Yeah, this is late. Sci’s STILL ILL (ARGH!!!) and also has a lot on her plate. But nothing holds back the blogging! I WILL GO ON.
(My blog will go oooonnnnn…I swear I didn’t even LISTEN to that because the song sucks THAT MUCH. Bet I gave you an earworm, though!!)
For today, I’d like us all to talk a bit about impulsivity. Impulsivity is the new hotness in a lot of fields right now, including drug abuse and addiction, compulsive gambling, schizophrenia, suicide, and bipolar disorder. But what IS impulsivity?
Impulsivity is about as broad in science as in daily life. It describes behaviors which involve actions without thinking about them, decreased ability to stop yourself from following these actions, and a disregard (or just lack of consideration) of the consequences of your actions. And of course, while some impulsivity is a good thing, too much is definitely not. The intolerance for delay, the constant inability to stop yourself from doing thing, and the disregard for consequences can be really bad things, and are implicated in the psychiatric disorders I listed above. The issue of impulsivity is one that involves many different levels of neural function. But while it may be complex, impulsivity is also HERITABLE. This means that there are probably genes out there which control certain aspects of impulsivity, and which scientists may be able to identify to find out what causes impulsivity, and how we might go about calming it down when it’s getting out of hand.
And we might have one of these genes in hand!
Bevilacqua et al. “A population-specific HTR2B stop codon predisposes to severe impulsivity” Nature, 2010.
Now keep in mind. There may end up being hype about how we’ve “DISCOVERED THE IMPULSIVITY GENE” or some such. But NO. It’s just not that simple. This paper has identified a gene which is linked strongly to impulsivity in a certain population. It’s not THE gene. It’s A gene. There are probably MORE genes, and probably interactions of genes, not to mention interactions of genes and environment, which will end up actually resulting in what we identify as maladaptive impulsive behavior. But it’s almost NEVER just one gene and “boom* you’re all impulsive. Don’t let people fool you.
Anyway, back to this paper and this gene. The scientists in this paper were gene sequencing a bunch of subjects from Finland. Why Finland? Well, Finland has both diversity of genes and a certain amount of isolation, which has helped to shape the gene pool there, and makes certain genes more or less abundant than they might be otherwise. This means that if there’s a certain gene which plays a role in impulsivity, it might be easier to pick it out in a population like the one in Finland, which is relatively homogeneous.
So they sequenced 96 Finnish dudes with impulsivity problems, and 96 dudes WITHOUT impulsivity problems. And when we’re talking impulsivity problems, we’re talking violent offenders, arsonists, that sort of thing. Not only were they violent, they were highly impulsive, and 94{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} of them had commited violence under the influence of alcohol. Alcohol use is ANOTHER thing associated with impulsivity. Think we’re dealing with a pretty impulsive population here.
And what they found were a couple of genes, most importantly the HTR2B. HTR2B stands for the serotonin 2B receptor. For more information on the serotonin system, you can see my background post on it here. Suffice it to say the serotonin system is REALLY complicated, but that certain receptors are thought to be involved in various aspects of things like aggression, so the involvement of the serotonin 2B receptor in impulsivity is not particularly surprising. Not only that, the serotonin 2B receptor is located all over the brain, but particularly in the frontal cortex, a good area for impulsivity related behaviors and especially for inhibition of behavior. The gene itself is located in an area of the genome that has been associated before with obsessive compulsive disorder and drug abuse, so it’s in a good location in the genome, a good location in the brain, and it’s part of neurotransmitter system associated with impulsivity, aggression, etc. We might be on to something.
The quirk in this receptor is what made it interesting. In 17/228 people with severe impulsivity (compared to 7/265 controls), they found that the serotonin 2B receptor had a funky stop codon, called Q20. The funky stop codon was also passed down in particular carrier families. But the question now is, what does that quirk in the receptor, the Q20 stop codon, DO? Well, first they assessed the people with the Q20 change. They found that these people showed very high impulsivity (well, duh), but otherwise appeared to be pretty normal, and in fact showed more empathy and attachment than other violent offenders. Interestingly, relatively few of the violent offenders were Q20 carriers (they got better results in family screens), but those that WERE were some of the most impulsive people by far.
