Dr Greg Jefferis, MRC Laboratory of Molecular Biology, Cambridge
I wanted to find out more about these pheromones that David mentioned. And so, join Dr. Greg Jefferis from the Medical Research Council Laboratory of Molecular Biological in Cambridge. He’s been looking not at wasps, but another flying insect – the fruit fly.
Greg - So, you might wonder why would we study flies. Well, my lab is interested in how the brain works. I think a lot of us are interested in how the brain works. In particular, we’re interested in how individual neurons within the brain talk to each other in order to allow them to process information about the outside world and control behaviour. Now, we’d love to study these processes in the human brain, but at least for me, the human brain is too complicated. There are about 100 billion neurons in the human brain, so that’s the nerve cells in the brain that are communicating with each other. So, even a mouse has 100 million neurons and that still is too complicated for me at least. So, we study the fly. The fly has 100,000 nerve cells and for me, this is a countable number and someday, maybe in the not-too-distant future, we might be able to understand how all of these neurons are connected to each other and what they're talking about when the fly is behaving.
Hannah - Greg and his lab are looking at how nerve cells connect in relation to one specific type of behaviour – courtship. So, typically, the male fly will approach the female fly by following her around. He’ll sing her a love song – essentially, serenading her then he’ll try to lick and touch her and eventually, try to copulate with her. She will respond to these courtship attempts by either becoming docile and letting the male do his thing or if she’s not impressed by his attempts, she will just kick the male in the face literally.
What's controlling this behaviour? Well, one key regulator is a chemical signal, a so-called pheromone called cVA. cVA is given off by the male fly and when other males smell this other pheromone, it increases their aggressiveness; sometimes they will even get up on their hind legs and boxing each other. Whereas usually, females increase their receptivity when they smell this chemical signal, and Greg is looking at how the nerve cells involved in cVA detection connect and make a circuit to give rise to these different behaviours as he explains.
Greg - So, what's really nice is that here, we have the same molecule that can trigger different behaviours in male and female flies. And so, what we’d like to know then is, why is this? What we did was, we recorded from nerve cells inside male and female flies while we were puffing pheromone onto them. So, to do this, we mobilise the fly, we make a very small hole in its very small head. The neurons that we’re interested in have been made to glow green, so that we can tell them from all the other neurons in the fly brain. We then approached those neurons with a very fine glass electrode and we see along to a single cell, and record its activity.
Hannah - So that’s some really neat technologies that you're combining there and I'm presuming that this is in the fully conscious living fly?
Greg - That’s right. So, the fly is alive and kicking, and it’s responding to these smells that we’re puffing onto it. It is pretty amazing when you're doing the experiment, when you look at the activity on these individual electrodes, you're sitting there, watching the fly think.
Hannah - So, Greg measures the electrical activity of nerve cells in the fly as it’s being puffed with pheromone. It turns out that the pheromone cVA is detected by the fly’s antennae. Here, there's the olfactory organ of the fly – the smell region and this activates the first nerve cell in the circuit. This nerve cell then talks to a second nerve cell and the second nerve cell passes that electrical activity onto the third nerve cell that’s deeper in the fly brain, and that’s the basic circuitry for pheromone perception. It’s a really simple 3-nerve cell circuit and the key difference in this circuit between the male and female fly is at that third deepest nerve cell level which Greg calls neurons A or B.
Greg - We’ve been able to show that A neurons are connected to the incoming pheromone information in males but not females, and B neurons are connected to that information in females but not males. So really, you’ve got a very simple setup here. You have a clear difference in wiring, in connectivity that’s resulting in a difference in their response of particular neurons in male and female brains.
Hannah - Gosh! That’s exciting! So, do you know what's controlling this switch, this circuitry which neurons are going to be connected?
Greg - We certainly are excited. It’s the first time that anybody has been able to demonstrate a sort of bidirectional switch like this in any animal as far as we’re aware. Now, in terms of what's controlling it, one of the nice things about the fly system is that we have a really good idea about that. So, there's a particular gene called fruitless is a transcription factor that means it controls other genes. This fruitless gene is actually only active males. So, the action of fruitless in males is to rewire the A and B neurons. So, what you can imagine is that fruitless unplugs the B neurons and it plugs in the A neurons. Normally in females, the default wiring pattern is that the B neurons will be plugged in and A neurons will not.
Hannah - So, if you take the analogy of a train on rail tracks, imagine the pheromone signal cVA is the train and the rail tracks are the cables with which the nerve cells and the circuit communicates. In both sexes, the train on the rail tracks goes past the first station – so the first nerve cell on the antenna. The cVA train goes past the second nerve cell deeper in the brain, and then at the level of the third nerve cell, something different happens. Here, the train can either go to station A to the right or station B to the left. So, in the female flies, the train will turn left and go to one part of the fly’s brain and in male flies, the train will go to the right, and this controls mating behaviour. Greg and his lab have found this out and also, that the simple circuit switch directing the train route is controlled by the gene fruitless.
Greg - What we’ve even been able to show is that the action of this gene only needs to be restricted to the A or the B neurons, and the rest of the brain doesn’t need the action of this gene in order to flip this switch.
Hannah - So, does that mean then that you can express fruitless in female baby flies and then change their behaviour so that they become male courting aggressive flies?
Greg - So, we haven't done that experiment, but somebody else has, Barry Dickson’s lab in Vienna, and that’s exactly what they found. So, they caused fruitless to be expressed in the male pattern in female flies, all the way through development. And the result of that was female flies that will actually try and mate with other females. And what we think we found is this little switch in olfactory processing is one of the changes that is required to turn a female brain into a male brain and produce these kinds of behavioural differences.
Hannah - So, that was Dr. Greg Jefferis from Cambridge, discussing how a switch within a simple 3-circuit system switches on mating mode in male and female flies. I also asked Greg whether such pheromones and such a switch may exist in humans. He emphasised that human brain is very, very complex and it’s hard to study these kinds of questions in humans at the moment. We don’t have a clear answer, but he’s not about to start buying pheromones that are being sold over the internet just yet.