juice. A cross meant 50{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} change of juice, or no juice. A square meant you got nothing. Like this:
Then they had a second set of conditions, this time connected with a puff of air in the eyes. Nothing painful, just the kind of thing to make you blink and get you irritated. In this condition, an open circle meant 100{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} chance of air puff, a triangle meant a 50{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} chance of an air puff or nothing, and a square meant nothing. Like this:
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{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} 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{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} 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{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} chance of an air puff, and totally inhibited neuronal activity. Clearly, no chance for juice. On the right, however, there is the 0{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} 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{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} 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.
Matsumoto, M., & Hikosaka, O. (2009). Two types of dopamine neuron distinctly convey positive and negative motivational signals Nature DOI: 10.1038/nature08028