And when they looked at some of the brain tissue from people with this Q20 mutation, they got something NICE.
That there is a Western Blot showing protein levels of the serotonin 2B receptor in humans. You can see on the left side of the blot you’ve got a normal individual, and on the right you’ve got someone with the Q20 mutation. And the Q20 mutation of the serotonin 2B receptor appears to really knock down the expression. It looks like Q20 stop codon mutation prevents the serotonin 2B receptor from being expressed.
But how do we know that this particular gene and this particular change is what we’re looking for? It’s time to make a mouse!
The scientists took mice and selectively knocked OUT the serotonin 2B receptor. This means they had no expression of the serotonin 2B receptor, making them more like the humans who have the Q20 mutation which decreases their serotonin 2B receptor expression. And they tested the mice on measures of impulsivity.
Let’s start on the upper left. That is a graph showing locomotor activity in mice with a serotonin 2B knockout vs normal mice, all when exposed to a novel environment. Exposure to a novel environment makes anxious mice explore cautiously, but these serotonin 2B knockout mice just WENT for it, showing higher locomotor activity in the novel environment. On the top right, you can see they looked at the change in locomotor activity following a dopamine D1 receptor agonist. This is a drug that promotes locomotor activity and the serotonin 2B knockout mice appeared to be more sensitive (I’m not sure why they included this graph, honestly, it seems a bit superfluous to me. They say they did it because D1 receptors are implicated in impulsivity, and that’s fine, but I think an interaction here between a serotonin 2B knockout and supersensitivity to D1 receptor agonists is a story for another paper, where they could really develop the idea).
Now, second row of the graphs. The one on the left is a nice measure, it’s the number of contacts made between the mouse you’re testing and a target novel object (like a block) for them to explore, a measure of impulsivity (cautious mice will contact the novel scary block less). You can see that the serotonin 2B knockout mice contacted the target object a lot MORE, showing high impulsivity. The graph on the right is a little more confusing, it’s a test called delay discounting. Basically, give a mouse two options. You can have one sugar pellet NOW, or you can have FIVE sugar pellets LATER. A prudent sensible mouse will take the five pellets later, which will be more pellets total. But the key is this, the delays become longer and longer. Pretty soon the prudent mouse will notice this and switch to just getting one pellet now. But the serotonin 2B knockout mouse did NOT do this. Even though the latency got very long indeed, they still preferred those larger rewards, suggesting that they were more impulsive.
In the bottom row of graphs, the left one is a measure of impulsivity, which is a latency to feed on something tasty in a novel environment. Normal mice exposed to a novel environment will eat less and take longer to do it, but the serotonin 2B knockout mice went straight for the food, showing higher impulsivity.
FINALLY we have the last graph, showing that serotonin 2B knockout mice have higher levels of testosterone, which is a hormone associated with impulsivity. Apparently some of the men they looked at had this too, but this is another graph where I’m not sure why it was included. Though it supports the hypothesis, it seems like an association which would be better explored in a separate paper. But hey, you gotta present a lot of data to be getting in to Nature.
So what all does this tell us? It tells us that changes in the serotonin 2B receptor gene may be responsible for some impulsivity issues in humans. Not ALL of them, it appears to be restricted to only Finnish people, but it’s a start. Because if this one mutation is associated with these symptoms, it’s possible that we could look at OTHER mutations in the serotonin 2B receptor to find other changes implicating impulsivity, which could lead us to more understanding of how impulsivity works, and when it can go wrong.
Bevilacqua L, Doly S, Kaprio J, Yuan Q, Tikkanen R, Paunio T, Zhou Z, Wedenoja J, Maroteaux L, Diaz S, Belmer A, Hodgkinson CA, Dell’osso L, Suvisaari J, Coccaro E, Rose RJ, Peltonen L, Virkkunen M, & Goldman D (2010). A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature, 468 (7327), 1061-6 PMID: 21179162
